****** 8260118 ----K I ----T Continuous versus intermittent sulphonylurea therapy in non-insulin-dependent diabetes mellitus. ----A Although it is 50 years since the discovery of the hypoglycaemic effects of sulphonylureas, the molecular basis of their effects are still not fully understood. It has been suggested that long term sulphonylurea therapy may desensitise the pancreatic beta-cells to further drug effects, and that intermittent sulphonylurea therapy may be the best approach to maintain their effectiveness. A randomised, double-blind study has been carried out to attempt to answer the question of whether intermittent sulphonylurea therapy is more effective then continuous administration. Responders to oral glibenclamide (glyburide) went on to receive continuous or intermittent treatment (glibenclamide for 2 weeks then placebo for 2 weeks) for 16 weeks. Glycaemic control was maintained in the continuous treatment group. However, glucose levels deteriorated in the intermittent treatment group, suggesting that there is no merit to intermittent sulphonylurea treatment. Other strategies to investigate include administration on an alternate-day basis or a shorter period off the drug (e.g. 1 week). The underlying question of optimal glycaemic control with sulphonylureas warrants a definitive answer. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Administration_Schedule_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 8269445 ----K I ----T Efficacy and safety of reformulated, micronized glyburide tablets in patients with non-insulin-dependent diabetes mellitus: a multicenter, double-blind, randomized trial. ----A The subjects were 206 patients (123 men, 83 women) with non-insulin-dependent diabetes mellitus, aged 33 to 80 years. For at least 4 weeks prior to the study each subject had been taking 5-mg tablets of original, nonmicronized glyburide (Micronase tablets) in doses of 5, 10, 15, or 20 mg daily. In a double-blind 12-week study, the subjects were randomly assigned to continue receiving 5-mg tablets of original glyburide or to substitute 3-mg tablets of reformulated, micronized glyburide (Glynase PresTab tablets) for the original tablets. Glyburide tablets had been reformulated to improve their bioavailability. Baseline mean fasting serum glucose levels in the groups taking reformulated and original glyburide were 169.3 and 168.3 mg/dl, respectively; at study end point, their respective serum glucose levels were 186.0 and 177.0 mg/dl. The differences between groups were not significant; in both groups, however, end point glucose levels were significantly higher than baseline levels. Baseline hemoglobin A1C levels in the groups taking reformulated and original glyburide were both 7.6%; at study end point, hemoglobin A1C levels had improved slightly in each group to 7.4% and 7.5%, respectively. The differences between and within groups at end point were not significant. No between-group differences at baseline or at end point were found in mean levels of postprandial serum glucose, fasting C-peptide, or postprandial C-peptide. Medical events experienced by the subjects in the two groups were similar in nature and number. Changes in other laboratory test results, vital signs, and weight were not clinically meaningful.(ABSTRACT TRUNCATED AT 250 WORDS) ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Chemistry__Pharmaceutical_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Tablets_MeSH ****** 8313208 ----K E ----T Effect of gliclazide on plasma lipids and pancreatic beta cell function in non-insulin-dependent diabetes mellitus. ----A Eighteen patients with non-insulin-dependent diabetes mellitus (NIDDM), who were newly diagnosed or had their oral hypoglycemic agents discontinued for more than 3 months, were studied to evaluate the effect of gliclazide on glycemic control, plasma lipids and beta cell function. The mean fasting plasma glucose (249 +/- 11 vs 170 +/- 10 mg/dl, p < 0.001), postprandial plasma glucose (353 +/- 16 vs 237 +/- 16 mg/dl, p < 0.001) and HbA1C (9.6 +/- 0.4 vs 6.5 +/- 0.3% p < 0.001) decreased significantly after 3-months of gliclazide treatment. The beta cell function showed a significant increase in fasting serum C-peptide (1.8 +/- 0.2 vs 2.1 +/- 0.3 ng/ml, p < 0.05) and an insignificant increment in serum C-peptide after glucagon stimulation (2.2 +/- 0.3 vs 2.2 +/- 0.4 ng/ml, p < 0.1). In 8 cases with an initial serum cholesterol above 200 mg/dl, the serum cholesterol decreased significantly (236 +/- 8 vs 200 +/- 12 mg/dl, p < 0.05). However, LDL-cholesterol (164 +/- 8 vs 145 +/- 13 mg, p > 0.05) and HDL-cholesterol (66 +/- 5 vs 54 +/- 9 mg, p > 0.05) showed insignificant decrease after gliclazide therapy. In 4 patients with hypertriglyceridemia, the serum triglyceride decreased (441 +/- 161 vs 239 +/- 73 mg/dl, p > 0.1), but this was not statistically significant. These findings suggest that hyperglycemia, fasting serum C-peptide levels and hypercholesteremia are significantly improved after a 3-month period of gliclazide therapy in NIDDM patients. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_C-Peptide_MeSH S_analysis_MeSH C-Peptide_analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Gliclazide_MeSH S_pharmacology_MeSH Gliclazide_pharmacology_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Human_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_physiology_MeSH Islets_of_Langerhans_physiology_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8111800 ----K I ----T Diabetes control in the elderly: a randomized, comparative study of glyburide versus glipizide in non-insulin-dependent diabetes mellitus. ----A This study sought to compare the efficacy and safety of glyburide and glipizide in elderly patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM). One hundred forty-five patients aged > or = 65 years with NIDDM that was controlled for at least 3 months with oral sulfonylurea therapy were enrolled. After a washout phase, 139 patients were randomized to receive glyburide, 1.25 or 2.5 mg/day, or glipizide, 2.5 or 5 mg/day. During a 4- to 8-week titration phase, doses were adjusted according to prescribing guidelines. Patients who achieved glycemic control (fasting plasma glucose of < or = 8.9 mmol/L, or 160 mg/dl, on two consecutive occasions) entered a maintenance phase, for a total treatment period of 4 months. Hypoglycemia was defined as a fasting plasma glucose of < 3.3 mmol/L (60 mg/dl) or a random plasma glucose of < 2.8 mmol/L (50 mg/dl), with associated signs and symptoms. Most patients in both the glyburide and glipizide groups achieved satisfactory glycemic control; there were no significant differences between groups in fasting plasma glucose or hemoglobin A1c levels at any time. Of note, the mean dose of glyburide (8.5 mg/day) was approximately half that of glipizide (15.4 mg/day) at the end of the maintenance period (P = 0.009). Both regimens were well tolerated and were associated with a similarly low incidence of hypoglycemia. It was concluded that both glyburide and glipizide are suitable for the treatment of NIDDM in properly selected elderly patients. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glipizide_adverse_effects_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Male_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Refusal_MeSH ****** 8111803 ----K I ----T Efficacy and safety of gliclazide in the treatment of non-insulin-dependent diabetes mellitus: a Canadian multicenter study. ----A A postmarketing study involving 114 office practices provides the largest body of clinical experience to date in Canada with the second-generation sulfonylurea gliclazide in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). This study focused on efficacy and safety in 411 NIDDM patients. Subjects included patients whose disease was not controlled by diet alone or by diet plus an antidiabetic drug. The dose of gliclazide was 80 mg/day to 320 mg/day. Patients were treated for 3 months, with monthly evaluations. Fasting and 2-hour blood glucose and glycated hemoglobin levels were measured before and after the study period, with all values showing a significant decrease (P = 0.01). Total cholesterol and triglyceride levels also decreased significantly during the study (P = 0.05). Adverse effects were recorded in 30 (7.3%) of patients and led to the withdrawal of 1.2% from the study. Hypoglycemia symptoms were less frequently encountered with gliclazide than with previous treatments (P = 0.001). Gliclazide was found to be safe and well tolerated in the majority of patients. The results of this study appear to confirm the established efficacy of gliclazide in treating NIDDM. ----P Clinical_Trial Journal_Article Multicenter_Study ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Canada_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_adverse_effects_MeSH Gliclazide_adverse_effects_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Product_Surveillance__Postmarketing_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 8112185 ----K E ----T Effects of the carbohydrase inhibitor miglitol in sulfonylurea-treated NIDDM patients. ----A OBJECTIVE--To examine the effects of the carbohydrase inhibitor miglitol (BAY m 1099) on the metabolic profiles of non-insulin-dependent diabetes mellitus (NIDDM) patients suboptimally controlled on maximal daily doses of sulfonylurea (SFU) agents. RESEARCH DESIGN AND METHODS--Multicenter, double-blind, randomized, placebo-controlled 14-week clinical trial with six-week, single-blind placebo lead-in and run-out periods. NIDDM volunteers (192) with fasting plasma glucose (FPG) 140-250 mg/dl and hemoglobin A1c (HbA1c) 6.5-12.0% after at least 4 weeks of treatment with SFU at maximal dose were stratified by baseline HbA1c (above and below 9.0%) and then randomly assigned within strata to placebo (n = 63), 50 mg miglitol 3 times a day (n = 61), or 100 mg miglitol 3 times a day (n = 68). Efficacy was assessed by HbA1c, FPG, insulin, and lipid concentrations, and by plasma glucose and serum insulin responses to a standard meal. RESULTS--In the 50 and 100 mg miglitol treatment groups, the mean changes from baseline in HbA1c (with placebo values subtracted) were 0.82 and 0.74%, respectively, and were highly significant (P = 0.0001 in each case). Mean peak plasma glucose levels after a standard test meal were comparably lowered by 57 mg/dl with the 50 mg miglitol dose, and by 64 mg/dl with the 100 mg miglitol dose compared with placebo (P = 0.0001 for each), with associated reductions in integrated serum insulin response (P < 0.05). No significant drug-associated changes in FPG, insulin, or cholesterol levels were noted, but fasting triglyceride levels were lowered significantly with the 50 mg miglitol dose. Miglitol's side effects were limited to flatulence, loose stools, and abdominal discomfort, which were dose-related, rapidly resolved on drug discontinuation, and led to withdrawal from the study of 5 and 15% of patients taking 50 and 100 mg miglitol, respectively. CONCLUSIONS--Miglitol may be indicated as effective adjuvant therapy in NIDDM patients with suboptimal metabolic control despite conventional treatment with diet and maximal daily doses of SFU. The dose of 50 mg miglitol 3 times a day may be preferable to 100 mg miglitol 3 times a day because of comparable efficacy and substantially reduced side effects. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Glucosamine_MeSH S_adverse_effects_MeSH Glucosamine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Glucosamine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Glucosamine_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 8112483 ----K E ----T Effect of an alpha-glucosidase inhibitor on intestinal fermentation and faecal lipids in diabetic patients. ----A Eight non-insulin-dependent diabetes mellitus patients, in whom oral hypoglycaemic agents were not effective, were treated with an alpha-glucosidase inhibitor, AO-128 (0.9 mg/day) for 6 months. After 6 months of treatment there was a statistically significant decrease in the blood glucose level 1 and 2 h postprandially. The 2 h blood glucose level was also significantly reduced after 2 months' treatment. The insulin and HbA1c levels after 2 and 6 months' treatment were lower than those before administration. Faecal weight, the frequency of bowel movements, the ratio of hydroxy fatty acids to total fatty acids, and faecal short-chain carboxylic acid content were all increased significantly during treatment. The initially hard stools became normal or soft, although no actual diarrhoea developed. Both faecal bile-acid excretion and the ratio of primary bile acids to total bile acids were increased significantly after 2 months, but they showed some recovery towards the pretreatment levels after 6 months' treatment. There was no distinct change in neutral sterol and fatty acid excretion. Breath hydrogen excretion showed a slight increase after treatment. These results suggest that intestinal fermentation was promoted and the intestinal transit time was shortened by AO-128 administration. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cyclohexanols_MeSH S_therapeutic_use_MeSH Cyclohexanols_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Diabetic_Diet_MeSH M_Eating_MeSH M_Energy_Intake_MeSH M_Feces_MeSH S_chemistry_MeSH Feces_chemistry_MeSH M_Female_MeSH M_Fermentation_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_metabolism_MeSH Lipids_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Treatment_Failure_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 8200602 ----K E ----T [Management of diabetes in general practice--current requirements. 2: Oral antidiabetics and insulin therapy] ----A Oral antidiabetic agents continue to play an important role in the treatment of type 2 diabetes. Of decisive importance is the timing of their use, together with a knowledge of their specific properties. Acarbose, which needs to be initiated at a low, slowly increasing dose, is noted for the fact that it has virtually no systemic side effects. Metformin reduces plasma glucose levels without inducing hyperinsulinemia, and carries virtually no risk of lactic acidosis. Glibenclamide can be used either alone to treat type 2 diabetes or in combination with other oral antidiabetics or insulin. Today, intensified insulin therapy represents the optimal standard of insulin replacement. It permits meal-oriented injection of normal insulin and the use of longer-acting insulin overnight. This form of treatment is now facilitated by the possibilities of plasma glucose selfmonitoring and the use of injection aids (pen). Intensified treatment should be initiated at the time type I diabetes is diagnosed. In the case of a particularly instable metabolic situation or neuropathy, it may become necessary to use insulin pumps. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH ****** 8003091 ----K I ----T Sulfonylureas induce cholesterol accumulation in cultured human intimal cells and macrophages. ----A Using primary cultures of human smooth muscle intimal cells and mouse peritoneal macrophages it was demonstrated that oral hypoglycemic agents, sulfonylurea derivatives, at concentrations 10(-5)-10(-4) mol/l caused significant (by 25%-60%) intracellular total cholesterol accumulation. This in vitro atherogenic effect was confirmed in an ex vivo model. Sera from Type 2 diabetic patients, taken after sulfonylurea administration, acquired the ability to induce cholesterol accumulation in cultured cells. This enhanced atherogenic effect of patients' sera was observed for the next 2-4 h following the treatment and corresponded well to the pharmacokinetic characteristics of the tested drugs. The results suggest that sulfonylureas may exert a direct atherogenic action at the level of arterial cells, by increasing intracellular cholesterol content. ----P Journal_Article ----M M_Adult_MeSH M_Animals_MeSH M_Cells__Cultured_MeSH M_Cholesterol_MeSH S_metabolism_MeSH Cholesterol_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Gliclazide_MeSH S_pharmacology_MeSH Gliclazide_pharmacology_MeSH M_Glipizide_MeSH S_pharmacology_MeSH Glipizide_pharmacology_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Macrophages__Peritoneal_MeSH S_metabolism_MeSH Macrophages__Peritoneal_metabolism_MeSH M_Male_MeSH M_Mice_MeSH M_Mice__Inbred_BALB_C_MeSH M_Middle_Aged_MeSH M_Muscle__Smooth__Vascular_MeSH S_metabolism_MeSH Muscle__Smooth__Vascular_metabolism_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH M_Tunica_Intima_MeSH S_metabolism_MeSH Tunica_Intima_metabolism_MeSH ****** 8015532 ----K E ----T [Effectiveness and tolerance of long-term acarbose therapy in diabetic patients with threatened secondary failure of sulfonylurea drug treatment] ----A The efficacy and tolerability of acarbose was studied in 14 type-2-diabetic patients poorly controlled with diet and sulfonylureas. Acarbose was given in addition to sulfonylureas in a single-blind, placebo-controlled study for three times three months (acarbose-placebo-acarbose). At the beginning of the study and every three months body weight, HbA1c and biochemical and hematological safety parameters were measured. The patients controlled their mid morning urine glucose and two to four times daily their blood glucose concentration with a memory glucometer. Diabetic control improved significantly: HbA1c was 8.5 +/- 1.4% at the beginning, 6.5 +/- 1.1% after three months with acarbose (p < 0.001), 7.2 +/- 0.9% after three months placebo (p < 0.01) and 6.7 +/- 1.3% again after three months with acarbose (p < 0.05). Thus, the effect of acarbose alone accounts for 0.7 or 0.5% respectively, whereas the effect of teaching and diet in a special diabetes unit (the difference from the study to placebo) accounts for 1.3% of HbA1c. Home monitored blood and urine glucose values were improved: The postprandial blood glucose concentrations, the postprandial differences, the mean blood glucose concentrations and the glycosuria were decreased during acarbose treatment in comparison with placebo. The preprandial blood glucose concentrations before breakfast and supper were not influenced by acarbose. Hematological and biochemical safety parameters as well as blood pressure and heart rate were unchanged. Meteorism and flatulence as typical side effects decreased during treatment. Acarbose is a safe and effective adjunct treatment for type-2-diabetic patients uncontrolled with diet and sulfonylurea alone. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acarbose_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Combined_Modality_Therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Diet_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Therapy__Combination_MeSH M_English_Abstract_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Single-Blind_Method_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH M_Trisaccharides_MeSH S_administration_&_dosage_MeSH Trisaccharides_administration_&_dosage_MeSH S_adverse_effects_MeSH Trisaccharides_adverse_effects_MeSH ****** 8021573 ----K E ----T Short-term effects of felodipine in hypertensive type II diabetic males on sulfonylurea treatment. ----A OBJECTIVES. To study the effects on blood pressure and glucose homeostasis of felodipine, a calcium antagonist. DESIGN. A double-blind randomized cross-over study comparing felodipine ER and placebo. SETTING. A university centre of diabetic care in Malmo, Sweden. SUBJECTS. Seventeen hypertensive type II diabetic males on oral sulfonylurea (glibenclamide) treatment. INTERVENTIONS. Four-week treatment periods separated by a 2-week wash-out period. Felodipine 10-20 mg once daily was given. MAIN OUTCOME MEASURES. Blood pressure, heart rate, HbA1c and response to oral glucose tolerance test; glucose, insulin and c-peptide. Measured before randomization and at the end of each double-blind treatment period. RESULTS. Blood pressure was significantly reduced during felodipine treatment and heart rate slightly increased. Felodipine did not influence insulin or c-peptide levels. There was no significant change in glucose levels but an increase in HbA1c. CONCLUSION: The study demonstrated that felodipine is an effective agent for type II diabetic patients on glibenclamide treatment. The effect on HbA1c is noteworthy even if not of clinical significance in the short term. Controlled long-term studies in diabetic patients are needed to fully evaluate antihypertensive agents. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_C-Peptide_MeSH S_drug_effects_MeSH C-Peptide_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH M_Felodipine_MeSH S_pharmacology_MeSH Felodipine_pharmacology_MeSH S_therapeutic_use_MeSH Felodipine_therapeutic_use_MeSH M_Heart_Rate_MeSH S_drug_effects_MeSH Heart_Rate_drug_effects_MeSH M_Hemoglobin_A_MeSH S_drug_effects_MeSH Hemoglobin_A_drug_effects_MeSH M_Human_MeSH M_Hypertension_MeSH S_complications_MeSH Hypertension_complications_MeSH S_drug_therapy_MeSH Hypertension_drug_therapy_MeSH S_physiopathology_MeSH Hypertension_physiopathology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Time_Factors_MeSH ****** 8025207 ----K E ----T The use of glipizide combined with intensive insulin treatment for the induction of remissions in new onset adult type I diabetes. ----A To determine if glipizide could enhance remission induction in new onset type 1 diabetes compared to intensive insulin treatment alone, 27 patients with type 1 diabetes were intensively treated in an open randomized trial with subcutaneous injections for one month. The insulin was randomly either discontinued (Group A) or the insulin discontinued and glipizide begun (Group B) Three patients in Group A (22%) and 7 in Group B (54%, p < .05) underwent insulin-free remissions for 10.3 +/- 4.4 and 8.7 +/- 2.6 months, respectively (p = NS). Mean blood glucose levels during insulin treatment were lower in patients entering remissions (94 +/- 3 mg/dl versus 102 +/- 5 mg/dl, p < 0.05). C-peptide levels were performed 0, 4, 8, and 24 weeks after insulin treatment. When all patients were examined, mean stimulated C-peptide levels at 4 weeks (0.58 +/- 0.09 pm/ml) were increased compared to time 0 (0.32 +/- 0.05 pm/ml, p < 0.02). Patients not entering remission had higher 4-week stimulated values (0.67 +/- 0.12 pm/ml) compared to time 0 values (0.29 +/- 0.06 pm/ml, p < .01), whereas remission patients' mean C-peptide levels remained similar at 0, 4, 8 and 24 weeks. These data indicate that a) insulin treatment plus glipizide induces higher rates of remission compared to intensive insulin treatment alone, b) the intensity of initial metabolic control may be an important determinant for remission induction, and c) endogenous insulin secretion is not associated with remission induction, suggesting that glipizide alters insulin sensitivity or is immunomodulatory in the context of new onset type 1 diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Age_of_Onset_MeSH M_Algorithms_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Combined_Modality_Therapy_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_I_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_I_epidemiology_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Injections__Subcutaneous_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Remission_Induction_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Weight_Gain_MeSH ****** 8033529 ----K E ----T Effect of sulphonylurea therapy on plasma insulin, intact and 32/33 split proinsulin in subjects with type 2 diabetes mellitus. ----A This study was undertaken to clarify the effect of sulphonylurea therapy on beta cell function in 27 subjects with newly diagnosed Type 2 diabetes mellitus. Plasma glucose, insulin, intact and 32/33 split proinsulin were measured at diagnostic OGTT. After 8-12 weeks on a conventional diet, subjects with a fasting glucose > 9 mmol l-1 (n = 12) were commenced on sulphonylurea therapy. At diagnosis, the sulphonylurea requiring group were more hyperglycaemic (p < 0.0001), less obese (p < 0.05) and more insulin deficient with a lower 30 min insulin (p < 0.0002) than the diet group. Following dietary intervention in the sulphonylurea group, weight remained unchanged but there was a reduction in fasting glucose (p < 0.009). Fasting insulin, intact proinsulin, and 32/33 split proinsulin remained unchanged. After 12 weeks of sulphonylurea therapy there was a weight gain of 1.5 kg (p < 0.01), but a reduction in fasting glucose (p < 0.0001). Fasting insulin and intact proinsulin increased (p < 0.004) but 32/33 split proinsulin remained unchanged. There was a significant increase in both the fasting insulin to glucose ratio (p < 0.005), and intact to 32/33 split proinsulin ratio (p < 0.02). Final fasting glucose following sulphonylurea therapy was positively correlated with the initial intact and 32/33 split proinsulin and the fasting glucose following dietary treatment. It is clear from this work that sulphonylureas have a complex effect on beta cell physiology and as well as stimulating release of insulin they increase the release of intact proinsulin but not that of 32/33 split proinsulin, hence they increase the intact to 32/33 split proinsulin ratio. ----P Clinical_Trial Journal_Article ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH P_Diabetic_Diet_MeSH M_Fasting_MeSH M_Female_MeSH M_Glucose_Tolerance_Test_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH M_Protein_Precursors_MeSH S_blood_MeSH Protein_Precursors_blood_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8043894 ----K E ----T Effects of glipizide on glucose metabolism and muscle content of the insulin-regulatable glucose transporter (GLUT 4) and glycogen synthase activity during hyperglycaemia in type 2 diabetic patients. ----A To examine whether sulphonylureas influence hyperglycaemia-induced glucose disposal and suppression of hepatic glucose production (HGP) in type 2 diabetes mellitus, a 150-min hyperglycaemic (plasma glucose 14 mmol/l) clamp with concomitant somatostatin infusion was used in eight type 2 diabetic patients before and after 6 weeks of glipizide (GZ) therapy. During the clamp a small replacement dose of insulin was given (0.15 mU/kg per min). Isotopically determined glucose-induced glucose uptake was similar before and after GZ administration which led to improved glycaemic control (basal plasma glucose 12.2 +/- 1.3 vs 8.9 +/- 0.7 mmol/l; P < 0.01). Glucose-induced suppression of HGP was, however, more pronounced during GZ treatment (0.96 +/- 0.14 vs 1.44 +/- 0.20 mg/kg per min; P < 0.02). Following GZ treatment hyperglycaemia failed to stimulate glycogen synthase activity. Moreover, GZ resulted in a significant increase in the immunoreactive abundance of the insulin-regulatable glucose transport protein (GLUT 4) (P < 0.02). In conclusion, these results suggest that GZ therapy in type 2 diabetic patients enhances hepatic sensitivity to hyperglycaemia, while glucose-induced glucose uptake remains unaffected. In addition, GZ tends to normalize the activity of glycogen synthase and increases the content of GLUT 4 protein in skeletal muscle. ----P Journal_Article ----M M_Adult_MeSH M_Biopsy_MeSH M_Blood_Glucose_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_enzymology_MeSH Diabetes_Mellitus__Type_II_enzymology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Glipizide_MeSH S_pharmacology_MeSH Glipizide_pharmacology_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Glucose_Clamp_Technique_MeSH M_Glycogen_Synthase_MeSH S_biosynthesis_MeSH Glycogen_Synthase_biosynthesis_MeSH S_drug_effects_MeSH Glycogen_Synthase_drug_effects_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_metabolism_MeSH Hyperglycemia_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Monosaccharide_Transport_Proteins_MeSH S_drug_effects_MeSH Monosaccharide_Transport_Proteins_drug_effects_MeSH S_metabolism_MeSH Monosaccharide_Transport_Proteins_metabolism_MeSH M_Muscles_MeSH S_metabolism_MeSH Muscles_metabolism_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8044938 ----K E ----T Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. ----A BACKGROUND: Brief episodes of ischemia render the heart more resistant to subsequent ischemia; this phenomenon has been called ischemic preconditioning. In some animal species, myocardial preconditioning appears to be due to activation of ATP-sensitive K+ (KATP) channels. The role played by KATP channels in preconditioning in humans remains unknown. The aim of this study was to establish whether glibenclamide, a selective KATP channel blocker, abolishes the ischemic preconditioning observed in humans during coronary angioplasty following repeated balloon inflations. METHODS AND RESULTS: Twenty consecutive patients undergoing one-vessel coronary angioplasty were randomized to receive 10 mg oral glibenclamide or placebo. Sixty minutes after glibenclamide or placebo administration, patients were given an infusion of 10% dextrose (8 mL/min) to correct glucose plasma levels or, respectively, an infusion of saline at the same infusion rate. Thirty minutes after the beginning of the infusion, both patient groups underwent coronary angioplasty. The mean values (+/- 1 SD) of ST-segment shifts on the surface 12-lead ECG and the intracoronary ECG were measured at the end of the first and second balloon inflations, both 2 minutes long. In glibenclamide-treated patients, the mean ST-segment shift during the second balloon inflation was similar to that observed during the first inflation (23 +/- 13 versus 20 +/- 8 mm, P = NS), and the severity of cardiac pain was greater (55 +/- 21 versus 43 +/- 23 mm on a scale of 0 to 100, P < .05). Conversely, in placebo-treated patients the mean ST-segment shift during the second inflation was less than that during the first inflation (9 +/- 5 versus 23 +/- 13 mm, P < .001), as was the severity of cardiac pain (15 +/- 15 versus 42 +/- 19 mm, P < .01). Blood glucose levels were significantly reduced 60 minutes after glibenclamide compared with those at baseline (53 +/- 9 versus 102 +/- 10 mg/100 mL, P < .001) in the glibenclamide group; however, before coronary angioplasty, blood glucose levels increased to 95 +/- 19 mg/100 mL, a value similar to that found in placebo group (96 +/- 11 mg/100 mL, P = NS). CONCLUSIONS: In humans, ischemic preconditioning during brief repeated coronary occlusions is completely abolished by pretreatment with glibenclamide, thus suggesting that it is mainly mediated by KATP channels. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adenosine_Triphosphate_MeSH S_pharmacology_MeSH Adenosine_Triphosphate_pharmacology_MeSH P_Angioplasty__Transluminal__Percutaneous_Coronary_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Calcium_Channel_Blockers_MeSH S_pharmacology_MeSH Calcium_Channel_Blockers_pharmacology_MeSH M_Calcium_Channels_MeSH S_drug_effects_MeSH Calcium_Channels_drug_effects_MeSH S_physiology_MeSH Calcium_Channels_physiology_MeSH M_Comparative_Study_MeSH M_Coronary_Circulation_MeSH S_physiology_MeSH Coronary_Circulation_physiology_MeSH M_Electrocardiography_MeSH M_Female_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Monitoring__Physiologic_MeSH M_Myocardial_Ischemia_MeSH S_diagnosis_MeSH Myocardial_Ischemia_diagnosis_MeSH S_physiopathology_MeSH Myocardial_Ischemia_physiopathology_MeSH M_Single-Blind_Method_MeSH ****** 8053971 ----K E ----T Alcohol tolerance in patients with non-insulin-dependent (type 2) diabetes treated with sulphonylurea derivatives. ----A The oral ethanol loading test (0.5 g/kg body mass given as 40% solution) was carried out in 5 groups, each of 10 out-patients with non-insulin-dependent (type 2) diabetes before and after 10 days of treatment with one of the following sulphonylurea derivatives: tolbutamide (CAS 64-77-7) 0.5 t.i.d., chlorpropamide (CAS 94-20-2) 0.5 once daily morning, glibornuride (CAS 26944-48-9) 0.025 t.i.d., glibenclamide (CAS 10238-21-8) 0.005 t.i.d. and glipizide (CAS 29094-61-9) 0.005 t.i.d. The response to alcohol (facial flush, heart rate, blood pressure) were compared, and blood concentrations of ethanol, acetaldehyde, pyruvate, lactate, hydrocarbonates as well as blood pH, pO2 and pCO2 were determined in fasting state and during 6 hours after alcohol ingestion. In all patients the family history of diabetes and the presence and degree of vascular complications were registered. Evident flushing phenomenon was observed in 6 patients treated with chlorpropamide, in 3 treated with tolbutamide, in 2 treated with glibenclamide, in one receiving glibornuride and in none treated with glipizide. All drugs caused a greater rise of blood ethanol and acetaldehyde levels in relation to the control tests, but the difference reached statistical significance only in the group receiving chlorpropamide. Moreover, patients (pooled) with positive thermographic response had also significantly higher blood levels of ethanol and acetaldehyde during the second test. The ratio of acetaldehyde to ethanol concentration in blood (mumol:mmol) was not significantly changed in any group indicating parallel impairment of both steps of ethanol metabolism.(ABSTRACT TRUNCATED AT 250 WORDS) ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Acetaldehyde_MeSH S_blood_MeSH Acetaldehyde_blood_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Gas_Analysis_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Temperature_Regulation_MeSH S_drug_effects_MeSH Body_Temperature_Regulation_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Angiopathies_MeSH S_physiopathology_MeSH Diabetic_Angiopathies_physiopathology_MeSH M_Ethanol_MeSH S_adverse_effects_MeSH Ethanol_adverse_effects_MeSH S_blood_MeSH Ethanol_blood_MeSH M_Female_MeSH M_Flushing_MeSH S_chemically_induced_MeSH Flushing_chemically_induced_MeSH M_Hemodynamic_Processes_MeSH S_drug_effects_MeSH Hemodynamic_Processes_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lactates_MeSH S_blood_MeSH Lactates_blood_MeSH M_Lactic_Acid_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Pyruvates_MeSH S_blood_MeSH Pyruvates_blood_MeSH M_Pyruvic_Acid_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8056129 ----K E ----T Metabolic effects of metformin addition to chronic glibenclamide treatment in type 2 diabetes. ----A In a randomized double-blind cross-over study the addition of metformin to chronic glibenclamide treatment was assessed conventionally (plasma glucose profile and HbA1c measurement) and with an euglycaemic-hyperinsulinaemic glucose clamp in ten non obese (body mass index 22.3 +/- 0.5 (+/- SE)kg.m-2) Type 2 diabetic patients with poor metabolic control. Metformin (500 mg twice a day) or placebo were added in randomized sequence for 6 weeks to their usual sulphonylurea treatment (glibenclamide 5 mg three times a day, before meals). On the last day of each administration period, an euglycaemic (glucose 5.5 +/- 0.5 mmol.l-1), hyperinsulinaemic (insulin 698.1 +/- 22.9 pmol.l-1) clamp was performed, together with a study of insulin binding to circulating monocytes. Metformin reduced fasting glucose levels (6.1 +/- 0.4 vs 6.4 +/- 0.4 mmol.l-1, P = 0.036), mean daily plasma glucose concentrations (9.2 +/- 0.4 mmol.l-1, P < 0.001), and HbA1c (8.7 +/- 0.3 vs 9.3 +/- 0.2%; P = 0.027). No variations were registered in fasting plasma insulin or body weight. A significant reduction of basal hepatic glucose production (12.8 +/- 2.7 vs 33.9 +/- 4.5 mumol.kg-1 min-1, P < 0.001), together with an increase in glucose utilization during the clamp (33.4 +/- 2.8 vs 25.9 +/- 1.1 mumol.kg-1.min-1, P = 0.033), was found after metformin, whereas residual glucose production during insulin infusion did not change. Insulin binding to circulating monocytes was higher after metformin (4.8 +/- 0.9 vs 3.2 +/- 0.6%, P = 0.020), while the lipaemic profile showed a reduction in triglycerides (1.2 +/- 0.1 vs 1.7 +/- 0.3 mmol.l-1, P = 0.039) and an increase in HDL-cholesterol (1.3 +/- 0.1 vs 1.0 +/- 0.1 mmol.l-1, P = 0.004) without variations in total cholesterol. These findings offer further evidence that metabolic control is improved after biguanide addition to sulphonylurea treatment, and support the hypothesis that biguanides improve insulin sensitivity both at the hepatic and peripheral (muscular) levels, as well as triglyceride metabolism. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glucose_Clamp_Technique_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8077888 ----K I ----T A long-term, randomized, comparative study of insulin versus sulfonylurea therapy in type 2 diabetes. ----A OBJECTIVES. To study the effect of insulin and sulfonylurea (SU) therapy on glycaemic control, insulin resistance and cardiovascular risk factors in type 2 diabetic subjects. DESIGN. A prospective, parallel, randomized, controlled, long-term study. SETTING. Outpatient clinic in tertiary referral centre. SUBJECTS. Thirty-six type 2 diabetic subjects treated with diet and SU, aged 44-69 years and a duration of diabetes of between 2 and 14 years. INTERVENTIONS. Individually adjusted doses of insulin and glibenclamide. MAIN OUTCOME MEASURES. Glycosylated haemoglobin (HbA1c), insulin resistance (euglycaemic glucose clamp), levels of lipids, lipoproteins and blood pressure. RESULTS. Glycaemic control improved during insulin treatment, but deteriorated on SU; HbA1c levels differed significantly between groups after 12 months of therapy (mean +/- SEM 7.9 +/- 0.3 vs. 9.5 +/- 0.4%, P = 0.004). Body mass index increased significantly during insulin treatment (26.4 +/- 0.7 to 27.8 +/- 0.7 kg/m2, P = 0.0001) and 30% of this increase was a result of an increase in lean body mass. The total glucose disposal rate showed a small increase in the insulin group. Levels of triglycerides and apolipoprotein B were significantly reduced during insulin treatment (1.8 +/- 0.2 to 1.5 +/- 0.2 mmol L-1, P = 0.03 and 1.58 +/- 0.1 to 1.40 +/- 0.08 g L-1, P = 0.003), and insulin prevented a reduction in the levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1 and an increase in Lp(a) lipoprotein observed in the SU group. Blood pressure levels did not change during therapy. CONCLUSIONS. Insulin therapy was superior to SU treatment in achieving good metabolic control. Despite a modest improvement in cardiovascular risk factors in the insulin-treated group, no significant differences were observed between the groups after 1 year's treatment. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Glucose_Clamp_Technique_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Insulin_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin_Resistance_MeSH S_physiology_MeSH Insulin_Resistance_physiology_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8082525 ----K I ----T Efficacy of 24-week monotherapy with acarbose, glibenclamide, or placebo in NIDDM patients. The Essen Study. ----A OBJECTIVE--To compare the different therapeutic principles of alpha-glucosidase inhibitors and sulphonylureas as first-line treatment in non-insulin-dependent diabetes mellitus (NIDDM) patients with dietary failure. RESEARCH DESIGN AND METHODS--Ninety-six NIDDM patients (35-70 years of age, body mass index [BMI] < or = 35), insufficiently treated with diet alone (HbA1c 7-9%) were randomized into three groups and treated for 24 weeks with acarbose, glibenclamide, or placebo. Efficacy, based on fasting blood glucose (BG), BG 1 h after ingestion of standard breakfast (postprandial), serum insulin, postprandial insulin increase, and HbA1c; and tolerability, based on subjective symptoms and laboratory values, were investigated every 6 weeks. Efficacy evaluation was valid for 85 patients. RESULTS--The test drugs were dosed as follows: 100 mg acarbose (A) three times a day, 1 placebo tablet three times a day, 3.5 mg glibenclamide tablets dosed 1-0-0 or 1-0-1, mean dose 4.3 mg/day. Compared with the placebo, both drugs showed the same mean efficacy on fasting BG (-1.4 mM with acarbose, -1.6 mM with glibenclamide), 1-h postprandial BG (-2.2 mM with acarbose, -1.9 mM with glibenclamide), and HbA1c (-1.1% with acarbose, -0.9% with glibenclamide); but they showed a marked difference in 1-h postprandial insulin values (-80.7 pM with acarbose, 96.7 pM with glibenclamide). The mean relative insulin increase (1-h postprandial) was 1.5 in the placebo group, 1.1 in the acarbose group, and 2.5 in the glibenclamide group. No changes in body weight could be observed. No adverse events were seen under placebo. Acarbose led to mild or moderate intestinal symptoms in 38% of patients. Glibenclamide led to hypoglycemia, which could be solved by dose reduction, in 6% of patients. No dropouts occurred in any of the treatment groups. CONCLUSIONS--Acarbose and glibenclamide are effective drugs for the monotherapy of NIDDM patients when diet alone fails. Because postprandial insulin increase has been shown to be associated with increased risk for cardiovascular disease, acarbose, which lowers pp increase, may be superior to glibenclamide, which elevates postprandial insulin increase. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acarbose_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_urine_MeSH Diabetes_Mellitus__Type_II_urine_MeSH M_Diabetic_Diet_MeSH M_Dietary_Carbohydrates_MeSH M_Energy_Intake_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Glycosuria_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_Trisaccharides_MeSH S_adverse_effects_MeSH Trisaccharides_adverse_effects_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 7926425 ----K E ----T [A comparative study of insulin and glyburide versus glyburide or insulin in the chronic control of patients with type-2 diabetes] ----A In order to know the usefulness of a combined treatment with gliburide and NPH insulin 25 patients with well controlled type II diabetes mellitus were studied. The patients were randomly divided in to three groups: Group I just received gliburide, Group II only insulin and Group III gliburide and insulin. Glucose in fast, glycosylated haemoglobin and C peptide levels were determined over five months. For the statistical data processing variance analysis was performed. The initial and final glucose determinations were: Group I, 169.3 mg% and 139.0 mg% respectively (p > 0.05); Group II, 202.1 mg% and 177 mg% (p > 0.05); Group III, 157.8 mg% and 158.8 mg% (p > 0.1) for the glycosylated haemoglobin the determinations were: Group I, 7.2% and 5.1% (p > 0.05); Group II, 6.2% and 5.1% (p > 0.05) and Group III, 5.7% and 4.7% (p > 0.05). For the C peptide were 2.5 and 4.5 for Group I (p > 0.05), 2 and 4.1 for Group II (p > 0.05) and 3.2 and 5.3 for Group III (p > 0.05) with no significant statistical differences. It is concluded that the combined treatment showed to be effective, but not superior, in order to control diabetic patients and it can be a useful therapeutic alternative in well selected patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Chronic_Disease_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH M_Drug_Therapy__Combination_MeSH M_English_Abstract_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH ****** 7942982 ----K I ----T Bedtime dosing of glyburide and the treatment of type II diabetes mellitus. ----A Suppression of nocturnal hepatic glucose production is key in the treatment of noninsulin-dependent diabetes mellitus (NIDDM). In this article, the authors compare the effectiveness of dosing glyburide at bedtime versus in the morning on glycemic control in patients with NIDDM under suboptimal control. In a placebo-controlled, double-blind crossover trial, 32 patients with NIDDM with suboptimal control on chronic glyburide treatment fulfilling entry criteria were randomized to receive one of two regimens: (1) glyburide at bedtime and placebo in morning or (2) placebo at bedtime and glyburide in the morning. After 6 months of a regimen, patients crossed over to the other treatment and completed an additional 6-month period. After baseline assessment, fasting blood sugar, history, physical exam, and compliance assessments were performed monthly. HbA1c was measured bimonthly and Sustacal tolerance tests were performed at the end of each 6-month treatment period. During the initial 6-month comparison fasting, blood sugar concentration decreased 5% in bedtime ingesters and rose 10% in the morning patients. These changes were not statistically significant. HbA1c decreased significantly in the morning group but remained unchanged in the bedtime group. At the end of 12 months, nighttime dosing resulted in better home glucose monitoring values, fasting blood sugar results, and Sustacal tolerance profiles, but the differences were not statistically significant. No hypoglycemia was observed in the monitored data collected. Bedtime dosing of glyburide resulted in measurable improvement in fasting blood sugar and carbohydrate tolerance curves, but not to a degree justifying general recommendation of this technique in patients with NIDDM with secondary failure to oral agents. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adolescent_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Circadian_Rhythm_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7958542 ----K E ----T Comparative dose-related time-action profiles of glibenclamide and a new non-sulphonylurea drug, AG-EE 623 ZW, during euglycaemic clamp in healthy subjects. ----A Insulin and glucose responses to glibenclamide were studied in comparison to a novel non-sulphonylurea drug (AG) by means of the euglycaemic clamp technique. Nine fasting male subjects were connected to a Biostator and 1.75, 3.5 or 7.0 mg glibenclamide or 1.0, 2.0 or 4.0 mg AG were given and blood glucose concentrations were clamped at 10% below basal values. Glucose infusion rates were registered over 10 h after administration of the tablet. Maximal glucose infusion rates after glibenclamide were 40% higher compared to AG (1.75 vs 1.0 mg, 3.5 vs 2.0 mg, 7.0 vs 4.0 mg, respectively) and were reached after 3-3.5 h for all doses. After glibenclamide, area under the glucose infusion curves and maximal incremental serum insulin responses were higher by 25-40% and by 30% compared to AG when low, medium and high doses of each drug were tested. However, a linear dose relationship was obtained for both drugs when the glucose infusion rate was plotted against the area under the insulin curve. In fact, both drugs were equipotent on a molecular weight basis. The hypoglycaemic index of both drugs (integrated glucose infusion rate divided by integrated insulin release) expressed per mumol of drug revealed a dose-dependent and parallel inverse curvilinear relation to increasing doses. This methodological approach allowed us to quantify and compare the metabolic effects of oral hypoglycaemic agents under standardised experimental conditions. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Carbamates_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH M_Comparative_Study_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Glucose_MeSH S_administration_&_dosage_MeSH Glucose_administration_&_dosage_MeSH M_Glucose_Clamp_Technique_MeSH M_Glyburide_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Male_MeSH M_Piperidines_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 7960692 ----K E ----T Prolonged response to glibenclamide in NIDDM patients in a normoglycemic state. ----A ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Biological_Availability_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Fasting_MeSH S_metabolism_MeSH Fasting_metabolism_MeSH M_Female_MeSH M_Glyburide_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_metabolism_MeSH Hyperglycemia_metabolism_MeSH M_Intestinal_Absorption_MeSH M_Male_MeSH M_Middle_Aged_MeSH ****** 7988301 ----K I ----T Hypoglycemic activity of glyburide (glibenclamide) metabolites in humans. ----A OBJECTIVE--To assess the hypoglycemic effect and the insulin-releasing effect of the main glyburide (glibenclamide) metabolites 4-trans-hydroxy-glibenclamide (M1) and 3-cis-hydroxy-glibenclamide (M2) in humans. RESEARCH DESIGN AND METHODS--Eight healthy subjects participated in a placebo-controlled, randomized, single-blind crossover study with five single-dose tests, 3 months apart: 3.5 mg glibenclamide (Gb) orally, 3.5 mg Gb intravenously, 3.5 mg M1 intravenously, 3.5 mg M2 intravenously, and placebo intravenously, each in the fasting state. Standardized meals were given 0.5 and 5.5 h after each medication. Blood glucose levels were measured by a glucose oxidase method, and serum insulin concentrations were analyzed by a specific immunoassay. RESULTS--Blood glucose levels during the first 5 h were significantly lowered not only by Gb but also by M1 and M2. The mean +/- SE blood glucose reductions (versus placebo) expressed as percent of area under the curve (AUC) (0-5 h) were 18.2 +/- 3.3% for M1, 12.5 +/- 2.3% for M2, 19.9 +/- 2.1% for intravenous Gb, and 23.8 +/- 1.2% for Gb orally. Serum insulin levels were significantly increased by Gb as well as by M1 and M2. and M2. CONCLUSIONS--The two main metabolites of glyburide (glibenclamide) have a hypoglycemic effect in humans, which is due to increased insulin secretion. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_metabolism_MeSH Glyburide_metabolism_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_blood_MeSH Hypoglycemia_blood_MeSH S_etiology_MeSH Hypoglycemia_etiology_MeSH S_metabolism_MeSH Hypoglycemia_metabolism_MeSH M_Injections__Intravenous_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Male_MeSH M_Single-Blind_Method_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7988624 ----K E ----T The effect of hyperglycaemia on the absorption of glibenclamide in patients with non-insulin-dependent diabetes mellitus. ----A We have studied the absorption of glibenclamide 10 mg as a single morning dose in 7 patients with non-insulin-dependent diabetes mellitus, comparing normoglycaemic and hyperglycaemic states. The maximal glibenclamide plasma concentrations were significantly higher in the normoglycaemic than in the hyperglycaemic state (448 vs 228 mg.l-1) and these peak concentrations were attained faster in normoglycaemia than in hyperglycaemia (3.7 vs 5 h). We conclude that the absorption of glibenclamide in the two states is different. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_blood_MeSH Glyburide_blood_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_metabolism_MeSH Hyperglycemia_metabolism_MeSH M_Intestinal_Absorption_MeSH M_Male_MeSH M_Middle_Aged_MeSH ****** 7988780 ----K E ----T Effect of glipizide treatment on postprandial lipaemia in patients with NIDDM. ----A The primary goal of the present study was to examine the effects of improved glycaemic control associated with glipizide treatment on postprandial lipaemia in non-insulin-dependent diabetic patients. The metabolism of triglyceride-rich lipoproteins of intestinal origin was assessed by measuring the retinyl palmitate content in plasma and the Svedberg flotation index (Sf) > 400 and Sf 20-400 lipoprotein fractions. Fasting plasma glucose concentrations (14.5 +/- 0.5 vs 9.0 +/- 0.5 mmol/l), glycated haemoglobin levels (13.1 +/- 0.6 vs. 9.7 +/- 0.6%), and daylong plasma glucose concentrations were all significantly lower after glipizide treatment (p < 0.001). The improvement in glycaemic control was associated with increases in insulin-mediated glucose uptake (p < 0.001) and plasma post-heparin lipoprotein and hepatic lipolytic activities (p < 0.02). Both fasting plasma triglyceride (3.09 +/- 0.51 vs 2.37 +/- 0.34 mmol/l), and postprandial triglyceride concentrations (p < 0.05-0.001) were lower following glipizide treatment, associated with a significant fall in retinyl palmitate content in all three lipoprotein fractions (p < 0.02-0.001), with the most substantial decrease seen in the Sf20-400 fraction. These data indicate that glipizide-induced improvement in glycaemic control was associated with changes in the metabolism of triglyceride-rich lipoproteins of intestinal origin that would be anticipated to reduce risk of coronary heart disease in non-insulin-dependent diabetic patients. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Circadian_Rhythm_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Eating_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Lipase_MeSH S_blood_MeSH Lipase_blood_MeSH M_Lipoprotein_Lipase_MeSH S_blood_MeSH Lipoprotein_Lipase_blood_MeSH M_Lipoproteins_MeSH S_blood_MeSH Lipoproteins_blood_MeSH M_Liver_MeSH S_enzymology_MeSH Liver_enzymology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Reference_Values_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_Vitamin_A_MeSH S_analogs_&_derivatives_MeSH Vitamin_A_analogs_&_derivatives_MeSH S_blood_MeSH Vitamin_A_blood_MeSH ****** 7991936 ----K E ----T Metabolic clearance rate of insulin in type 2 diabetic patients treated with combined insulin and sulfonylurea therapy. ----A The metabolic clearance rate of insulin (MCRI) in 10 non-obese type 2 diabetic patients treated with either insulin alone or combined insulin plus sulfonylurea therapy is investigated. A classical 2-hour euglycaemic hyperinsulinaemic glucose clamp using the artificial pancreas was performed in a randomized order after two 6-week periods of treatment: either with subcutaneous injections of insulin alone or with insulin plus oral administration of the sulfonylurea compound glipizide at the dose of 3 x 10 mg/day. The MCRI was calculated knowing the constant insulin infusion rate (0.1 U.kg-1.h-1) and measuring basal and steady-state plasma free insulin and C-peptide levels. When the test was performed at the end of the period of treatment with insulin plus glipizide and 30 min after the ingestion of the last dose of 10 mg glipizide, plasma C-peptide levels were significantly increased and steady-state free insulin levels tended to be slightly higher whereas the metabolic clearance rate of glucose was not affected. The MCRI was significantly reduced by glipizide from 23.3 +/- 2.9 to 18.9 +/- 2.0 ml.kg-1.min-1 p < 0.05. These results demonstrate that the sulfonylurea glipizide decreases the MCRI. This effect may play a role in the hypoglycemic action of sulfonylureas. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Drug_Interactions_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glipizide_MeSH S_pharmacology_MeSH Glipizide_pharmacology_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glucose_Clamp_Technique_MeSH M_Human_MeSH M_Insulin_MeSH S_pharmacokinetics_MeSH Insulin_pharmacokinetics_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metabolic_Clearance_Rate_MeSH S_drug_effects_MeSH Metabolic_Clearance_Rate_drug_effects_MeSH M_Middle_Aged_MeSH ****** 7821127 ----K E ----T Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM. ----A OBJECTIVE--To quantify the effect of metformin on the metabolism of triglyceride (TG)-rich lipoprotein of intestinal origin in patients with non-insulin-dependent diabetes mellitus (NIDDM) who had responded to sulfonylurea but still had fasting hyperglycemia. RESEARCH DESIGN AND METHODS--Sixteen patients with NIDDM who had demonstrated a fall in fasting plasma glucose concentration > 2.2 mmol/l in response to glipizide treatment but continued to have fasting plasma glucose concentrations > 8.3 mmol/l were studied. Fasting glucose, GHb, lipid and lipoprotein concentrations were determined, and resistance to insulin-mediated glucose disposal was estimated by measuring the steady-state plasma glucose (SSPG) concentration at the end of a 180-min infusion of somatostatin, glucose, and insulin. In addition, plasma glucose, insulin, and TG concentrations were measured at frequent intervals from 0800 to 2400, with patients eating breakfast at 0800 and lunch at 1200. Vitamin A was also given at lunch, and the retinyl ester content in plasma and in chylomicron (Svedberg flotation constant [Sf] > 400) and the chylomicron remnant (Sf 20-400) fractions were used to quantify the concentration of postprandial intestinal TG-rich lipoprotein from 1200 to 2400. RESULTS--Fasting plasma glucose concentrations (6.8 +/- 0.4 vs. 10.5 +/- 0.4 mmol/l), GHb levels (7.9 +/- 0.3 vs. 10.8 +/- 0.5%), and day-long plasma glucose concentrations were all significantly lower after metformin treatment (P < 0.001), which was associated with a significant (P < 0.001) fall in SSPG concentration (11.0 +/- 0.9 to 9.6 +/- 0.6 mmol/l). In addition, postprandial concentrations of glucose, insulin, free fatty acids, and TG were lower (P < 0.001) following metformin treatment. Postprandial retinyl ester concentrations were also lower in plasma by 33 +/- 5.7% (P < 0.001) and in both the chylomicron (32 +/- 7.2%, P < 0.001) and chylomicron remnant (26 +/- 7.0%, P < 0.005) fractions. CONCLUSIONS--Addition of metformin to sulfonylurea-treated patients with NIDDM with less than optimal glycemic control was associated with improved glycemic control, lower postprandial insulin and TG concentrations, and a decrease in postprandial concentration of TG-rich lipoproteins of intestinal origin. All of these changes might be expected to decrease risk of coronary heart disease. ----P Journal_Article ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Coronary_Disease_MeSH S_prevention_&_control_MeSH Coronary_Disease_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Drug_Therapy__Combination_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Food_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Intestines_MeSH S_metabolism_MeSH Intestines_metabolism_MeSH M_Lipoproteins_MeSH S_drug_effects_MeSH Lipoproteins_drug_effects_MeSH S_metabolism_MeSH Lipoproteins_metabolism_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Risk_Factors_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Triglycerides_MeSH S_metabolism_MeSH Triglycerides_metabolism_MeSH ****** 7821128 ----K I ----T Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. ----A OBJECTIVE--To assess and compare the therapeutic efficacy and safety of metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS--Of 165 patients (fasting blood glucose [FBG] > or = 6.7 mmol/l) initially treated with diet alone, 144 (FBG still > or = 6.7 mmol/l) were randomized to double-blind, double-dummy controlled treatment with M, G, or primary combination therapy (MG). The dose was titrated, with FBG < 6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the second three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed dose titration. RESULTS--The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG +/- SE was reduced (P = 0.001) from 9.1 +/- 0.4 to 7.0 +/- 0.2 mmol/l in those maintained on single-drug treatment or low-dose primary combination. Those treated with different high-dose combinations had a large mean FBG reduction, from 13.3 +/- 0.8 to 7.8 +/- 0.6 mmol/l. HbA1c levels showed corresponding reductions, and glycemic levels rose after drug discontinuation. Fasting C-peptide rose during treatment with G and MGL but not with M, while fasting insulin was not significantly changed. Meal-stimulated C-peptide and insulin levels were unchanged by M but increased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combinations (M/G, G/M, and MGH). Body weight did not change following treatment with M or combination but increased by 2.8 +/- 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipids were small, with no significant differences between groups. Drug safety was satisfactory, even if the reporting of (usually modest) adverse events was high; the profile, but not the frequency, differed between groups. CONCLUSIONS--Dose-effect titrated treatment with either metformin or glyburide promotes equal degrees of glycemic control. The former, but not the latter, is able to achieve this control without increasing body weight or hyperinsulinemia. Near-normal glycemia can be obtained by a combination of metformin and sulfonylurea, even in advanced NIDDM. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH S_physiology_MeSH Blood_Pressure_physiology_MeSH M_Body_Weight_MeSH S_physiology_MeSH Body_Weight_physiology_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7821133 ----K E ----T Improved visual evoked potential latencies in poorly controlled diabetic patients after short-term strict metabolic control. ----A OBJECTIVE--To determine whether short-term strict control of blood glucose can improve abnormal visual evoked potentials (VEPs) in poorly controlled diabetic patients with no overt diabetic complications. RESEARCH DESIGN AND METHODS--VEPs (P100 wave latencies) were recorded in 12 poorly controlled diabetic patients (7 with insulin-dependent diabetes mellitus and 5 with non-insulin-dependent diabetes mellitus) before and after at least 3 days of near normoglycemia obtained by continuous subcutaneous insulin infusion (CSII). Exclusion criteria were overt diabetic neuropathy or retinopathy. The control subjects were 12 healthy subjects matched for age and sex. Fifty-two other subjects formed a reference control population. The intra-individual coefficient of variation for P100 latency was < 3%. RESULTS--The P100 latencies were longer in diabetic patients than in control subjects (means of both eyes +/- SD: 116.8 +/- 10.1 vs. 106.2 +/- 4.5 ms, P < 0.01), and 4 of the 12 diabetic patients had abnormal VEPs. After 3 days of close blood glucose control (mean blood glucose profile fell from 13.7 +/- 2.2 mmol/l to 6.8 +/- 1.2 mmol/l, P < 0.01), the mean P100 latencies were significantly shorter (112.5 +/- 7.6 ms, P < 0.01) but were still significantly longer than control values. The longer the initial P100 latency, the greater the decrease after CSII. There was no correlation between the fall in blood glucose and improvement in VEPs. CONCLUSIONS--Short-term blood glucose normalization is associated with improved P100 wave latency in uncomplicated diabetic patients. These data suggest that abnormal VEPs are partly reversible and include functional disturbances related to glucose metabolism. ----P Journal_Article ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_I_physiopathology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Evoked_Potentials__Visual_MeSH S_physiology_MeSH Evoked_Potentials__Visual_physiology_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Reaction_Time_MeSH S_physiology_MeSH Reaction_Time_physiology_MeSH ****** 7821171 ----K I ----T Comparison of pharmacokinetics and pharmacodynamics of short- and long-term glyburide therapy in NIDDM. ----A OBJECTIVE--To examine the pharmacokinetics and pharmacodynamics of glyburide after single- and multiple-dose administration in patients with type II diabetes. RESEARCH DESIGN AND METHODS--Twenty patients with type II diabetes between 40 and 70 years of age participated in the study. A 24-h pharmacokinetic evaluation including a 4-h Sustacal tolerance test was conducted before instituting glyburide therapy (baseline), after the first 2.5-mg test dose of glyburide and at weeks 6 and 12 of chronic glyburide therapy. Glyburide doses were titrated with a target goal of achieving a fasting plasma glucose of < or = 7.8 mmol/l or to reach maximum daily doses of 20 mg. RESULTS--A significant prolongation in the elimination half-life (t1/2: week 0, 4.0 +/- 1.9 h; week 6, 13.7 +/- 10.5 h; and week 12, 12.1 +/- 8.2 h) and an increased volume of distribution of glyburide was observed during chronic dosing. These results strongly suggest possible drug accumulation. No differences in pharmacokinetic parameters were noted between evaluations at week 6 or week 12. Changes in pharmacodynamic response of glucose, insulin, and C-peptide to chronic glyburide therapy were observed. Glyburide therapy significantly reduced plasma glucose levels at weeks 6 and 12 (percent changes in AUC0-->4. glucose from baseline: week 0, -3 +/- 11%; week 6, -29 +/- 13%; and week 12, -26 +/- 19%). Pancreatic insulin secretion was acutely enhanced and maintained during long-term therapy. Responsiveness to therapy as assessed by the ratio of AUC0-->4.glucose:AUC0-->4.C-peptide was significantly improved at all weeks compared with baseline. No pharmacodynamic response differences were observed between the week 6 and the week 12 evaluations. CONCLUSIONS--This study demonstrates that significant differences in glyburide pharmacokinetics and pharmacodynamics exist between single-dose and steady-state conditions. These differences support the need for careful dosage titration of glyburide to achieve a desired therapeutic response in patients with type II diabetes. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Half-Life_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7825173 ----K E ----T Control of diabetes during rehabilitation for diabetic stroke. ----A Changes of diabetic control during rehabilitation therapy was studied retrospectively in 33 cases of diabetic stroke. Diabetic control was not deteriorated in any cases during rehabilitation therapy. In 21 cases, treatment of diabetes was not changed during rehabilitation therapy and the levels of fasting plasma glucose were decreased in all of them. Doses of hypoglycemic agents was reduced without significant deterioration of diabetic control in 9 cases whose diabetic control was excellent, and in 2 cases who experienced hypoglycemic attack during rehabilitation therapy. In these cases, oral hypoglycemic agent was reduced from 2 to 1 tablet and insulin from 32 to 21 units per day on average. These results indicate that training in the stroke rehabilitation moderately improves diabetic control. ----P Journal_Article ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Cerebrovascular_Disorders_MeSH S_blood_MeSH Cerebrovascular_Disorders_blood_MeSH S_complications_MeSH Cerebrovascular_Disorders_complications_MeSH S_rehabilitation_MeSH Cerebrovascular_Disorders_rehabilitation_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_II_prevention_&_control_MeSH M_Diet_Therapy_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH M_Human_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Retrospective_Studies_MeSH ****** 7836551 ----K E ----T Lack of interaction between glipizide and co-trimoxazole. ----A To identify the effects of co-trimoxazole on the elimination and disposition kinetics of glipizide, eight healthy male volunteers were studied in an unblinded, randomized, cross-over trial with two phases (no treatment or co-trimoxazole 160/800 mg twice a day). During each phase, subjects were treated at home for 7 days with one of the treatment regimens, followed by a 24-hour hospitalization for a single-dose challenge with 10-mg oral glipizide and detailed blood studies. A 7-day washout period was interspersed between the phases. Pharmacokinetic and pharmacodynamic parameters were determined and compared using the Student's t-test for paired observations. Glipizide area under the curve (AUC), clearance, and half life for treatment and control phases were 5758 +/- 1874 versus 5176 +/- 1505 micrograms/L/hour (P = .21), 0.41 +/- 0.15 versus 0.45 +/- 0.14 mL/min/kg (P = .27), and 5.13 +/- 2.10 versus 3.95 +/- 1.37 hours (P = .04), respectively. Twenty-four-hour glucose AUCs for treatment and control phases were 112.24 +/- 8.76 versus 114.86 +/- 11.98 mmol/L/hour (P = .55), respectively. The only parameter reaching statistical significance was glipizide half life, but the difference is of doubtful clinical significance because of difficulty in identifying a clear elimination phase in several subjects. It is concluded that co-trimoxazole administration did not significantly alter glipizide disposition and elimination kinetics in this study population. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cross-Over_Studies_MeSH M_Glipizide_MeSH S_blood_MeSH Glipizide_blood_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH M_Half-Life_MeSH M_Human_MeSH M_Male_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Trimethoprim-Sulfamethoxazole_Combination_MeSH S_pharmacology_MeSH Trimethoprim-Sulfamethoxazole_Combination_pharmacology_MeSH ****** 7843470 ----K I ----T One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. ----A Forty-eight diabetic subjects with diet-failed Type 2 mellitus, aged 40-69 years, were randomised to metformin (24 patients) or glipizide (24 patients) therapy, and followed prospectively for 12 months. Most subjects were obese. Metformin gave better fasting plasma glucose control compared to glipizide at 24 (p < 0.01), 36 (p < 0.05) and 52 weeks (p < 0.05) with a lower HbA1 concentration at 52 weeks (p < 0.05). Metformin treated patients lost weight whereas glipizide treated subjects gained weight. The weight change between the treatment groups reached significance at 4 weeks (p < 0.05) and was highly significant (p < 0.001) at 8, 12, 24, 36 and 52 weeks. There were no significant changes in either fasting plasma lipid or blood lactate levels in either the metformin or glipizide treated groups. Both drugs caused a similar reduction in albumin excretion rates. In conclusion, metformin gave better glycaemic control than glipizide, with weight loss rather than weight gain in obese Type 2 patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Human_MeSH M_Lactates_MeSH S_blood_MeSH Lactates_blood_MeSH M_Lactic_Acid_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH ****** 7848543 ----K I ----T Comparative tolerability profiles of oral antidiabetic agents. ----A The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption. ----P Clinical_Trial Journal_Article Review Review__Tutorial ----M M_Acarbose_MeSH M_Administration__Oral_MeSH M_Biguanides_MeSH S_adverse_effects_MeSH Biguanides_adverse_effects_MeSH S_pharmacokinetics_MeSH Biguanides_pharmacokinetics_MeSH S_therapeutic_use_MeSH Biguanides_therapeutic_use_MeSH M_Biological_Availability_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Hypersensitivity_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Mortality_MeSH M_Prospective_Studies_MeSH M_Structure-Activity_Relationship_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Trisaccharides_MeSH S_adverse_effects_MeSH Trisaccharides_adverse_effects_MeSH S_pharmacokinetics_MeSH Trisaccharides_pharmacokinetics_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 7851069 ----K E ----T Ethnic differences in secretion, sensitivity, and hepatic extraction of insulin in black and white Americans. ----A Hyperinsulinaemia and abnormalities in hepatic insulin extraction commonly coexist in ethnic groups with severe insulin resistance. Therefore, we compared the effects of ethnicity on glucose/insulin/C-peptide dynamics, hepatic insulin extraction, and insulin sensitivity in healthy black (n = 32) and white (n = 30) Americans. Standard oral glucose tolerance test (OGTT) and tolbutamide-modified, frequently sampled, intravenous glucose tolerance (FSIVGT) tests were performed in each subject. Insulin sensitivity index (S1)) was calculated using the MINIMOD method described by Bergman et al. Basal and post-stimulation hepatic insulin extraction were calculated by the molar ratios of C-peptide and insulin concentrations during the basal steady state and areas under the post-stimulation hormone curves, respectively. Apart from a slightly greater mean serum glucose peak response after oral glucose in the whites, mean glucose levels were identical in the blacks and whites during both stimulations. In contrast, serum insulin levels at basal and during both stimulations were significantly greater (2-3 fold) in the blacks than whites. However, the corresponding C-peptide responses were identical in both groups. The basal and postprandial hepatic insulin extraction were 33% and 45% lower in the blacks when compared to whites, respectively. The mean S1 was significantly (p < 0.02) lower in the blacks (4.93 +/- 0.46) than the whites (7.17 +/- 0.88 x 10(-4).min-1 (mU l-1)-1). We conclude that ethnicity may be a major determinant of the mechanism of peripheral hyperinsulinaemia and insulin insensitivity in black and white Americans. ----P Clinical_Trial Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH P_African_Continental_Ancestry_Group_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH P_European_Continental_Ancestry_Group_MeSH M_Female_MeSH M_Glucose_MeSH S_administration_&_dosage_MeSH Glucose_administration_&_dosage_MeSH S_pharmacology_MeSH Glucose_pharmacology_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Hyperinsulinism_MeSH S_blood_MeSH Hyperinsulinism_blood_MeSH S_genetics_MeSH Hyperinsulinism_genetics_MeSH M_Insulin_MeSH S_analysis_MeSH Insulin_analysis_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Insulin_Resistance_MeSH S_genetics_MeSH Insulin_Resistance_genetics_MeSH M_Liver_MeSH S_chemistry_MeSH Liver_chemistry_MeSH M_Male_MeSH M_United_States_MeSH ****** 7858767 ----K E ----T Effects of glibenclamide on ventricular fibrillation in non-insulin-dependent diabetics with acute myocardial infarction. ----A BACKGROUND: Glibenclamide, a hypoglycemic sulfonylurea, has shown antiarrhythmic effects in acutely ischemic myocardium. The aim of the present study was to evaluate the effectiveness of the drug in preventing ventricular fibrillation in diabetic patients with acute myocardial infarction. METHODS: We studied 232 patients with non-insulin-dependent diabetes mellitus (106 on glibenclamide, group A1; 126 treated with another hypoglycemic drug or with diet only, group A2) and 830 non-diabetic people. All the patients were admitted to our coronary care unit with their first myocardial infarction. RESULTS: Ventricular fibrillation occurred in 1.9% of group A1, 7.9% of group A2, and 9.9% of the non-diabetic (A1 versus A2, P < 0.05; A2 versus the non-diabetic group, NS; A1 versus the non-diabetic group, P < 0.01). Sustained ventricular tachycardia was not significantly different among the groups. CONCLUSIONS: The antiarrhythmic effectiveness of glibenclamide might be related to its blocking action on the ATP-dependent potassium channel, with consequent attenuation of the efflux of potassium induced by ischemia. We also observed a higher mortality rate resulting from heart failure in group A2 than in group A1 or the non-diabetic group. Since glibenclamide has never shown significant effects on myocardial contractility, this finding remains to be elucidated. Glibenclamide therefore appears to have an antifibrillatory effect in acute myocardial infarction; with respect to acute coronary events, the drug might be able to prevent ventricular fibrillation, which is most often fatal when it occurs before hospitalization. ----P Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Myocardial_Infarction_MeSH S_complications_MeSH Myocardial_Infarction_complications_MeSH M_Ventricular_Fibrillation_MeSH S_etiology_MeSH Ventricular_Fibrillation_etiology_MeSH S_prevention_&_control_MeSH Ventricular_Fibrillation_prevention_&_control_MeSH ****** 7862618 ----K E ----T Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. ----A Metformin is a biguanide antidiabetic medication, that has been in use for over 30 years. Its mechanism of action, unknown until a few years ago, is now linked to an improved peripheral sensitivity to insulin, through a stimulated tissue glucose uptake by a transporter linked system. Interest in metformin has been revived by the recent observation of a specific activity of this agent on some of the major traits of the so called 'polymetabolic syndrome' (or 'syndrome X'), characterized by: insulin resistance, hypertriglyceridemia, hypertension and reduced fibrinolytic activity. Metformin, in studies examining one or more of these, has been shown, possibly through its peripheral insulin sensitizing mechanism, to correct most of the major symptoms characterizing this insulin resistance syndrome. Metformin, similarly to the other biguanide phenformin, has been rated as potentially dangerous, because of the possible induction of lactic acidosis, in some cases with a fatal outcome. Metformin is, however, associated with a very low incidence of lactic acidosis because, differently from phenformin, it does not undergo liver metabolism and, as a consequence, there are no high-risk groups, displaying an impaired metabolic handling. In this review, in addition to an overall evaluation of the more recent data on the mechanism of action and clinical use of metformin, a detailed clinical analysis of all published cases of lactic acidosis is provided. These data indicate that the risk in metformin use is negligible, provided that care is taken when prescribing the drug to patients with suspected clinical risks of lactic acidosis. ----P Journal_Article Review Review_of_Reported_Cases Review__Tutorial ----M M_Acidosis__Lactic_MeSH S_chemically_induced_MeSH Acidosis__Lactic_chemically_induced_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH P_Insulin_Resistance_MeSH M_Male_MeSH P_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_metabolism_MeSH Metformin_metabolism_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Risk_Factors_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7882817 ----K I ----T Comparative efficacy of a once-daily controlled-release formulation of glipizide and immediate-release glipizide in patients with NIDDM. ----A OBJECTIVE--To compare the efficacy and safety of controlled-release glipizide (glipizide-GITS [gastrointestinal therapeutic system]) and immediate-release glipizide in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS--In a multicenter, open-label, randomized, two-way crossover study, 132 patients with NIDDM received daily doses of 5, 20, or 40 mg of either glipizide-GITS or immediate-release glipizide for 8 weeks followed by 8 weeks of the alternate formulation. Plasma glucose, serum insulin, C-peptide, and plasma glipizide levels were measured at fasting and post-Sustacal challenge at the end of 1 and 8 weeks of each treatment phase. HbA1c was measured at the end of weeks 7 and 8 of each treatment phase. RESULTS--Both formulations of glipizide yielded similar mean HbA1c values. However, mean fasting plasma glucose (FPG) levels were significantly lower with glipizide-GITS treatment than with immediate-release glipizide at the end of week 1 (11.0 vs. 11.6 mmol/l; P < 0.01) and at the end of the 8-week treatment phase (10.9 vs. 11.7 mmol/l; P < 0.001). Fasting insulin and C-peptide levels were lower after 5 mg glipizide-GITS vs. immediate-release glipizide. Glucose responses to Sustacal were similar after both formulations of glipizide; however, serum insulin (P < 0.01) and C-peptide responses (P < 0.05) were lower with glipizide-GITS than with immediate-release glipizide treatment at the end of the 8-week treatment phase. Mean plasma glipizide concentrations were stable by the end of week 1, and the concentrations increased proportionately with dose. Once-daily Glipizide-GITS provided effective mean glipizide concentrations (> 50 ng/ml) 24 h after dosing, even at the lowest (5 mg) dose level. Both formulations were well tolerated. CONCLUSIONS--Glipizide-GITS was significantly more effective than immediate-release glipizide in reducing FPG levels. Both formulations reduced postprandial plasma glucose levels equally; however, glipizide-GITS exerted its control in the presence of lower plasma glipizide concentrations in addition to significantly lower insulin and C-peptide levels. This suggests that glipizide-GITS improves insulin sensitivity. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Delayed-Action_Preparations_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_blood_MeSH Glipizide_blood_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Radioimmunoassay_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7886271 ----K E ----T Relation of abnormal composition of lipoproteins to HbA1c levels in non-insulin dependent diabetes. ----A Plasma lipids and VLDL and HDL composition were studied in a control group of 20 non diabetic subjects and in 31 male middle-age patients with non-insulin dependent diabetes treated by oral hypoglycemic agent glibenclamide and a weight maintaining diet. Data for the diabetics were separated based on haemoglobin A1c of less or greater than 7%. VLDL composition abnormalities were more frequent in the diabetic patients with HbA1c of > 7%. VLDL-cholesterol, VLDL-triglycerides and VLDL-phospholipids were high in all diabetics whereas VLDL-apo B increased only in diabetics with HbA1c > 7%. Apo CII and apo CIII levels and also apo CII/apo CIII ratio were also reduced in the diabetic patients with HbA1c levels of more than 7%. Increases in the apo E and apo E/apo C ratio were also seen in the more hyperglycemic diabetics with HbA1c levels > 7%. In contrast apo CII and apo CIII levels and also Apo CII/Apo CIII ratio remained unaltered in diabetic patients with less than 7% HbA1c levels. In these patients increases in the apo E levels were found while the apo E/apo C ratio remained unaltered. All diabetic patients showed increases in HDL-triglycerides and triglyceride/total cholesterol ratio with respect to control. Decreases in HDL-apo AI were also seen in both groups of diabetics, but the HDL-apo AI/HDL-apo AII ratio did not differ from control. ----P Journal_Article ----M M_Apolipoproteins_MeSH S_blood_MeSH Apolipoproteins_blood_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Body_Mass_Index_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Combined_Modality_Therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Life_Style_MeSH M_Lipoproteins_MeSH S_blood_MeSH Lipoproteins_blood_MeSH M_Lipoproteins__HDL_MeSH S_blood_MeSH Lipoproteins__HDL_blood_MeSH M_Lipoproteins__VLDL_MeSH S_blood_MeSH Lipoproteins__VLDL_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phospholipids_MeSH S_blood_MeSH Phospholipids_blood_MeSH M_Smoking_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 7895460 ----K E ----T Antihyperglycaemic efficacy, response prediction and dose-response relations of treatment with metformin and sulphonylurea, alone and in primary combination. ----A The short-term (2-12 weeks) antihyperglycaemic efficacy of metformin (M), glibenclamide (G), and their primary combination (MG) was assessed in a double-blind study including 165 unselected patients with Type 2 diabetes. Patients with diet failure were randomized to M, G or MG. The dose was titrated with a fasting blood glucose concentration (FBG) of < 6.7 mmol l-1 as the target, using at most six dose levels, the first three comprising increasing monotherapy (M or G) or low-dose primary combination (MGL), and the second three add-on therapies (M/G and G/M) and primary combination therapy escalated to high dose (MGH). Success rates were higher on MGL than on monotherapy. The difference in achieving acceptable control (FBG < or = 7.8 mmol 1(-1)) was 70% versus 51% (95% confidence interval 3-36%, p = 0.032). When the drugs were combined, a slightly greater FBG reduction (p = 0.026) was observed, at lower dosage (p = 0.013). The response could not be predicted from body weight, but depended upon initial FBG (p = 0.019) and meal-stimulated C-peptide (p = 0.007). FBG declined progressively with increasing doses of metformin, whereas glibenclamide exerted most of its effect at low dose. Primary combination therapy with metformin and sulphonylurea may be clinically useful. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_blood_MeSH Hyperglycemia_blood_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH S_etiology_MeSH Hyperglycemia_etiology_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7895463 ----K E ----T Glibenclamide vs gliclazide in type 2 diabetes of the elderly. ----A The objective of this study was to compare the effect of two sulphonylureas on the frequency of hypoglycaemic events and glycaemic control in elderly patients with Type 2 diabetes. Twenty-two untreated elderly patients were treated with glibenclamide or gliclazide in a randomized double-blind fashion. Prior to treatment, a biochemical profile, an oral glucose tolerance test, and a 2-h hyperglycaemic glucose clamp (glucose 5.4 mmol l-zs-1 above baseline) were performed. Patients were seen regularly over 6 months to assess glycaemic control and the frequency of hypoglycaemic reactions. Hyperglycaemic clamp studies and oral glucose tolerance tests were repeated at 1 and 6 months. The area under the curve for the oral glucose tolerance test (glibenclamide: 15.5 +/- 0.7; gliclazide: 14.9 +/- 0.8 mmol l-1 (p = NS)) and the haemoglobin A1C (glibenclamide: 7.4 +/- 0.2%; gliclazide: 7.9 +/- 0.5% (p = NS)) were similar at 6 months. Hypoglycaemic reactions were significantly more frequent with glibenclamide than with gliclazide: 17 vs 4 (p < 0.01). Insulin sensitivity index (ml kg-1 min-1 pmol-1 x 100) was increased significantly by glibenclamide but not gliclazide (glibenclamide: 0.284 +/- 0.116 (baseline) vs 0.518 +/- 0.102 (6 months) (p < 0.05), gliclazide: 0.260 +/- 0.048 (baseline) vs 0.358 +/- 0.048 (6 months) (p = NS)). We conclude that glycaemic control was equivalent with the two drugs but the incidence of hypoglycaemic reactions was significantly greater with glibenclamide probably because this drug increases insulin sensitivity to a greater degree. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Gliclazide_MeSH S_adverse_effects_MeSH Gliclazide_adverse_effects_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Male_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7697692 ----K E ----T Effect of insulin-glipizide combination on skeletal muscle capillary basement membrane width in diabetic patients. ----A This study investigated the long-term effect of insulin or the combination of insulin and an oral hypoglycemic compound (glipizide) on the skeletal muscle capillary basement membrane width in insulin-requiring diabetic patients. Seventy diabetic patients were randomized to treatment with either insulin-placebo or insulin-glipizide (5 mg/d) for 3 years. Of these, only 61 patients completed the study; 27 patients received insulin-placebo and 34 patients received insulin-glipizide. Three skeletal muscle (quadriceps femoris) biopsies were performed in all patients over a 3-year period. Glycosylated hemoglobin A1 was determined every 100 +/- 20 days, including plasma glucose levels. Muscle capillary basement membrane width was quantitated by a previously described method. After approximately 16 months, glycosylated hemoglobin A1 decreased significantly in each group from its baseline (P < 0.001 insulin-glipizide group and P < 0.025 insulin-placebo), although no statistically significant difference was seen between the two groups. After 3 years this decrease was statistically significant (P < 0.001) only in the insulin-glipizide group. At baseline, no statistically significant difference was found in the muscle capillary basement membrane width between the two groups. In spite of the significant decrease in glycosylated hemoglobin A1 in both groups after 14 to 16 months, only muscle capillary basement membrane width in the insulin-glipizide group decreased significantly compared with baseline. Patients receiving insulin-placebo showed a gradual increase in the muscle capillary basement membrane width, which after 3 years was significantly higher than baseline (P < 0.02). Although the mechanisms by which the addition of glipizide to insulin treatment reduced the thickening of the muscle capillary basement membrane are not clearly understood, the current findings suggest that diabetic microangiopathy is not necessarily progressive and that prophylaxis may be attained. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Basement_Membrane_MeSH S_drug_effects_MeSH Basement_Membrane_drug_effects_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Muscles_MeSH S_drug_effects_MeSH Muscles_drug_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH ****** 7705380 ----K E ----T Minimal model analyses of insulin sensitivity and glucose-dependent glucose disposal in black and white Americans: a study of persons at risk for type 2 diabetes. ----A We have examined the impact of race and positive family history of type 2 diabetes on glucose/insulin dynamics and the two components of glucose disposal in healthy, first-degree relatives of black and white American patients with type 2 diabetes mellitus who are at a greater risk from the disease and their healthy control subjects. Seventeen black and 15 white relatives were studied. Twenty-two black people and 24 white people, without family history of type 2 diabetes, served as healthy control subjects. Standard oral glucose tolerance test (OGTT) and tolbutamide-modified frequent sampling intravenous glucose tolerance (FSIGT) tests were performed in each subject. Insulin sensitivity index (SI) and glucose effectiveness (SG) were calculated using the MINIMOD method described by Bergman et al. Mean fasting and post-stimulation serum glucose levels were not significantly different in the black and white relatives. However, mean serum insulin responses to oral and/or intravenous stimulation were significantly greater in the blacks than whites, irrespective of positive family history of diabetes. The mean SI was significantly (P < 0.02) lower (52%) in the black (3.67 +/- 0.56) than the white [7.50 +/- 1.93 x 10(-4) min-1 (mU1)-1] relatives. Comparing the healthy controls, the mean SI was significantly (P < 0.02) lower (51%) in black than white controls (4.84 +/- 0.78 vs. 9.71 +/- 1.27 x 10 min-1(mU1)-1]. Mean SG and KG were greater (P < 0.05) in the blacks than whites, irrespective of family history of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS) ----P Journal_Article ----M M_Adult_MeSH P_African_Continental_Ancestry_Group_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_ethnology_MeSH Diabetes_Mellitus__Type_II_ethnology_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH P_European_Continental_Ancestry_Group_MeSH M_Female_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Glucose_Tolerance_Test_MeSH M_Homeostasis_MeSH M_Human_MeSH M_Insulin_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH M_Male_MeSH M_Risk_MeSH ****** 10534139 ----K E ----T A review of metabolic and cardiovascular effects of oral antidiabetic agents: beyond glucose-level lowering. ----A It has become evident that cardiovascular disease is the major cause of morbidity and mortality in type 2 diabetes mellitus. This raises the possibility that glucose lowering agents with other nonglucose-lowering effects, might have added benefits. In this review, we focus on the metabolic and cardiovascular effects of oral antidiabetic agents that go beyond glucose-level lowering. Such effects include lipid modifying actions, antithrombotic and profibrinolytic activities, and direct action at the level of the vessel wall to improve endothelial function or prevent smooth muscle hyperplasia. These additional activities, particularly those seen with the newer oral antidiabetic agents, hold the promise of reducing cardiovascular complications beyond that achievable by glucose lowering alone. ----P Journal_Article Review Review__Tutorial ----M M_Antioxidants_MeSH S_pharmacology_MeSH Antioxidants_pharmacology_MeSH S_therapeutic_use_MeSH Antioxidants_therapeutic_use_MeSH M_Blood_Coagulation_MeSH S_drug_effects_MeSH Blood_Coagulation_drug_effects_MeSH M_Cardiovascular_Diseases_MeSH S_etiology_MeSH Cardiovascular_Diseases_etiology_MeSH S_physiopathology_MeSH Cardiovascular_Diseases_physiopathology_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Cardiovascular_System_MeSH S_drug_effects_MeSH Cardiovascular_System_drug_effects_MeSH M_Chromans_MeSH S_pharmacology_MeSH Chromans_pharmacology_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_drug_therapy_MeSH Hyperlipidemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_Resistance_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH M_Metformin_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 10547208 ----K E ----T The lipoprotein profile differs during insulin treatment alone and combination therapy with insulin and sulphonylureas in patients with Type 2 diabetes mellitus. ----A AIMS: To study whether changes in endogenous insulin secretion at the same glycaemic control affect the plasma concentrations of lipoproteins in patients with Type 2 diabetes mellitus. METHODS: Fifteen patients, age 59+/-2 years (mean +/- SEM), body weight 86.3+/-3.0kg, body mass index 29.6+/-0.9 kg/m2 were treated with sulphonylurea and insulin in combination or with insulin alone in a randomized, double-blind, crossover study. All patients were treated with a multiple daily injection regimen with the addition of glibenclamide 10.5 mg daily or placebo tablets. RESULTS: During combination therapy, the dose of insulin was 25% less (P < 0.002) and there was a 29% increase in plasma C-peptide concentration (P = 0.01). Plasma levels of free insulin were not changed. Plasma levels of sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein (IGFBP)-1 were lowered. There were no differences in the 24-h blood glucose profiles or HbA1c (6.0+/-0.2 vs. 6.3+/-0.2%; P = 0.16). Body weight was similar. There was a significant decrease in plasma LDL cholesterol (3.04+/-0.24 vs. 3.41+/-0.21 mmol/l; P = 0.04), apolipoprotein A1 and of lipoprotein(a) but an increase in VLDL-triglycerides (1.36+/-0.31 vs. 0.96+/-0.16 mmol/l; P = 0.02) during combination therapy. The ratio between LDL cholesterol and apolipoprotein B concentrations was significantly lower during combination therapy (P < 0.01). CONCLUSIONS: Combination therapy with insulin and sulphonylureas increases portal insulin supply and thereby alters liver lipoprotein metabolism when compared with insulin therapy alone. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Human_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin-Like_Growth_Factor_I_MeSH S_analysis_MeSH Insulin-Like_Growth_Factor_I_analysis_MeSH M_Insulin-Like_Growth-Factor_Binding_Protein_1_MeSH S_blood_MeSH Insulin-Like_Growth-Factor_Binding_Protein_1_blood_MeSH M_Lipoproteins_MeSH S_blood_MeSH Lipoproteins_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Lipoproteins__VLDL_MeSH S_blood_MeSH Lipoproteins__VLDL_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sex_Hormone-Binding_Globulin_MeSH S_analysis_MeSH Sex_Hormone-Binding_Globulin_analysis_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 10547209 ----K E ----T The role of sulphonylurea in combination therapy assessed in a trial of sulphonylurea withdrawal. Scandinavian Insulin-Sulphonylurea Study Group Research Team. ----A AIMS: To evaluate the effect of adding insulin to sulphonylurea (SU) and the effect of SU withdrawal on glycaemic control in Type 2 diabetic patients who failed on treatment with SU alone. METHOD: One hundred and seventy-five patients were included in a placebo-controlled multicentre study. During phase I (4 months), premixed insulin was added to glibenclamide therapy; during phase II (1-4 months, depending on response) the insulin dose was fixed, while placebo or glibenclamide replaced the open SU therapy. Insulin sensitivity (KITT), beta-cell function (C-peptide) and metabolic control (HbA1c) were monitored. RESULTS: HbA1c improved from 9.65% to 7.23% (P < 0.0001) during phase I. A high HbA1c value (P < 0.0001) and a high KITT-value (P = 0.045) at baseline were associated with a beneficial response to combination treatment. During phase II, glycaemic control was unchanged in the control (glibenclamide) group. In the placebo group, after SU withdrawal, fasting blood glucose (FBG) increased by 10% or more within 4 weeks in 79% of the patients. Patients (67 of 112) with an FBG increase > or =40% during phase II were defined as 'SU responders' by protocol. In a multivariate analysis only a long duration of diabetes was associated with SU response. There were more GAD-antibody-positive patients among non-responders (18% vs. 4%, P = 0.0263). CONCLUSIONS: Poor glycaemic control in combination with preserved insulin sensitivity and lack of GAD antibodies predicts a beneficial response to combination therapy, which can be achieved in 75% of patients with SU failure. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Multivariate_Analysis_MeSH M_Placebos_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10566566 ----K E ----T Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. ----A This study assessed the safety profile and efficacy of a new combination therapy (insulin lispro plus sulfonylurea) in patients with type 2 diabetes mellitus experiencing secondary oral agent failure. A total of 423 patients were randomly assigned to 3 treatment groups: preprandial insulin lispro plus sulfonylurea (L + S), bedtime neutral protamine Hagedorn (NPH) insulin plus sulfonylurea (N + S), and preprandial insulin lispro plus bedtime NPH insulin (L + N). Mean decreases in glycosylated hemoglobin from baseline were 1.60%+/-1.27% for patients receiving L + S, 1.21%+/-1.21% for those receiving N + S, and 1.40%+/-1.46% for those receiving L + N (within treatment, P<0.001; for L + S vs. N + S, P = 0.003). Fasting blood glucose level was higher in patients receiving L + S (171+/-46.5 mg/dL) or L + N (166+/-52.5 mg/dL) than in those receiving N + S (144+/-48.2 mg/dL) (P<0.001, for both comparisons). Conversely, postprandial blood glucose level was lower in patients receiving L + S (165+/-41.6 mg/dL) or L + N (165+/-46.3 mg/dL) than in those receiving N + S (213+/-58.3 mg/dL) (P<0.001, for both comparisons). The overall rate of hypoglycemia (episodes per 30 days) was not statistically significant when the L + S, N + S, and L + N therapies were compared (0.99+/-1.74 vs. 0.87+/-2.31 vs. 1.16+/-2.38, respectively). The rate of nocturnal hypoglycemia was lowest in the L + S group (0.00+/-0.00 vs. 0.10+/-0.37 for the N + S group vs. 0.15+/-0.54 for the L + N group; P = 0.004). L + S, which has a safety profile equal to those of N + S and L + N, is an effective treatment for patients with type 2 diabetes who experience oral sulfonylurea agent failure. L + S offers an alternative to these established combination therapies in patients whose type 2 diabetes cannot be controlled with a sulfonylurea alone. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH ****** 10566126 ----K E ----T The effect of octreotide on glucose and insulin levels in a patient with type 2 diabetes on glibenclamide. ----A We report the case of a 35 year-old woman with recurrent gastrointestinal bleeding in a type 2 diabetic patient well controlled with glibenclamide. After volume resuscitation and transfusion with packed blood cells an infusion of octreotide at 50 mcg/hr was started. It was decided to start a long term octreotide treatment and the potential effect on her glycemic control was studied. A 75 gram oral glucose tolerance test was performed in two consecutive days with and then without octreotide infusion. With octreotide blood glucose was higher and insulin levels were lower. As clinical indications expand, situations will arise where patients with diabetes on sulfonylureas may require octreotide with a conceivable dramatic worsening of glycemic control. ----P Case_Reports Journal_Article ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemostatics_MeSH S_therapeutic_use_MeSH Hemostatics_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Octreotide_MeSH S_therapeutic_use_MeSH Octreotide_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10576528 ----K E ----T Strategies for better diabetes control in the US. ----A Recent surveys in the US have indicated that 71% of the total diabetes care is delivered by primary care physicians, and that current management practices in terms of the point of initiation of pharmacological treatment fall considerably short of the American Diabetes Association's recommendations. In part, this delay in initiating treatment is due to a fear of provoking hypoglycaemia, which in itself results from a general avoidance of blood glucose monitoring on the part of patients. As a consequence of this apparent disregard for diabetes care, blood glucose concentrations are not adequately controlled in the US and this is reflected in a high incidence of chronic complications, particularly diabetic neuropathy. This is likely to have major cost implications in the future. In an effort to improve the standard of diabetes care, a number of US authorities have begun producing guidelines for primary care physicians, and in the State of Texas, treatment algorithms that incorporate recommendations based on the current US registration trial data have been developed. These recommendations, which have now been adopted by the State of Texas and form part of the minimum standard of care mandated by the State Department of Health's Diabetes Council, provide guidance on the selection and use of oral antidiabetic drugs (including sulphonylureas, metformin, troglitazone, repaglinide and acarbose) in patients with type 2 diabetes, both for glycaemic control and for prevention of cardiovascular complications. It is hoped that organised implementation of these treatment algorithms will produce better control of diabetes and its complications than the current ad hoc strategies used by individual practitioners. ----P Journal_Article Review Review_Literature ----M M_Cardiovascular_Diseases_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_II_prevention_&_control_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Texas_MeSH S_epidemiology_MeSH Texas_epidemiology_MeSH M_United_States_MeSH S_epidemiology_MeSH United_States_epidemiology_MeSH ****** 10587839 ----K E ----T Low-dose ethanol predisposes elderly fasted patients with type 2 diabetes to sulfonylurea-induced low blood glucose. ----A OBJECTIVE: It has previously been demonstrated that the risk of hypoglycemia is low among otherwise healthy elderly fasted patients with type 2 diabetes taking oral sulfonylurea medications. Nevertheless, these agents do cause hypoglycemia in clinical practice, suggesting that accompanying factors must typically be present for hypoglycemia to occur. Ethanol is one putative risk factor that has not been evaluated as a mechanism for low blood glucose among sulfonylurea users. We hypothesized that low concentrations of ethanol would reduce blood glucose concentrations in elderly type 2 diabetic patients receiving sulfonylureas during a short-term fast. RESEARCH DESIGN AND METHODS: A total of 10 type 2 diabetic patients, aged 68 +/- 3 years and receiving 20 mg glyburide daily, participated in a prospective double-blind placebo-controlled in-patient study consisting of two 24-h fasts at least 1 week apart. During hours 14 and 15 of the fasting studies, subjects received intravenous infusions of either 4.35 mmol.kg-1.h-1 ethanol (equivalent to one or two alcoholic beverages) or saline placebo in random order. Ethanol, plasma glucose, insulin, and counterregulatory hormones were assessed very 30-60 min during the final 10 h of the fast. RESULTS: Blood ethanol levels peaked at 17 +/- 2 mmol/l (the lower legal limit of intoxication in New Mexico) during the ethanol study. Plasma glucose concentrations did not differ at baseline (placebo 8.5 +/- 1.8 vs. ethanol 8.7 +/- 1.7 mmol/l; P = 0.50), but nadir plasma glucose was lower after the ethanol infusion compared with placebo (4.4 +/- 1.2 vs. 5.0 +/- 1.4 mmol/l; P = 0.01), and the absolute decline in plasma glucose was also greater during the ethanol study than the placebo study (4.7 +/- 0.9 vs. 3.6 +/- 1.2 mmol/l; P = 0.01). Counterregulatory hormone levels were increased during the ethanol study and nonesterified fatty acid concentrations were suppressed compared with the placebo study. CONCLUSIONS: Low doses of ethanol predispose fasted elderly type 2 diabetic patients to low blood glucose during a short-term fast. This may be one of several mechanisms by which sulfonylurea-induced hypoglycemia occurs in elderly patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH M_Drug_Interactions_MeSH M_Ethanol_MeSH S_administration_&_dosage_MeSH Ethanol_administration_&_dosage_MeSH S_pharmacology_MeSH Ethanol_pharmacology_MeSH P_Fasting_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH M_Human_MeSH M_Human_Growth_Hormone_MeSH S_blood_MeSH Human_Growth_Hormone_blood_MeSH M_Male_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Time_Factors_MeSH ****** 10593133 ----K E ----T Repaglinide--a new compound for the treatment of patients with type 2 diabetes. ----A Repaglinide is a new oral blood glucose lowering agent, a member of the carbamoylmethyl benzoic acid (CMBA) family. Its mechanism of action is partly similar to that of the sulphonylurea: the release of insulin from the pancreatic beta cells is stimulated by closure of ATP-dependent potassium channels. However, repaglinide regulates these channels via a different binding site on the beta cell than glibenclamide, and the drug does not cause insulin release in the absence of glucose, or during voltage-clamping. After oral administration the drug is rapidly absorbed and eliminated. It is therefore used in a meal-related dosing regimen; repaglinide is taken with each main meal. This meal-related use may give a more physiological mimick of daytime insulin requirement than once-daily or twice-daily use of sulphonylurea. Patients using repaglinide are less likely to develop hypoglycaemic symptoms when they miss or postpone a meal in comparison with patients on glibenclamide treatment. In long-term comparative phase 3 clinical studies it was found that repaglinide is equally effective in maintaining glycaemic control as existing sulphonylurea, but it gives significantly better control of postprandial blood glucose levels. Repaglinide can be used as monotherapy both in obese and non-obese type 2 diabetic patients, and is also very effective in combination with drugs like metformin or thiazolidines. Because of its excretion through liver and bile it is also an attractive drug for diabetic patients with diminished kidney function, especially the elderly diabetic. Although the overall incidence of hypoglycaemia was similar during use of repaglinide and of sulphonylurea, fewer serious hypoglycaemic episodes were observed in repaglinide-treated patients. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Carbamates_MeSH S_chemistry_MeSH Carbamates_chemistry_MeSH S_classification_MeSH Carbamates_classification_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Food_Habits_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_chemistry_MeSH Hypoglycemic_Agents_chemistry_MeSH S_classification_MeSH Hypoglycemic_Agents_classification_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Intestinal_Absorption_MeSH M_Metabolic_Clearance_Rate_MeSH M_Piperidines_MeSH S_chemistry_MeSH Piperidines_chemistry_MeSH S_classification_MeSH Piperidines_classification_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH ****** 10594485 ----K E ----T Lack of interaction between thioctic acid, glibenclamide and acarbose. ----A AIMS: Thioctic acid (TA), glibenclamide and acarbose are widely used to either alone or concomitantly treat patients suffering from noninsulin-dependent diabetes (NIDDM). This study systematically investigated drug-drug interactions between TA and glibenclamide and TA and acarbose. METHODS: Fourteen male and 10 female healthy volunteers participated a randomized, open three period cross over trial (treatments A-C) followed by a fourth period (treatment D). A baseline profile for plasma insulin and glucose concentrations, variables which served as pharmacodynamic measures, was assessed before entering the trial. Treatments were A=600 mg TA orally, B=3.5 mg glibenclamide orally, C=600 mg TA+3.5 mg glibenclamide, D=600 mg TA+50 mg acarbose. Time courses of R(+)-TA and S(-)-TA as well as glibenclamide concentrations were measured with specific analytical methods. RESULTS: There was no clinically relevant change of TA enantiomer pharmacokinetics by glibenclamide or acarbose. Also, glibenclamide pharmacokinetics were not altered by TA to a clinically meaningful extent. Plasma insulin and glucose concentrations did not indicate an interaction between TA and glibenclamide or TA and acarbose. Glibenclamide had the expected effect on insulin and glucose levels independent of comedication. There were only minor and short lasting adverse events with the majority being (expected) hypoglycaemic symptoms occurring during the treatments with glibenclamide. CONCLUSIONS: Coadministration of single doses of TA and glibenclamide or TA and acarbose does not appear to cause drug-drug interactions. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acarbose_MeSH S_pharmacokinetics_MeSH Acarbose_pharmacokinetics_MeSH S_pharmacology_MeSH Acarbose_pharmacology_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cross-Over_Studies_MeSH M_Drug_Interactions_MeSH M_Enzyme_Inhibitors_MeSH S_pharmacokinetics_MeSH Enzyme_Inhibitors_pharmacokinetics_MeSH S_pharmacology_MeSH Enzyme_Inhibitors_pharmacology_MeSH M_Female_MeSH M_Glyburide_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Thioctic_Acid_MeSH S_pharmacokinetics_MeSH Thioctic_Acid_pharmacokinetics_MeSH S_pharmacology_MeSH Thioctic_Acid_pharmacology_MeSH ****** 10605995 ----K E ----T Oral pharmacologic management of type 2 diabetes. ----A Epidemiologic and interventional studies have led to lower treatment targets for type 2 diabetes (formerly known as non-insulin-dependent diabetes), including a glycosylated hemoglobin level of 7 percent or less and a before-meal blood glucose level of 80 to 120 mg per dL (4.4 to 6.7 mmol per L). New oral medications make these targets easier to achieve, especially in patients with recently diagnosed diabetes. Acarbose, metformin, miglitol, pioglitazone, rosiglitazone and troglitazone help the patient's own insulin control glucose levels and allow early treatment with little risk of hypoglycemia. Two new long-acting sulfonylureas (glimepiride and extended-release glipizide) and a short-acting sulfonylurea-like agent (repaglinide) simply and reliably augment the patient's insulin supply. Combinations of agents have additive therapeutic effects and can restore glucose control when a single agent is no longer successful. Oral therapy for early type 2 diabetes can be relatively inexpensive, and evidence of its cost-effectiveness is accumulating. ----P Journal_Article Review Review__Tutorial ----M M_Acarbose_MeSH S_therapeutic_use_MeSH Acarbose_therapeutic_use_MeSH M_Administration__Oral_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH M_Drug_Therapy__Combination_MeSH M_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Enzyme_Inhibitors_therapeutic_use_MeSH M_Glucosamine_MeSH S_analogs_&_derivatives_MeSH Glucosamine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Glucosamine_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_economics_MeSH Hypoglycemic_Agents_economics_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_United_States_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 10611897 ----K E ----T Improving management of type 2 diabetes mellitus: 4. Meglitinides. ----A ----P Journal_Article ----M M_Carbamates_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_contraindications_MeSH Carbamates_contraindications_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_contraindications_MeSH Hypoglycemic_Agents_contraindications_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Piperidines_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_contraindications_MeSH Piperidines_contraindications_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH ****** 10631622 ----K I ----T Repaglinide in type 2 diabetes: a 24-week, fixed-dose efficacy and safety study. ----A In this 24-week multicenter, double-blind, randomized, fixed-dose trial, 361 patients having type 2 diabetes received daily preprandial treatment with placebo (n = 75), repaglinide 1 mg (n = 140), or repaglinide 4 mg (n = 146). By a last-observation carried-forward calculation, repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose (FPG) values (by -47 mg/dL or -49 mg/dL) while the placebo group had increased FPG values (by 19 mg/dL). For the repaglinide treatment groups at the end of the study, changes in HbA1c from baseline values ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no events of severe hypoglycemia. Nearly all hypoglycemic symptom episodes had blood glucose levels above 45 mg/dL. Repaglinide was well tolerated in a preprandial fixed-dose regimen of 1 mg or 4 mg, assigned without adjustment for clinical parameters. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Patient_Dropouts_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH M_Treatment_Outcome_MeSH ****** 10641958 ----K E ----T The use of sulphonylureas in the elderly. ----A Type 2 diabetes mellitus is a heterogeneous disorder characterised by defects in insulin secretion as well as reduced insulin action. During aging, glucose intolerance will gradually develop, and this is manifested primarily by an increase in the postprandial blood glucose response while fasting blood glucose levels are often less elevated. Abnormal beta-cell secretion of insulin is a main feature of this. Treatment of elderly patients with type 2 diabetes mellitus focuses on reduction of (hyperglycaemic) complaints and prevention of the development or progression of secondary complications. Although regular physical activity and dietary measures, aiming at bodyweight normalisation, are the cornerstones of therapy, pharmacological treatment with oral blood glucose lowering-agents often proves necessary to control the hyperglycaemia. In the United Kingdom Prospective Diabetes Study (UKPDS) it was clearly shown that patients with type 2 diabetes mellitus who were intensively treated with oral blood glucose-lowering agents or insulin developed less microvascular complications. The question whether achievement of strict metabolic control is also of benefit in elderly patients, is still unanswered. Sulphonylureas are drugs which stimulate insulin secretion by enhancing the release of insulin from the pancreatic beta-cells without an effect on insulin synthesis. They are frequently used in the treatment of type 2 diabetes mellitus, and several preparations are available. In general, there are no major differences in effectiveness between the various sulphonylureas. Long term treatment with sulphonylureas will decrease fasting and postprandial plasma glucose levels by 3 to 5 mmol/L, and glycosylated haemoglobin by 20%. However, after its initial decline, plasma glucose level will often go up slightly during the following months to years. Sulphonylureas are usually well tolerated. Hypoglycaemia is the most frequently occurring adverse effect, which may be very serious and damaging in the elderly. It has been associated primarily with long-acting sulphonylureas, like chlorpropamide and glibenclamide (glyburide). Hypoglycaemic episodes may trigger serious events like myocardial infarction or stroke. Therefore, shorter-acting compounds like tolbutamide and gliclazide have been relatively well tolerated and appear to be the best choice to treat elderly patients. It is advisable to start with a low dose and increase the dose, when needed, in small steps. The efficacy of sulphonylureas is much greater when they are taken before a meal. Because of the fact that type 2 diabetes mellitus is a progressive disease, and residual beta-cell function decreases with time, insulin therapy may ultimately be warranted in a significant number of patients. ----P Journal_Article Review Review__Tutorial ----M M_Aged_MeSH P_Aging_MeSH S_drug_effects_MeSH Aging_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 10643211 ----K E ----T New directions in type 2 diabetes mellitus: an update of current oral antidiabetic therapy. ----A This article reviewed the relevant literature including published clinical trials and reviews on currently available oral hypoglycemic agents. Results showed that the benefits of glycemic control have been established through multiple clinical trials. Long-term control of blood glucose levels in type 1 and type 2 diabetic patients will decrease the incidence and prolong the time until progression of diabetic retinopathy, nephropathy, and neuropathy. Our increased understanding of the pathophysiology behind type 2 diabetes has led to the development of many new agents that are aimed at treating the underlying insulin resistance and relative insulinopenia. The sulfonylureas as a group have been used for many years and act by stimulating insulin secretion. They are useful alone or as combination therapy with insulin or another oral hypoglycemic agent. The biguanides act by decreasing hepatic glucose production and by increasing peripheral insulin sensitivity. The alpha-glucosidase inhibitors act nonsystemically by blocking the metabolism of digested polysaccharides and therefore lowering the amount of carbohydrate absorbed in a meal. Benzoic acid derivatives act in a manner similar to that of sulfonylureas by enhancing pancreatic insulin production. They offer a shorter duration of action, lowering the risk of hypoglycemia. The thiazolidinediones increase peripheral insulin sensitivity and are effective as both monotherapy and combination therapy. Oral hypoglycemic agents, when properly administered, are very effective in controlling type 2 diabetes and preventing long-term complications. ----P Journal_Article Review Review__Tutorial ----M M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 10664920 ----K I ----T Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease. ----A Repaglinide is a novel insulin secretagogue developed in response to the need for a fast-acting, oral prandial glucose regulator for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Repaglinide is metabolized mainly in the liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. This open, parallel-group study compared the pharmacokinetics and tolerability of a single 4 mg dose of repaglinide in healthy subjects (n = 12) and patients with chronic liver disease (CLD) (n = 12). Values for AUC and Cmax were significantly higher in CLD patients compared with healthy subjects, and the MRT was prolonged in CLD patients. Values for tmax did not differ between the groups, but t1/2 was significantly prolonged in CLD patients compared with previously determined values in healthy subjects. AUC was inversely correlated with caffeine clearance in CLD patients but not in healthy subjects. Blood glucose profiles were similar in both groups. Adverse events (principally hypoglycemia) were similar in the two groups; none was serious. Repaglinide clearance is significantly reduced in patients with hepatic impairment; the agent should be used with caution in this group. ----P Clinical_Trial Clinical_Trial__Phase_I Journal_Article ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Blood_Proteins_MeSH S_metabolism_MeSH Blood_Proteins_metabolism_MeSH M_Caffeine_MeSH S_pharmacokinetics_MeSH Caffeine_pharmacokinetics_MeSH M_Carbamates_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH M_Chronic_Disease_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Liver_Diseases_MeSH S_metabolism_MeSH Liver_Diseases_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH M_Protein_Binding_MeSH ****** 10663449 ----K I ----T Pharmacodynamics and pharmacokinetics of intravenous glibenclamide in Caucasian and Chinese patients with type-2 diabetes. ----A OBJECTIVE: We analysed the kinetics and effects of glibenclamide (Gb) on glucose, insulin and proinsulin secretion in two ethnic groups (10 in each) of type-2 diabetic patients, one of Caucasian, the other of Chinese origin. BACKGROUND: Diabetes mellitus type 2 is a global disease affecting all ethnic groups. There are ethnic differences in both the prevalence and metabolic characteristics of the disease. Important interethnic pharmacodynamic and pharmacokinetic differences have been reported for several drugs. With few exceptions, detailed studies on sulphonylurea are lacking. MATERIAL AND METHODS: The patients were studied on two occasions when either no Gb (control) or 1.25 mg Gb was administered i.v., immediately before the administration of a 75-g oral glucose tolerance test. Concentrations of insulin and proinsulin were determined by means of radioimmunoassay without cross-reactivities. Gb concentration was determined using high-performance liquid chromatography. Pharmacodynamic results were calculated using net areas under the curves, with basal values set as zero. A P value less than 0.05 was considered significant. RESULTS: When glucose was administered orally without Gb, Chinese patients had higher plasma glucose increases at 10 min (7.6 mmol/l x min vs 2.6 mmol/l x min) and higher increases of plasma insulin levels than Caucasians at both 10 min (198 pmol/l x min vs 54 pmol/l x min) and 30 min (2286 pmol/l x min vs 1198 pmol/l x min). When Gb was administered, the plasma glucose increases were reduced, and the increases of serum insulin and proinsulin levels were greater in both ethnic groups. Compared with the basal values (-1 min), proinsulin/insulin ratios (RPI) were lowest at 10-30 min, followed by an increase. Chinese patients had higher increases of serum insulin levels at 10 min (1109 pmol/l x min vs 550 pmol/l x min) and a lower RPI at 30 min (6. 0% vs 7.6%) and 240 min (15.0% vs 21.0%) relative to Caucasians. Serum Gb data were best fitted to a biexponential i.v. model. There were no interethnic differences in any of the pharmacokinetic parameters. CONCLUSION: In summary, following oral glucose administration without Gb, Chinese type-2 diabetic patients had higher plasma insulin levels but also higher plasma glucose levels during the first 10 min, which might reflect reduced insulin sensitivity or more rapid glucose absorption. Gb augmented glucose-induced release of both insulin and proinsulin in both ethnic groups; the effect on insulin secretion was more pronounced. In conclusion, minor pharmacodynamic but no pharmacokinetic differences were found between the two groups. It seems appropriate to employ the same dosage principles when using Gb in Caucasians and Chinese. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH P_Asian_Continental_Ancestry_Group_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Chromatography__High_Pressure_Liquid_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH P_European_Continental_Ancestry_Group_MeSH M_Female_MeSH M_Glucose_MeSH S_administration_&_dosage_MeSH Glucose_administration_&_dosage_MeSH M_Glyburide_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Infusions__Intravenous_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH M_Radioimmunoassay_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 10688395 ----K E ----T Economic assessment of troglitazone as an adjunct to sulfonylurea therapy in the treatment of type 2 diabetes. ----A OBJECTIVE: To assess the economic efficiency of adding troglitazone to sulfonylurea therapy to improve glycemic control. BACKGROUND: Despite the high prevalence of type 2 diabetes, existing treatment strategies often fail. New oral agents give a wider segment of the population with type 2 diabetes hope of achieving near-normal blood-glucose levels. Troglitazone, a novel chemical entity, is one promising new agent. METHODS: We conducted an economic analysis based on glycemic-control data from a randomized clinical trial comparing troglitazone with placebo, each added to glyburide. A patient simulation model was used to translate these data to long-term outcomes associated with diabetes. Patients had poorly controlled type 2 diabetes mellitus despite glyburide therapy. Risk functions of developing and progressing through nephropathy, retinopathy, neuropathy, hypoglycemia, and macrovascular disease were developed from the Diabetes Control and Complications Trial and large epidemiologic studies. Cost estimates were based on data from 5 states, all payor databases, surveys, and literature. The main outcomes of the model were cost-consequences, number of patients developing each type of complication, mean time to development of the complication, cost per life-year gained (LYG), and cost per quality-adjusted life-year. RESULTS: The model predicts that for every 1000 patients treated with troglitazone, the improved glycemic control could mean that 95 to 140 fewer patients would experience one of the most severe diabetic complications (eg, blindness, end-stage renal disease, amputation), which may increase life expectancy by 2.0 years. These benefits are obtained at an additional $2100 per LYG (undiscounted). The ratio remains <$50,000 per LYG for most variations in input. CONCLUSIONS: The clinical trial demonstrated that troglitazone + glyburide improves glycemic control compared with glyburide alone. Based on these results, the model estimates fewer diabetic complications at a cost well below accepted cost-effective thresholds. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Chromans_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH S_economics_MeSH Chromans_economics_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Cohort_Studies_MeSH M_Cost-Benefit_Analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH M_Drug_Costs_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_economics_MeSH Hypoglycemic_Agents_economics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Models__Economic_MeSH M_Randomized_Controlled_Trials_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_economics_MeSH Sulfonylurea_Compounds_economics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_economics_MeSH Thiazoles_economics_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_United_States_MeSH ****** 10691158 ----K E ----T Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. ----A AIMS: This study was designed to test the efficacy and safety of low-dose rosiglitazone, a potent, insulin-sensitizing thiazolidinedione, in combination with sulphonylurea in Type 2 diabetic patients. METHODS: For the intention-to-treat analysis, 574 patients (59% male, mean age 61 years) were available, randomized to receive 26 weeks of twice-daily placebo (n = 192), rosiglitazone 1 mg (n = 199) or rosiglitazone 2 mg (n = 183) in addition to existing sulphonylurea treatment with gliclazide (47.6% of patients), glibenclamide (41.8%) or glipizide (9.4%) (two patients were taking carbutamide or glimepiride). Change in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), fructosamine, insulin, C-peptide, albumin, and lipids were measured, and safety was evaluated. RESULTS: Mean baseline HbA1c was 9.2% and FPG was 11.4 mmol/l. Rosiglitazone at doses of 1 and 2 mg b.d. plus sulphonylurea produced significant decreases, compared with sulphonylurea plus placebo, in HbA1c (-0.59% and -1.03%, respectively; both P<0.0001) and FPG (1.35 mmol/l and 2.44 mmol/l, respectively; both P<0.0001). Both HDL-cholesterol and LDL-cholesterol increased and potentially beneficial decreases in non-esterified fatty acids and gamma glutamyl transpeptidase levels were seen in both rosiglitazone groups. The overall incidence of adverse experiences was similar in all three treatment groups, with no significant cardiac events, hypoglycaemia or hepatotoxicity. CONCLUSIONS: Overall, the combination of rosiglitazone and a sulphonylurea was safe, well tolerated and effective in patients with Type 2 diabetes. ----P Clinical_Trial Clinical_Trial__Phase_III Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Europe_MeSH M_Female_MeSH M_Fructosamine_MeSH S_blood_MeSH Fructosamine_blood_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Safety_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 10718777 ----K I ----T Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes. ----A AIMS: Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Caucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes. METHODS: Subjects were on a stable dose of 80 mg gliclazide twice daily, took 160 mg on the morning of study and had a standard breakfast. No further gliclazide was given over the next 48 h. Regular blood samples were drawn for serum glucose, insulin and gliclazide assay. Gliclazide was measured using h.p.l.c. Noncompartmental analysis was used to describe primary data. A multicompartment model incorporating entero-hepatic recirculation was fitted to group mean serum gliclazide profiles. RESULTS: The Caucasians were older than the Aborigines (mean +/- s.d. age 53.4 +/- 12.2 vs 40.3 +/- 6.9 years, P < 0.05) but had similar diabetes duration, body mass index and glycated haemoglobin. Noncompartmental analysis revealed no between-group differences in gliclazide kinetics. Post-breakfast serum glucose and insulin responses were also similar apart from a longer time to maximum concentration (tmax) for glucose amongst the Aborigines (2.6 +/- 0.4 vs 2.2 +/- 0. 3 h in Caucasians; P = 0.024). Gliclazide tmax exhibited a skewed unimodal distribution and was not associated with gliclazide maximum concentration, or glucose or insulin responses. Most patients had a serum gliclazide profile suggestive of enterohepatic recirculation and/or biphasic absorption. Model-derived estimates of the extent of putative enterohepatic recirculation were 30% and 20% of dose in Caucasians and Aborigines, respectively. CONCLUSIONS: Gliclazide is equally effective in Caucasian and Aboriginal diabetic patients. The pharmacokinetics of oral gliclazide appear more complex than previously thought. Gliclazide pharmacodynamics are unrelated to rate and extent of absorption, consistent with a threshold concentration for hypoglycaemic effect. ----P Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Australia_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH P_European_Continental_Ancestry_Group_MeSH M_Female_MeSH M_Gliclazide_MeSH S_pharmacokinetics_MeSH Gliclazide_pharmacokinetics_MeSH S_pharmacology_MeSH Gliclazide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH P_Oceanic_Ancestry_Group_MeSH M_Postprandial_Period_MeSH S_physiology_MeSH Postprandial_Period_physiology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10746824 ----K I ----T Comparative efficacy and potency of long-term therapy with glipizide or glyburide in patients with type 2 diabetes mellitus. ----A BACKGROUND: Long-term studies on the comparative efficacy and relative potency of glipizide and glyburide are sparse and controversial. METHODS: In a randomized prospective trial, we compared the effectiveness and relative potency of glipizide and glyburide over a 15-month period in 18 patients with type 2 diabetes mellitus (DM2) (9 on glyburide and 9 on glipizide) who were unresponsive to diet therapy. Glycemic control was assessed using 4 methods: 1) quarterly fasting plasma glucose (FPG), and 2-hour postprandial plasma glucose after a standard breakfast; 2) insulin and glucose response to Sustacal (test meal) challenge every 3 to 6 months; 3) quarterly hemoglobin A1c; and 4) intravenous glucose tolerance testing every 6 months to measure first and second phase insulin secretion. Patient characteristics were similar in each treatment group. RESULTS: Similar doses of glipizide (11 mg/day) or glyburide (10 mg/day) resulted in comparable reduction of FPG and hemoglobin A1c and increase in first phase insulin response to intravenous glucose tolerance testing. There was greater reduction in FPG and 2-hour postprandial plasma glucose with glipizide than with glyburide in 6 months. Contrary to the Physicians' Desk Reference, but consistent with another short-term study, our long-term study demonstrated that glipizide and glyburide are equipotent at similar doses in controlling hyperglycemia in DM2. CONCLUSIONS: Glipizide and glyburide are effective in controlling hyperglycemia with similar doses in DM2. Glipizide exhibits greater reduction in FPG and 2PPG at 6 months. Additional studies are needed to validate equipotency of these drugs. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Therapeutic_Equivalency_MeSH M_Time_Factors_MeSH M_Treatment_Outcome_MeSH ****** 10746009 ----K E ----T [Repaglinide in combination therapy in type 2 diabetes] ----A In addition to dietary and lifestyle changes, standing as the cornerstone of type 2 diabetes care, pharmacological treatments, whether as single or multidrug patterns, are often necessary for an efficient blood glucose control. Besides insulin, four different oral antidiabetic drug categories are available, each of them acting through different and potentially synergistic ways. Oral antidiabetic drugs include: 1) biguanides acting through the reduction of hepatic glucose production and are most efficient in obese patients; 2) alpha-glucosidase inhibitors delaying carbohydrate intestinal absorption; 3) thiazolidinediones or "glitazones", acting as insulin sensitizers; 4) insulin secretion enhancers, mainly including sulfonylureas, which increase insulin secretion and are being credited by a long clinical usage; these are now joined by the new generation of insulin secretion enhancers, led by repaglinide, which can mimic the physiological insulin secretion profile by a specific stimulatory effect on beta-cells characterized by its fast onset and short half-life. Obviously, the combination of these different antidiabetic drugs, by targetting different synergistic and additive pathways, can help to further improve blood glucose. ----P Journal_Article ----M M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_classification_MeSH Hypoglycemic_Agents_classification_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Islets_of_Langerhans_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH ****** 10776834 ----K E ----T Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus. ----A Miglitol, the first pseudomonosaccharide alpha-glucosidase inhibitor, smooths postprandial peak plasma glucose levels and thus improves glycaemic control, which is reflected in a reduced glycosylated haemoglobin (HbA1c) level. This oral antihyperglycaemic agent is indicated for the treatment of patients with type 2 diabetes mellitus. Miglitol is generally well tolerated and, unlike the sulphonylurea agents, is not associated with bodyweight gain or hypoglycaemia when administered as monotherapy. The drug is systemically absorbed but is not metabolised and is rapidly excreted via the kidneys. Clinical trials with miglitol (usually 50 or 100 mg 3 times daily) in patients with type 2 diabetes mellitus consistently demonstrated a significant improvement in glycaemic control for periods of 6 to 12 months. There were also marked reductions in postprandial serum insulin levels, although miglitol generally had no effect on fasting insulin levels. In comparative studies miglitol had similar efficacy to acarbose, but at lower therapeutic doses (50 and 100 mg 3 times daily, respectively). In addition, although sulphonylurea agents provided superior reductions in HbA1c levels, miglitol provided similar or superior reductions in fasting and postprandial plasma glucose levels. In combination with other oral antidiabetic agents or insulin, miglitol improved glycaemic control in patients in whom metabolic control was suboptimal despite dietary and pharmacological intervention. Most adverse events associated with miglitol treatment involve disturbances of the gastrointestinal tract (most common effects are flatulence, abdominal pain and diarrhoea). These symptoms are usually dose dependent, mild to moderate in severity, occur at the onset of treatment, decline with time and resolve promptly on discontinuation of the drug or with dosage adjustment. As monotherapy, miglitol is not associated with hypoglycaemia, but concomitant use with other oral antidiabetic agents may necessitate dosage adjustment of the other agents. Miglitol had no significant effects on renal, cardiovascular, respiratory or haematological parameters in long term studies. No dosage adjustments are required in elderly patients, in those with hepatic impairment or in those with mild to moderate renal insufficiency. Conclusions: In long term, well designed trials miglitol reduces fasting and postprandial plasma glucose levels, thus improving glycaemic control, which is reflected in a reduced HbA1c level in patients with type 2 diabetes mellitus. Most adverse events associated with miglitol involve disturbances of the gastrointestinal tract. This agent is a useful first-line therapy in patients with type 2 diabetes mellitus insufficiently controlled by diet alone and as second-line or as adjuvant therapy in those insufficiently controlled with diet and sulphonylurea agents. Miglitol may prove particularly beneficial in elderly patients and those with hepatic impairment or mild to moderate renal impairment, in whom other oral antidiabetic agents are contraindicated or need to be used with caution. ----P Journal_Article Review Review__Tutorial ----M M_Biological_Availability_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Administration_Schedule_MeSH M_Glucosamine_MeSH S_adverse_effects_MeSH Glucosamine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Glucosamine_analogs_&_derivatives_MeSH S_pharmacology_MeSH Glucosamine_pharmacology_MeSH S_therapeutic_use_MeSH Glucosamine_therapeutic_use_MeSH M_Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH Glucosidases_antagonists_&_inhibitors_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Intestinal_Absorption_MeSH M_Liver_MeSH S_drug_effects_MeSH Liver_drug_effects_MeSH S_metabolism_MeSH Liver_metabolism_MeSH M_Postprandial_Period_MeSH M_Randomized_Controlled_Trials_MeSH M_Tissue_Distribution_MeSH ****** 10784228 ----K I ----T Effects of the new oral hypoglycaemic agent nateglinide on insulin secretion in Type 2 diabetes mellitus. ----A AIMS: The new non-sulphonylurea oral hypoglycaemic agent nateglinide has been shown to enhance insulin secretion in animals and in healthy human volunteers and thus offers a potential advance in the treatment of Type 2 diabetes mellitus. This study examined whether nateglinide can enhance insulin secretion, and particularly the first phase insulin response, in patients with Type 2 diabetes. METHODS: A double-blind, placebo-controlled trial, examining the effects of a single oral dose of 60 mg nateglinide, given 20 min prior to an intravenous glucose tolerance test (IGTT), on insulin secretion in 10 otherwise healthy Caucasian men with recently diagnosed Type 2 diabetes (duration since diagnosis 0-44 months). RESULTS: Insulin secretion (both overall and first phase) was significantly increased by nateglinide (P < 0.001), as were C-peptide (P < 0.001) and proinsulin (P < 0.001) secretion. Overall glucose concentrations following glucose challenge were lower after nateglinide than after placebo (P = 0.05). CONCLUSIONS: Nateglinide significantly increases insulin secretion in Type 2 diabetic patients, in particular restoring the first phase insulin response. Further study is necessary to determine the effects of chronic administration on insulin secretion and blood glucose concentration. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_secretion_MeSH C-Peptide_secretion_MeSH M_Cyclohexanes_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Kinetics_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Placebos_MeSH M_Proinsulin_MeSH S_secretion_MeSH Proinsulin_secretion_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10806608 ----K I ----T Lack of interaction between tolcapone and tolbutamide in healthy volunteers. ----A To assess the effect of tolcapone (an inhibitor of cytochrome P450 [CYP] 2C9 in vitro) on the pharmacokinetics and hypoglycemic effect of the CYP 2C9 substrate tolbutamide, 12 healthy male volunteers were randomized to receive a single dose of tolbutamide 500 mg plus either placebo or tolcapone 200 mg after an overnight fast and 30 minutes after the start of a 6.5-hour 5% glucose infusion (150 mL/h). The participants crossed over to receive the alternative regimen after a washout period of at least 7 days. Tolcapone had no effect on the pharmacokinetics of tolbutamide or its metabolites and did not influence the effect of tolbutamide on plasma glucose concentrations. No serious adverse events or abnormal laboratory results or vital signs were reported. In conclusion, clinically relevant drug-drug interactions between tolcapone and tolbutamide when given together in clinical practice appear unlikely. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Area_Under_Curve_MeSH P_Aryl_Hydrocarbon_Hydroxylases_MeSH M_Benzophenones_MeSH S_adverse_effects_MeSH Benzophenones_adverse_effects_MeSH S_pharmacology_MeSH Benzophenones_pharmacology_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cross-Over_Studies_MeSH M_Cytochrome_P-450_Enzyme_System_MeSH S_antagonists_&_inhibitors_MeSH Cytochrome_P-450_Enzyme_System_antagonists_&_inhibitors_MeSH S_metabolism_MeSH Cytochrome_P-450_Enzyme_System_metabolism_MeSH M_Drug_Interactions_MeSH M_Enzyme_Inhibitors_MeSH S_adverse_effects_MeSH Enzyme_Inhibitors_adverse_effects_MeSH S_pharmacology_MeSH Enzyme_Inhibitors_pharmacology_MeSH M_Glucose_MeSH S_pharmacokinetics_MeSH Glucose_pharmacokinetics_MeSH M_Headache_MeSH S_chemically_induced_MeSH Headache_chemically_induced_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Infusions__Intravenous_MeSH M_Male_MeSH M_Single-Blind_Method_MeSH P_Steroid_16-alpha-Hydroxylase_MeSH M_Steroid_Hydroxylases_MeSH S_antagonists_&_inhibitors_MeSH Steroid_Hydroxylases_antagonists_&_inhibitors_MeSH S_metabolism_MeSH Steroid_Hydroxylases_metabolism_MeSH M_Tolbutamide_MeSH S_blood_MeSH Tolbutamide_blood_MeSH S_metabolism_MeSH Tolbutamide_metabolism_MeSH S_pharmacokinetics_MeSH Tolbutamide_pharmacokinetics_MeSH ****** 10817086 ----K E ----T Efficacy and safety of cerivastatin for type 2 diabetes and hypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators. ----A BACKGROUND: The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia. METHODS: This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks. RESULTS: Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period. CONCLUSIONS: Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Chi-Square_Distribution_MeSH M_Coronary_Disease_MeSH S_prevention_&_control_MeSH Coronary_Disease_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Human_MeSH M_Hydroxymethylglutaryl-CoA_Reductase_Inhibitors_MeSH S_therapeutic_use_MeSH Hydroxymethylglutaryl-CoA_Reductase_Inhibitors_therapeutic_use_MeSH M_Hypercholesterolemia_MeSH S_drug_therapy_MeSH Hypercholesterolemia_drug_therapy_MeSH M_Hypertriglyceridemia_MeSH S_drug_therapy_MeSH Hypertriglyceridemia_drug_therapy_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Pyridines_MeSH S_therapeutic_use_MeSH Pyridines_therapeutic_use_MeSH M_Risk_Factors_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10819233 ----K E ----T Erythromycin improves glycaemic control in patients with Type II diabetes mellitus. ----A AIMS/HYPOTHESIS: Erythromycin mimics the effect of the gastrointestinal hormone motilin by binding to its receptor and acting as a motilin agonist. We recently found that motilin stimulates insulin secretion at lower doses than doses required to stimulate gastric contractile activity. We studied the effects of erythromycin on insulin secretion and glycaemic control in patients with diabetes mellitus. METHODS: Inpatients (n = 34) with Type II (non-insulin-dependent) diabetes mellitus were randomly assigned to receive either erythromycin (400 mg orally three times a day, n = 19) or a placebo (n = 15) for 1 week (first study). Another 34 outpatients with Type II diabetes were also treated with erythromycin (200 mg orally three times a day, n = 17) or a placebo (n = 17) for 4 weeks (second study). Finally, nine inpatients with Type II diabetes and eight normal control subjects received intravenous erythromycin (10 mg x kg(-1) x h(-1)) or saline infusion and insulin secretion was examined (third study). RESULTS: Erythromycin lowered fasting blood glucose and fructosamine concentrations (p < 0.01) and increased basal as well as glucose-stimulated insulin secretion (p <0.05-0.01) (first study). Low doses of erythromycin treatment for 4 weeks also significantly improved glycaemic control in Type II diabetic patients (second study). Erythromycin infusion significantly increased plasma insulin and decreased glucose concentrations in Type II diabetic and control subjects and greatly potentiated glucose-induced insulin secretion in the latter (third study). CONCLUSION/INTERPRETATION: These results indicate that erythromycin given orally has an antidiabetogenic effect and therefore erythromycin derivatives that lack the antibacterial activity could have a therapeutic value in Type II diabetic patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Erythromycin_MeSH S_administration_&_dosage_MeSH Erythromycin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Erythromycin_therapeutic_use_MeSH M_Female_MeSH M_Gastrointestinal_Agents_MeSH S_administration_&_dosage_MeSH Gastrointestinal_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Gastrointestinal_Agents_therapeutic_use_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10818026 ----K I ----T Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (UKPDS 41). United Kingdom Prospective Diabetes Study Group. ----A OBJECTIVE: To estimate the cost effectiveness of conventional versus intensive blood glucose control in patients with type 2 diabetes. DESIGN: Incremental cost effectiveness analysis alongside randomised controlled trial. SETTING: 23 UK hospital clinic based study centres. PARTICIPANTS: 3867 patients with newly diagnosed type 2 diabetes (mean age 53 years). INTERVENTIONS: Conventional (primarily diet) glucose control policy versus intensive control policy with a sulphonylurea or insulin. Main outcome measures: Incremental cost per event-free year gained within the trial period. RESULTS: Intensive glucose control increased trial treatment costs by pound 695 (95% confidence interval pound 555 to pound 836) per patient but reduced the cost of complications by pound 957 (pound 233 to pound 1681) compared with conventional management. If standard practice visit patterns were assumed rather than trial conditions, the incremental cost of intensive management was pound 478 (-pound 275 to pound 1232) per patient. The within trial event-free time gained in the intensive group was 0.60 (0.12 to 1.10) years and the lifetime gain 1.14 (0.69 to 1.61) years. The incremental cost per event-free year gained was pound 1166 (costs and effects discounted at 6% a year) and pound 563 (costs discounted at 6% a year and effects not discounted). CONCLUSIONS: Intensive blood glucose control in patients with type 2 diabetes significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Blood_Glucose_Self-Monitoring_MeSH S_economics_MeSH Blood_Glucose_Self-Monitoring_economics_MeSH M_Cost-Benefit_Analysis_MeSH M_Costs_and_Cost_Analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Nephropathies_MeSH S_economics_MeSH Diabetic_Nephropathies_economics_MeSH M_Diabetic_Retinopathy_MeSH S_economics_MeSH Diabetic_Retinopathy_economics_MeSH M_Disease-Free_Survival_MeSH M_Follow-Up_Studies_MeSH M_Hospitalization_MeSH S_economics_MeSH Hospitalization_economics_MeSH M_Human_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 10820647 ----K E ----T Recent developments and emerging therapies for type 2 diabetes mellitus. ----A Most patients with type 2 (non-insulin-dependent) diabetes mellitus require pharmacotherapy, initially as monotherapy and subsequently in combination, as adjuncts to diet and exercise. Exogenous insulin is ultimately required in a substantial proportion, reflecting the progressive natural history of the disease. Sulphonylureas and biguanides have been employed for over 4 decades as oral antidiabetic agents, but they have a limited capacity to provide long term glycaemic control and can cause serious adverse effects. Thus, more efficacious and tolerable antidiabetic agents are required. Recent years have witnessed the introduction of agents with novel modes of action, that is, the alpha-glucosidase inhibitors acarbose and miglitol (which reduce postprandial hyperglycaemia) and the first of the thiazolidinedione insulinsensitising drugs--troglitazone and rosiglitazone. Although the former has been withdrawn in some countries due to adverse effects, another 'glitazone' pioglitazone is expected to be approved in the near future. Other recently introduced drugs include glimepiride and the meglitinide insulin secretagogue, repaglinide. Attention is also focusing increasingly on combination therapy using insulin together with sulphonylureas, metformin or troglitazone. Rapid-acting insulin analogues are now being used as alternatives to conventional insulins; their role in the management of type 2 diabetes mellitus is presently uncertain but reports of a reduced frequency of hypoglycaemia are encouraging. The development of new drugs aims to counter the principal metabolic defects of the disorder, respectively, relative insulin deficiency and insulin resistance. Novel classes of rapid-acting secretagogues under evaluation include the morphilinoguanide BTS 67582 and the meglitinides mitiglinide (KAD 1229) and senaglinide (A-4166). Succinate ester derivatives represent a potential novel approach to improving beta-cell function through enhancement of insulin biosynthesis and secretion. Enhancement of nutrient-induced insulin secretion is a mechanism with several putative targets within the beta-cell; potentiators of insulin secretion include glucagon-like peptide-1 and its analogues, phosphodiesterase inhibitors and the imidazoline derivative PMS 812 (S 21663). The amylin agonist pramlintide slows gastric emptying and suppression of glucagon secretion. Non-thiazolidinedione insulin-sensitising agents include the gamma-receptor agonist G 1262570X (GG 570) and D-chiro-inositol. Insulin analogues with prolonged action and inhaled insulin preparations are also under investigation. Insulin-mimetic agents include organic vanadium compounds. Whether newer agents will offer clinically relevant efficacy and tolerability advantages over existing therapies remains to be determined. ----P Journal_Article Review Review__Academic ----M M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_classification_MeSH Hypoglycemic_Agents_classification_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH ****** 10823010 ----K E ----T [Pharma-clinics. Medication of the month. Glimepiride (Amarylle)] ----A Glimepiride, commercialized in Belgium under the trade name of Amarylle by Aventis, is a new sulphonylurea compound which is indicated in the treatment of type 2 diabetes, after diet and exercise failure. It is available as 2 mg tablets. The initial doses is 1 mg, to be progressively increased up to 4 mg per day, if necessary, with a maximal daily dose of 6 mg. It is recommended to take glimepiride once a day, with the first main meal. Because of a particular binding of this sulphonylurea to the B cells of Langerhans pancreatic islets and, perhaps, of the presence of some extrapancreatic effects, both hypoglycaemic risk and circulating plasma insulin levels are lower with glimepiride than with glibenclamide, the reference sulphonylurea agent used in comparative clinical trials. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 10834429 ----K I ----T Repaglinide acutely amplifies pulsatile insulin secretion by augmentation of burst mass with no effect on burst frequency. ----A OBJECTIVE: Repaglinide is a new oral hypoglycemic agent that acts as a prandial glucose regulator proposed for the treatment of type 2 diabetes by stimulating insulin secretion. The aim of this study was to explore actions of repaglinide on the rapid pulsatile insulin release by high-frequency insulin sampling and analysis of insulin-concentration time series. RESEARCH DESIGN AND METHODS: We examined 8 healthy lean male subjects in a single-dose double-blind placebo-controlled crossover design. After the subjects underwent an overnight fast, blood sampling was initiated and continued every minute for 120 min. After 40 min, a single dose (0.5 mg) of repaglinide or placebo was given. Serum insulin-concentration time series were assessed by deconvolution analyses and the regularity statistic by approximate entropy (ApEn). RESULTS: Average insulin concentration was increased after repaglinide administration (basal vs. stimulated period, P values are placebo vs. repaglinide) (25.1 +/- 3.6 vs. 33.5 +/- 4.1 pmol/l, P < 0.001). Insulin secretory burst mass (15.8 +/- 2.2 vs. 19.6 +/- 2.8 pmol x l(-1) x pulse(-1), P = 0.02) and amplitude (6.1 +/- 0.9 vs. 7.7 +/- 1.2 pmol x l(-1) x min(-1), P = 0.008) were augmented after repaglinide administration. A concomitant trend toward an increase in basal insulin secretion was observed (2.5 +/- 0.3 vs. 3.2 +/- 0.4 pmol x l(-1) x min(-1), p = 0.06), while the interpulse interval was unaltered (6.8 +/- 1.0 vs. 5.4 +/- 0.4 min/pulse, P = 0.38). ApEn increased significantly after repaglinide administration (0.623 +/- 0.045 vs. 0.670 +/- 0.034, P = 0.04), suggesting less orderly oscillatory patterns of insulin release. CONCLUSIONS: In conclusion, a single dose of repaglinide amplifies insulin secretory burst mass (and basal secretion) with no change in burst frequency. The possible importance of these mechanisms in the treatment of type 2 diabetes characterized by disrupted pulsatile insulin secretion remains to be clarified. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Carbamates_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH M_Cross-Over_Studies_MeSH M_Double-Blind_Method_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Kinetics_MeSH M_Male_MeSH M_Piperidines_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH M_Placebos_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 10857945 ----K I ----T Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. ----A OBJECTIVE: To examine the dose-related pharmacodynamics and pharmacokinetics of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 16 Caucasian men with type 2 diabetes participated in two placebo-controlled double-blind randomized cross-over studies. Patients were randomized to receive a single oral dose of repaglinide (0.5, 1.0, and 2.0 mg in study 1 and 4.0 mg in study 2) or placebo (both studies) administered 15 min before the first of two sequential identical standard meals (breakfast and lunch) that were 4 h apart. During each of the study days, which were 1 week apart, blood samples were taken at frequent intervals over a period of approximately 8 h for measurement of plasma glucose, insulin, C-peptide, and repaglinide concentrations. RESULTS: During the first meal period (0-240 min), administration of repaglinide reduced significantly the area under the curve (AUC) for glucose concentration and significantly increased the AUC for insulin levels, C-peptide levels, and the insulin secretion rate. These results, compared with those of administering placebo, were dose dependent and log linear. The effect of repaglinide administration on insulin secretion was most pronounced in the early prandial period. Within 30 min, it caused a relative increase in insulin secretion of up to 150%. During the second meal period (240-480 min), there was no difference between repaglinide and placebo administration in the AUC for glucose concentration, C-peptide concentration, and the estimated insulin secretion rate. CONCLUSIONS: A single dose of repaglinide (0.5-4.0 mg) before breakfast improves insulin secretion and reduces prandial hyperglycemia dose-dependently Administration of repaglinide had no effect on insulin secretion with the second meal, which was consumed 4 h after breakfast. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Cohort_Studies_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Eating_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_prevention_&_control_MeSH Hyperglycemia_prevention_&_control_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10857959 ----K I ----T Effects of oral hypoglycemic agents and diet on protein metabolism in type 2 diabetes. ----A OBJECTIVE: We tested whether oral hypoglycemic agents (OHA), gliclazide with or without metformin, during an isoenergetic (ISO) and then a low-energy diet (LED) improve the altered kinetics of whole-body protein metabolism in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 13 type 2 diabetic patients (aged 51+/-2 years, weight 110+/-5 kg, BMI 41+/-1 kg/m2, fasting glucose [FSG] 11.5+/-0.9 mmol/l) (means+/-SEM) and 10 obese control subjects (48+/-3 years, 98+/-6 kg, 37+/-2 kg/m2, FSG 5.5+/-0.3 mmol/l) consumed an ISO, 1.5 g x kg(-1) x day(-1) protein for a body weight corresponding to a BMI of 25 (BMI25), a formula diet (7 days for obese control subjects, 15 days for diabetic patients), and then a 28-day LED with 50% of the energy of ISO but the same protein intake (101+/-2 g/day). OHAs were given during ISO (days 8-15) and LED. On days 6-8 (and 12-14 for diabetic subjects) of ISO and 26-28 of LED, the 60-h oral 15N-glycine method was used to obtain nitrogen flux (Q), synthesis (S), and breakdown (B). Muscle protein catabolism was estimated from N(tau)-methylhistidine (3MH) excretion. RESULTS: During ISO with hyperglycemia, Q, and B adjusted for fat-free mass, sex, and age were higher and nitrogen balance and net endogenous protein synthesis (S-B) lower than in control subjects (P<0.05). OHA decreased FSG (9+/-1 mmol/l) and 3MH and increased plasma insulin-to-glucose ratio, nitrogen retention, and S-B to levels in control subjects. The change in S-B correlated with that in FSG (r = -0.845, P = 0.001) and in fasting plasma C-peptide (r = 0.852, P = 0.0005). With LED and OHA, weight decreased 6.3 kg, glycemia reached near-normal levels, and nitrogen equilibrium was maintained; Q decreased by 7%, S and B by 11% (P<0.05) to values found in control subjects. CONCLUSIONS: OHA during ISO corrected protein turnover in relation to glycemia and plasma C-peptide. The LED maintained protein homeostasis in obese control subjects and, in diabetes patients with OHA, normalized protein metabolism. These findings have implications for diet and OHA prescription. ----P Journal_Article ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH P_Diabetic_Diet_MeSH M_Drug_Therapy__Combination_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glycosuria_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Kinetics_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_MeSH S_diet_therapy_MeSH Obesity_diet_therapy_MeSH S_metabolism_MeSH Obesity_metabolism_MeSH M_Obesity_in_Diabetes_MeSH S_diet_therapy_MeSH Obesity_in_Diabetes_diet_therapy_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH S_metabolism_MeSH Obesity_in_Diabetes_metabolism_MeSH M_Proteins_MeSH S_metabolism_MeSH Proteins_metabolism_MeSH M_Support__Non-U_S__Gov't_MeSH M_Urea_MeSH S_blood_MeSH Urea_blood_MeSH M_Weight_Loss_MeSH ****** 10868832 ----K I ----T Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia. ----A OBJECTIVE: The objective of the study was to assess the efficacy and safety of four fixed doses of nateglinide compared with placebo in the treatment of patients with type 2 diabetes with focus on the prandial state. RESEARCH DESIGN AND METHODS: This randomized double-blind placebo-controlled multicenter study was conducted in 289 patients who received either nateglinide at doses of 30 mg (n = 51), 60 mg (n = 58), 120 mg (n = 63), or 180 mg (n = 57) or placebo (n = 60) before three main meals for 12 weeks. Levels of HbA1c, fasting plasma glucose (FPG), fructosamine, and plasma lipids were measured at predetermined intervals, and the effects of nateglinide on prandial glucose insulin, C-peptide, and triglyceride levels were measured after a liquid standard meal (Sustacal; Mead Johnson, Evansville, IN). Adverse events and hypoglycemic episodes were recorded. RESULTS: After a liquid meal challenge, nateglinide rapidly increased mealtime insulin levels within 30 min of drug intake and reduced mealtime glucose excursions without affecting triglyceride levels. At study end point, reduction of HbA1c levels was statistically significantly greater with nateglinide at doses of 60, 120, and 180 mg than placebo (-0.45, -0.62, and -0.64%, respectively; P<0.05). The mean level of FPG was significantly reduced versus placebo in the nateglinide 120-mg group only (-1.14 mmol/l P<0.01). Overall, nateglinide was well tolerated. CONCLUSIONS: This study demonstrated that nateglinide improves mealtime and mean glycemic control in a dose-dependent manner by restoring early insulin secretion phase. Nateglinide was well tolerated and is suitable for the treatment of patients with type 2 diabetes. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cyclohexanes_MeSH S_administration_&_dosage_MeSH Cyclohexanes_administration_&_dosage_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Eating_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_administration_&_dosage_MeSH Phenylalanine_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Placebos_MeSH M_Safety_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10868864 ----K I ----T Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin. ----A OBJECTIVE: Nateglinide, a new short-acting D-phenylalanine derivative for treating type 2 diabetes, reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. This study evaluated the pharmacokinetic and pharmacodynamic interactions of nateglinide and metformin in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 12 type 2 diabetic subjects with the following baseline characteristics were enrolled: age, 56 +/- 13 years; BMI, 28.7 +/- 4.5 kg/m2; HbA1c, 8.4 +/- 1.3%; and fasting plasma glucose 13 +/- 2.8 mmol/l. All subjects had been previously treated with glyburide and were switched to metformin monotherapy for 3 weeks before study start. Subjects then randomly received, in combination with 500 mg metformin, either 120 mg nateglinide or placebo before meals for 1 day, followed by the alternate treatment 7 days later. After 1 week of washout from both drugs, subjects received 1 day of open-label nateglinide treatment. Plasma concentrations of glucose, insulin, nateglinide, and metformin were assessed frequently during inpatient periods. RESULTS: Postmeal plasma glucose levels were significantly lower in subjects treated with nateglinide plus metformin than in those treated with either drug alone (P < 0.001), especially after lunch and dinner. Coadministration of nateglinide and metformin did not affect the pharmacokinetics of either drug. All treatments were safe and well tolerated. CONCLUSIONS: Combination therapy with nateglinide and metformin was more effective than either treatment alone and did not result in any pharmacokinetic interactions. Coadministration of nateglinide and metformin appears to be an excellent option for treating patients with type 2 diabetes not controlled with monotherapy. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cyclohexanes_MeSH S_administration_&_dosage_MeSH Cyclohexanes_administration_&_dosage_MeSH S_blood_MeSH Cyclohexanes_blood_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Eating_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_blood_MeSH Metformin_blood_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_administration_&_dosage_MeSH Phenylalanine_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_blood_MeSH Phenylalanine_blood_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH P_Postprandial_Period_MeSH ****** 10877006 ----K I ----T Mealtime glucose regulation by nateglinide in type-2 diabetes mellitus. ----A OBJECTIVES: Pharmacodynamic effects of nateglinide, a novel antidiabetic agent, were investigated in patients with type-2 diabetes mellitus. METHODS: Ten patients participated in this single-center, double-blind, crossover study. Plasma glucose and insulin levels were measured over 24 h following five 7-day treatment periods with nateglinide (30, 60, or 120 mg) or placebo given three times daily before breakfast, lunch, and dinner. A fifth treatment consisted of 120 mg nateglinide four times daily, with the fourth dose given before an evening snack. RESULTS: Taken 10 min before meals, doses of 30-120 mg nateglinide caused dose-dependent increases in plasma insulin levels that were significantly greater than with placebo. Higher doses were more effective and had a longer duration of action than lower doses. Nateglinide was also significantly better than placebo in lowering plasma glucose levels; the 60-mg and 120-mg doses were similarly effective and superior to the 30-mg nateglinide treatment. Following the fourth 120-mg dose, the glucose-lowering effects of treatment were maintained through the night. No serious adverse events occurred during the study. There were no events of hypoglycemia and no clinically meaningful changes in safety parameters. CONCLUSIONS: Nateglinide produced rapid, short-lived, dose-related increases in plasma insulin that significantly lowered mealtime glucose excursions compared with placebo with no incidence of hypoglycemia. The decrease in mealtime glucose levels produced a significant improvement in overall 24-h glycemia. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Cross-Over_Studies_MeSH M_Cyclohexanes_MeSH S_administration_&_dosage_MeSH Cyclohexanes_administration_&_dosage_MeSH S_adverse_effects_MeSH Cyclohexanes_adverse_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_administration_&_dosage_MeSH Phenylalanine_administration_&_dosage_MeSH S_adverse_effects_MeSH Phenylalanine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH M_Placebos_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10894443 ----K I ----T Effects of glibenclamide, a K(ATP) channel blocker, on warm-up phenomenon in type II diabetic patients with chronic stable angina pectoris. ----A BACKGROUND: Warm-up phenomenon, one of the clinical models of ischemic preconditioning, refers to an increased tolerance to myocardial ischemia during the second of two consecutive exercise tests. HYPOTHESIS: Blockers of K(ATP) channels, such as the sulfonylurea drugs, can induce loss of ischemic preconditioning. This study aimed to investigate the effects of glibenclamide, a sulfonylurea with a high affinity for myocardial K(ATP) channels, on the results of two consecutive exercise tests in diabetic patients with coronary artery disease. METHODS: Eighteen type II diabetic patients with chronic stable angina pectoris participated in this study. All patients underwent two consecutive treadmill exercise tests with a recovery period of 15 min in fasting state. On the day after these exercise tests, 10 mg oral glibenclamide was given to the same patients and 30 min later 200 ml of 30% glucose solution was given orally. Half an hour later, which is the time of peak plasma levels of glibenclamide, two exercise tests were repeated consecutively with a 15 min recovery period. RESULTS: There was no difference in blood glucose levels before and after exercise tests on each day (p > 0.05). Without glibenclamide, heart rate, rate-pressure product at 1.5 mm ST depression, and peak exercise increased significantly (p < 0.05). Time to 1.5 mm ST-segment depression and onset of pain, as well as duration of exercise also increased, but ST-segment depression and ST-recovery time significantly decreased (p < 0.05). In contrast, these values did not significantly change after glibenclamide (p>0.05), with a significant drug-test interaction (p < 0.05, at two-way ANOVA). CONCLUSIONS: Glibenclamide, an oral hypoglycemic agent with a K(ATP) channel-blocker activity, with a 10 mg oral dose, abolished the warm-up phenomenon which is a clinical finding of ischemic preconditioning on two consecutive exercise tests. Therefore, glibenclamide should be used carefully in patients with coronary heart disease and diabetes mellitus since this agent leads to a decrease in ischemic threshold and exercise capacity. ----P Journal_Article ----M M_Adenosine_Triphosphate_MeSH S_blood_MeSH Adenosine_Triphosphate_blood_MeSH M_Adenosinetriphosphatase_MeSH S_antagonists_&_inhibitors_MeSH Adenosinetriphosphatase_antagonists_&_inhibitors_MeSH S_blood_MeSH Adenosinetriphosphatase_blood_MeSH M_Administration__Oral_MeSH M_Adult_MeSH M_Angina_Pectoris_MeSH S_blood_MeSH Angina_Pectoris_blood_MeSH S_complications_MeSH Angina_Pectoris_complications_MeSH S_radiography_MeSH Angina_Pectoris_radiography_MeSH S_therapy_MeSH Angina_Pectoris_therapy_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Chronic_Disease_MeSH M_Comparative_Study_MeSH M_Coronary_Angiography_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Electrocardiography_MeSH S_drug_effects_MeSH Electrocardiography_drug_effects_MeSH M_Exercise_Test_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH M_Heart_Rate_MeSH S_drug_effects_MeSH Heart_Rate_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH P_Ischemic_Preconditioning__Myocardial_MeSH S_methods_MeSH Ischemic_Preconditioning__Myocardial_methods_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Potassium_Channels_MeSH S_blood_MeSH Potassium_Channels_blood_MeSH S_drug_effects_MeSH Potassium_Channels_drug_effects_MeSH ****** 10895850 ----K 3 ----T Repaglinide/troglitazone combination therapy: improved glycemic control in type 2 diabetes. ----A OBJECTIVE: This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured. RESULTS: The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups. CONCLUSIONS: Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Carbamates_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Chromans_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 10905487 ----K E ----T Response of pancreatic beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes. ----A The purpose of this study was to examine the response of pancreatic beta-cells to changes in insulin sensitivity in women at high risk for type 2 diabetes. Oral glucose tolerance tests (OGTTs) and frequently sampled intravenous glucose tolerance tests (FSIGTs) were conducted on Latino women with impaired glucose tolerance and a history of gestational diabetes before and after 12 weeks of treatment with 400 mg/day troglitazone (n = 13) or placebo (n = 12). Insulin sensitivity was assessed by minimal model analysis, and beta-cell insulin release was assessed as acute insulin responses to glucose (AIRg) and tolbutamide (AIRt) during FSIGTs and as the 30-min incremental insulin response (30-min dINS) during OGTTs. Beta-cell compensation for insulin resistance was assessed as the product (disposition index) of minimal model insulin sensitivity and each of the 3 measures of beta-cell insulin release. In the placebo group, there was no significant change in insulin sensitivity or in any measure of insulin release, beta-cell compensation for insulin resistance, or glucose tolerance. Troglitazone treatment resulted in a significant increase in insulin sensitivity, as reported previously. In response, AIRg did not change significantly, so that the disposition index for AIRg increased significantly from baseline (P = 0.004) and compared with placebo (P = 0.02). AIRt (P = 0.001) and 30-min dINS (P = 0.02) fell with improved insulin sensitivity during troglitazone treatment, so that the disposition index for each of these measures of beta-cell function did not change significantly from baseline (P > 0.20) or compared with placebo (P > 0.3). Minimal model analysis revealed that 89% of the change from baseline in insulin sensitivity during troglitazone treatment was accounted for by lowered plasma insulin concentrations. Neither oral nor intravenous glucose tolerance changed significantly from baseline or compared with placebo during troglitazone treatment. The predominant response of beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes was a reduction in insulin release to maintain nearly constant glucose tolerance. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH M_Diabetes__Gestational_MeSH S_complications_MeSH Diabetes__Gestational_complications_MeSH M_Female_MeSH M_Glucose_MeSH S_diagnostic_use_MeSH Glucose_diagnostic_use_MeSH M_Glucose_Intolerance_MeSH S_blood_MeSH Glucose_Intolerance_blood_MeSH S_drug_therapy_MeSH Glucose_Intolerance_drug_therapy_MeSH S_etiology_MeSH Glucose_Intolerance_etiology_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_diagnostic_use_MeSH Hypoglycemic_Agents_diagnostic_use_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Islets_of_Langerhans_MeSH S_metabolism_MeSH Islets_of_Langerhans_metabolism_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Pregnancy_MeSH M_Risk_Factors_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Tolbutamide_MeSH S_diagnostic_use_MeSH Tolbutamide_diagnostic_use_MeSH ****** 10907625 ----K E ----T Troglitazone or metformin in combination with sulfonylureas for patients with type 2 diabetes? ----A BACKGROUND: Combination oral therapy is often used to control the hyperglycemia of patients with type 2 diabetes. We compared the effectiveness of metformin and troglitazone when added to sulfonylurea therapy for patients with type 2 diabetes who had suboptimal blood glucose control. METHODS: We used a randomized 2-group design to compare the efficacy, safety, and tolerability of troglitazone and metformin for patients with type 2 diabetes mellitus that was inadequately controlled with diet and oral sulfonylureas. Thirty-two subjects were randomized to receive either troglitazone or metformin for 14 weeks, including a 2-week drug-titration period. The primary outcome variable was mean change in the level of glycosylated hemoglobin (Hb A1c) from baseline. Secondary outcomes included mean changes from baseline in fasting plasma glucose and C-peptide levels, renal or metabolic side effects, and symptomatic tolerability. RESULTS: The addition of either troglitazone or metformin to oral sulfonylurea therapy significantly decreased Hb A1c levels. Both treatment regimens also significantly reduced fasting plasma glucose and C-peptide levels. We found no significant differences between the treatment arms in efficacy, metabolic side effects, or tolerability. CONCLUSIONS: Our results demonstrate that troglitazone and metformin each significantly improved Hb A1c, fasting plasma glucose, and C-peptide levels when added to oral sulfonylurea therapy for patients with type 2 diabetes who had inadequate glucose control. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Chromans_MeSH S_administration_&_dosage_MeSH Chromans_administration_&_dosage_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH M_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH P_Thiazolidinediones_MeSH ****** 10929931 ----K I ----T A rational approach to drug therapy of type 2 diabetes mellitus. ----A Several new pharmacological agents have recently been developed to optimise the management of type 2 (non-insulin-dependent) diabetes mellitus. The aim of this article is to briefly review the various therapeutic agents available for management of patients with type 2 diabetes mellitus and to suggest a potential approach to drug selection. There are three general therapeutic modalities relevant to diabetes care. The first modality is lifestyle adjustments aimed at improving endogenous insulin sensitivity or insulin effect. This can be achieved by increased physical activity and bodyweight reduction with diet and behavioural modification, and the use of pharmacological agents or surgery. This first modality is not discussed in depth in this article. The second modality involves increasing insulin availability by the administration of exogenous insulin, insulin analogues, sulphonylureas and the new insulin secretagogue, repaglinide. The most frequently encountered adverse effect of these agents is hypoglycaemia. Bodyweight gain can also be a concern, especially in patients who are obese. The association between hyperinsulinaemia and premature atherosclerosis is still a debatable question. The third modality consists of agents such as biguanides and thiazolidinediones which enhance insulin sensitivity, or agents that decrease insulin requirements like the alpha-glucosidase inhibitors. Type 2 diabetes mellitus is a heterogeneous disease with multiple underlying pathophysiological processes. Therapy should be individualised based on the degree of hyperglycaemia, hyperinsulinaemia or insulin deficiency. In addition, several factors have to be considered when prescribing a specific therapeutic agent. These factors include efficacy, safety, affordability and ease of administration. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Forecasting_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH ****** 10934787 ----K E ----T A bioequivalence study of two brands of glipizide tablets. ----A In this open, randomized, two way crossover, bioequivalence study, two 5 mg tablet preparations of glipizide (Glipizyd tabl. 5 mg, Tarchominskie Zaklady Farmaceutyczne POLFA S.A., and Glibenese tabl. 5 mg, Pfizer), were compared in 24 healthy male volunteers. Pharmacokinetic variables (mean maximum plasma concentration, mean time to reach maximum plasma concentration, and the mean area under the plasma concentration-time curve) were not statistically significantly different for the two formulations. It can be concluded that the two tablet preparations of glipizide are likely to be bioequivalent. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Area_Under_Curve_MeSH M_Chromatography__High_Pressure_Liquid_MeSH M_Comparative_Study_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_analysis_MeSH Glipizide_analysis_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_analysis_MeSH Hypoglycemic_Agents_analysis_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Male_MeSH M_Reproducibility_of_Results_MeSH M_Tablets_MeSH M_Therapeutic_Equivalency_MeSH ****** 10937510 ----K E ----T Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. ----A OBJECTIVE: Available basal insulin formulations do not provide a constant and reliable 24-h insulin supply. We compared the efficacy and safety of glargine (a long-acting insulin analog) and NPH insulins in insulin-naive type 2 diabetic patients treated with oral antidiabetic agents. RESEARCH DESIGN AND METHODS: There were 426 type 2 diabetic patients (age 59 +/- 9 years, BMI 28.9 +/- 4.3 kg/m2, mean +/- SD) with poor glycemic control on oral antidiabetic agents randomized to treatment for 1 year with bedtime insulin glargine or bedtime NPH insulin. Oral agents were continued unchanged. The fasting blood glucose (FBG) target was 6.7 mmol/l (120 mg/dl). RESULTS: Average glycemic control improved similarly with both insulins (HbA(1c), [reference range <6.5%] 8.3 +/- 0.1 vs. 8.2 +/- 0.1% at 1 year, glargine vs. NPH, mean +/- SEM, P < 0.001 vs. baseline for both). However, there was less nocturnal hypoglycemia (9.9 vs. 24.0% of all patients, glargine vs. NPH, P < 0.001) and lower post-dinner glucose concentrations (9.9 +/- 0.2 vs. 10.7 +/- 0.3 mmol/l, P < 0.02) with insulin glargine than with NPH. Insulin doses and weight gain were comparable. In patients reaching target FBG, HbA(1c) averaged 7.7 and 7.6% in the glargine and NPH groups at 1 year. CONCLUSIONS: Use of insulin glargine compared with NPH is associated with less nocturnal hypoglycemia and lower post-dinner glucose levels. These data are consistent with peakless and longer duration of action of insulin glargine compared with NPH. Achievement of acceptable average glucose control requires titration of the insulin dose to an FBG target < or =6.7 mmol/l. These data support use of insulin glargine instead of NPH in insulin combination regimens in type 2 diabetes. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Circadian_Rhythm_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_prevention_&_control_MeSH Hypoglycemia_prevention_&_control_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin_Antibodies_MeSH S_blood_MeSH Insulin_Antibodies_blood_MeSH M_Insulin__Isophane_MeSH S_administration_&_dosage_MeSH Insulin__Isophane_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin__Isophane_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 10937524 ----K 5 ----T Response to training in blood glucose awareness is related to absence of previous hypoglycemic coma. ----A ----P Clinical_Trial Comment Controlled_Clinical_Trial Letter ----M M_Adult_MeSH M_Anxiety_MeSH M_Awareness_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH S_rehabilitation_MeSH Diabetes_Mellitus__Type_I_rehabilitation_MeSH M_Diabetic_Coma_MeSH S_prevention_&_control_MeSH Diabetic_Coma_prevention_&_control_MeSH M_Fear_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_physiopathology_MeSH Hypoglycemia_physiopathology_MeSH S_psychology_MeSH Hypoglycemia_psychology_MeSH M_Male_MeSH P_Patient_Education_MeSH M_Perception_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10969849 ----K E ----T The K121Q variant of the human PC-1 gene is not associated with insulin resistance or type 2 diabetes among Danish Caucasians. ----A The human plasma-cell membrane differentiation antigen-1 (PC-1) has been shown to inhibit insulin receptor tyrosine kinase activity. Recently, a K121Q polymorphism in the human PC-1 gene was found in a Sicilian population and was shown to be strongly associated with insulin resistance. The objectives of the present investigation were to examine in the Danish Caucasian population whether the K121Q variant was associated with type 2 diabetes or, in glucose-tolerant subjects, with impaired whole-body insulin sensitivity. We genotyped 404 Danish type 2 diabetic patients and found that the allele frequency of the variant was 0.14 (95% CI 0.12-0.16), whereas the allele frequency was 0.16 (95% CI 0.13-0.19) among 237 matched glucose-tolerant control subjects (P = 0.6). In the control subjects, there were no significant differences among wild-type, heterozygous, or homozygous subjects in regard to 1) serum insulin and plasma glucose levels at fasting, 60 min, or 120 min during an oral glucose tolerance test (OGTT) or 2) the estimates of insulin resistance obtained from the homeostasis model assessment (HOMA). Furthermore, we investigated the impact of the variant in 2 other Danish population samples that comprised 356 young healthy subjects and 226 glucose-tolerant offspring of type 2 diabetic probands, respectively. In all of the study populations, the polymorphism was not associated with an altered insulin sensitivity index as estimated from an intravenous glucose tolerance test in combination with an intravenous injection of tolbutamide. In addition, among the 226 offspring, the variations in serum insulin and serum C-peptide responses measured during an OGTT were not related to the PC-1 genotype. In conclusion, the K121Q polymorphism of the human PC-1 gene is not associated with type 2 diabetes or insulin resistance among Danish Caucasians. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Amino_Acid_Substitution_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Denmark_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH M_European_Continental_Ancestry_Group_MeSH S_genetics_MeSH European_Continental_Ancestry_Group_genetics_MeSH M_Female_MeSH M_Heterozygote_MeSH M_Homozygote_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Insulin_Resistance_MeSH S_genetics_MeSH Insulin_Resistance_genetics_MeSH M_Male_MeSH M_Membrane_Glycoproteins_MeSH S_genetics_MeSH Membrane_Glycoproteins_genetics_MeSH M_Middle_Aged_MeSH P_Phosphoric_Diester_Hydrolases_MeSH P_Pyrophosphatases_MeSH M_Support__Non-U_S__Gov't_MeSH P_Variation_(Genetics)_MeSH ****** 10972579 ----K I ----T Oral hypoglycaemic agents in 118 diabetic pregnancies. ----A AIMS: To assess maternal and neonatal complications in pregnancies of diabetic women treated with oral hypoglycaemic agents during pregnancy. METHODS: A cohort study including all consecutively registered, orally treated pregnant diabetic patients set in a diabetic obstetrical service at a university hospital: 50 women treated with metformin, 68 women treated with sulphonylurea during pregnancy and a reference group of 42 diabetic women treated with insulin during pregnancy. RESULTS: The prevalence of pre-eclampsia was significantly increased in the group of women treated with metformin compared to women treated with sulphonylurea or insulin (32 vs. 7 vs. 10%, P < 0.001). No difference in neonatal morbidity was observed between the orally treated and insulin-treated group; no cases of severe hypoglycaemia or jaundice were seen in the orally treated groups. However, in the group of women treated with metformin in the third trimester, the perinatal mortality was significantly increased compared to women not treated with metformin (11.6 vs. 1.3%, P < 0.02). CONCLUSION: Treatment with metformin during pregnancy was associated with increased prevalence of pre-eclampsia and a high perinatal mortality. ----P Journal_Article ----M M_Abruptio_Placentae_MeSH S_epidemiology_MeSH Abruptio_Placentae_epidemiology_MeSH M_Adult_MeSH M_Birth_Weight_MeSH M_Cesarean_Section_MeSH S_statistics_&_numerical_data_MeSH Cesarean_Section_statistics_&_numerical_data_MeSH M_Cohort_Studies_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetes__Gestational_MeSH S_drug_therapy_MeSH Diabetes__Gestational_drug_therapy_MeSH M_Female_MeSH M_Fetal_Death_MeSH S_epidemiology_MeSH Fetal_Death_epidemiology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Infant__Newborn_MeSH M_Infant__Newborn__Diseases_MeSH S_classification_MeSH Infant__Newborn__Diseases_classification_MeSH S_epidemiology_MeSH Infant__Newborn__Diseases_epidemiology_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Morbidity_MeSH M_Pre-Eclampsia_MeSH S_epidemiology_MeSH Pre-Eclampsia_epidemiology_MeSH M_Pregnancy_MeSH M_Pregnancy_Outcome_MeSH M_Pregnancy_in_Diabetics_MeSH S_drug_therapy_MeSH Pregnancy_in_Diabetics_drug_therapy_MeSH M_Tolbutamide_MeSH S_therapeutic_use_MeSH Tolbutamide_therapeutic_use_MeSH ****** 10975046 ----K E ----T [Pharmacological treatment of postprandial hyperglycemia] ----A Every diabetes treatment contributes to the control of postprandial blood glucose, yet some agents more specifically target this goal. Alpha-glucosidase inhibitors, led by acarbose, mainly address postprandial glucose control. These agents inhibit intestinal disaccharidases through a competitive effect and can be used either as the sole treatment or in combination with other antidiabetic drugs. Other agents improve insulin secretion kinetics. This is the case for repaglinide et nateglinide, which are efficient in controlling postprandial blood glucose, and to a lesser degree, fasting blood glucose. These agents shortly and quickly stimulate insulin secretion and should be available soon. In oral therapy secondary failures, trials are currently being conducted to clarify the role of fast-acting insulin analogs, as monotherapy or in combination. Finally, insulin sensitizing agents are being investigated as a way to improve postprandial glucose efflux by potentiating insulin effects. The optimal strategy for the use of these different therapeutic agents remains to be established, as well as their long-term effects on diabetic complications. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH S_physiopathology_MeSH Hyperglycemia_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Postprandial_Period_MeSH S_drug_effects_MeSH Postprandial_Period_drug_effects_MeSH S_physiology_MeSH Postprandial_Period_physiology_MeSH ****** 10977012 ----K I ----T Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. IOEZ Study Group. ----A OBJECTIVE: To compare the overall efficacy of combination therapies focused on fasting or postprandial blood glucose in patients with type 2 diabetes not adequately controlled with oral sulfonylurea agents alone. RESEARCH DESIGN AND METHODS: A total of 135 patients were randomly assigned for 3 months to 1 of 3 combination regimens with glyburide (G) that addressed postprandial blood glucose with insulin lispro (L+G), premeal blood glucose with metformin (M+G), or fasting blood glucose (FBG) with bedtime NPH insulin (NPH+G). RESULTS: At end point, HbA1c was significantly lower with all therapies (P = 0.001) and was significantly lower for L+G (7.68+/-0.88%) compared with either NPH+G (8.51+/-1.38%, P = 0.003) or M+G (8.31+/-1.31%, P = 0.025). FBG at end point was significantly lower for NPH+G (8.49+/-2.36 mmol/l) compared with either L+G (10.57+/-1.97 mmol/l, P = 0.001) or M+G (9.69+/-2.89 mmol/l, P = 0.029). The mean 2-h postprandial glucose after a test meal was significantly lower for L+G (10.87+/-2.88 mmol/l) versus NPH+G (12.21+/-3.12 mmol/, P = 0.052) or versus M+G (12.72+/-3.26 mmol/l, P = 0.009). The overall rate of hypoglycemia (episodes per 30 days) was low and not statistically significant between groups (P = 0.156). CONCLUSIONS: Adding a second antihyperglycemic agent, regardless of its timing of action, lowers HbA1c and glucose values. However, when insulin lispro was used to focus on postprandial blood glucose, there was a greater impact on overall metabolic control. These data support the importance of lowering postprandial blood glucose to optimize overall glycemic control and thus improve long-term outcomes. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin__Isophane_MeSH S_administration_&_dosage_MeSH Insulin__Isophane_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin__Isophane_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH ****** 10983737 ----K E ----T Pioglitazone. ----A Pioglitazone is an orally administered insulin sensitising thiazolidinedione agent that has been developed for the treatment of type 2 diabetes mellitus. Pioglitazone activates the nuclear peroxisome proliferator activated receptor-gamma (PPAR-gamma), which leads to the increased transcription of various proteins regulating glucose and lipid metabolism. These proteins amplify the post-receptor actions of insulin in the liver and peripheral tissues, which leads to improved glycaemic control with no increase in the endogenous secretion of insulin. In placebo-controlled clinical trials, monotherapy with pioglitazone 15 to 45 mg/day has been shown to decrease blood glycosylated haemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus. The addition of pioglitazone 30 mg/day to preexisting therapy with metformin, or of pioglitazone 15 or 30 mg/day to sulphonylurea, insulin or voglibose therapy, has been shown to decrease HbA1c and fasting blood glucose levels significantly in patients with poorly controlled type 2 diabetes mellitus. Pioglitazone has also been associated with improvements in serum lipid profiles in randomised placebo-controlled clinical studies. The drug has been well tolerated by adult patients of all ages in clinical studies. Oedema has been reported with monotherapy, and pooled data have shown hypoglycaemia in 2 to 15% of patients after the addition of pioglitazone to sulphonylurea or insulin treatment. There have been no reports of hepatotoxicity. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Clinical_Trials_MeSH M_Drug_Therapy__Combination_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipids_MeSH S_metabolism_MeSH Lipids_metabolism_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 11019600 ----K E ----T Does holiday hypoglycaemia exist? ----A BACKGROUND: To determine whether an excessive, prolonged and, above all, unusual physical exertion could be associated with episodes of mild hypoglycaemia in non-insulin-dependent diabetes mellitus (NIDDM) patients treated with glibenclamide. METHODS: Experimental design: 11 months of observation with retrospective analysis of patient personal diaries to determine the hypoglycaemic risk. Setting: Diabetic Unit-Department of Medicine and Aging-Chieti University School of Medicine. Patients: We enrolled 340 NIDDM outpatients adjusted for sex, age, body mass index, alcohol intake and oral treatment regimen with glibenclamide. Patients were tested monthly for circadian blood glucose profiles and glycosylated hemoglobin. Mild hypoglycaemia was defined on the basis of blood glucose values < 2.8 mmol/l associated with mild autonomic symptoms, without requiring external assistance. Each diabetic patient filled personal diary indicating the therapy regimen and the characteristics of eventual hypoglycaemic episodes occurring during the observation period. RESULTS: 21.8% of NIDDM patients experienced one or two episodes of mild hypoglycaemia during the observation period. The analysis of the patients' diaries showed that 60% of the hypoglycaemic episodes was associated with excessive, prolonged and unexpected physical exertions. Within this group, about 70% of the episodes occurred during a holiday ("holiday hypoglycaemia"). After analyzing the socio-demographic and clinical characteristics of the diabetic patients reporting hypoglycaemic events, we found a higher risk for "holiday hypoglycaemia" in patients with a lower educational level, with a sedentary occupation or among the ex-farmers. CONCLUSIONS: As resulted in the present study, unexpected physical exertions may represent a relevant cause of mild hypoglycaemia in diabetic patients receiving oral antidiabetic therapy. However, this hypoglycaemic cause may have been underestimated in the literature. Educational programs conducted by general practitioners or diabetologists could be useful for the patients in reducing the number of mild hypoglycaemic episodes. ----P Journal_Article ----M M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Exertion_MeSH S_physiology_MeSH Exertion_physiology_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_etiology_MeSH Hypoglycemia_etiology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Retrospective_Studies_MeSH ****** 11036118 ----K I ----T A comparison of glyburide and insulin in women with gestational diabetes mellitus. ----A BACKGROUND: Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug, because of concern about teratogenicity and neonatal hypoglycemia. There is little information about the efficacy of these drugs in this group of women. METHODS: We studied 404 women with singleton pregnancies and gestational diabetes that required treatment. The women were randomly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin according to an intensified treatment protocol. The primary end point was achievement of the desired level of glycemic control. Secondary end points included maternal and neonatal complications. RESULTS: The mean (+/-SD) pretreatment blood glucose concentration as measured at home for one week was 114+/-19 mg per deciliter (6.4+/-1.1 mmol per liter) in the glyburide group and 116+/-22 mg per deciliter (6.5+/-1.2 mmol per liter) in the insulin group (P=0.33). The mean concentrations during treatment were 105+/-16 mg per deciliter (5.9+/-0.9 mmol per liter) in the glyburide group and 105+/-18 mg per deciliter (5.9+/-1.0 mmol per liter) in the insulin group (P=0.99). Eight women in the glyburide group (4 percent) required insulin therapy. There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age (12 percent and 13 percent, respectively); who had macrosomia, defined as a birth weight of 4000 g or more (7 percent and 4 percent); who had lung complications (8 percent and 6 percent); who had hypoglycemia (9 percent and 6 percent); who were admitted to a neonatal intensive care unit (6 percent and 7 percent); or who had fetal anomalies (2 percent and 2 percent). The cord-serum insulin concentrations were similar in the two groups, and glyburide was not detected in the cord serum of any infant in the glyburide group. CONCLUSIONS: In women with gestational diabetes, glyburide is a clinically effective alternative to insulin therapy. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Abnormalities_MeSH S_epidemiology_MeSH Abnormalities_epidemiology_MeSH M_Adolescent_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Comparative_Study_MeSH M_Diabetes__Gestational_MeSH S_drug_therapy_MeSH Diabetes__Gestational_drug_therapy_MeSH M_Female_MeSH M_Fetal_Blood_MeSH S_chemistry_MeSH Fetal_Blood_chemistry_MeSH M_Fetal_Macrosomia_MeSH S_epidemiology_MeSH Fetal_Macrosomia_epidemiology_MeSH M_Glyburide_MeSH S_blood_MeSH Glyburide_blood_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_epidemiology_MeSH Hypoglycemia_epidemiology_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Infant__Newborn_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Pregnancy_MeSH M_Pregnancy_Outcome_MeSH ****** 11036125 ----K I ----T Oral hypoglycemic drugs for gestational diabetes. ----A ----P Comment Editorial ----M M_Abnormalities_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Diabetes__Gestational_MeSH S_drug_therapy_MeSH Diabetes__Gestational_drug_therapy_MeSH M_Female_MeSH M_Fetal_Blood_MeSH S_chemistry_MeSH Fetal_Blood_chemistry_MeSH M_Fetal_Macrosomia_MeSH M_Glyburide_MeSH S_blood_MeSH Glyburide_blood_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Infant__Newborn_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Pregnancy_MeSH M_Pregnancy_Outcome_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 11023137 ----K E ----T Long-term dietary treatment with increased amounts of fiber-rich low-glycemic index natural foods improves blood glucose control and reduces the number of hypoglycemic events in type 1 diabetic patients. ----A OBJECTIVE: To evaluate in type 1 diabetic patients 1) the long-term feasibility of a high-fiber (HF) diet composed exclusively of natural foodstuffs and 2) the efficacy of this diet in relation to blood glucose control and incidence of hypoglycemic episodes. RESEARCH DESIGN AND METHODS: The study was randomized with parallel groups. Participants were part of a larger multicenter study on the effects of acarbose on glucose control in diabetes. A total of 63 type 1 diabetic patients, age 28 +/- 9 years, BMI 24 +/- 0.6 kg/m2, after a 4-week run-in period on their habitual diet, were randomized to either an HF (n = 32) or a low-fiber (LF) diet (n = 31) for 24 weeks. The two diets, composed exclusively of natural foodstuffs, were weight-maintaining and, aside from their fiber content, were similar for all nutrients. At the end of the run-in period and the dietary treatment, fasting blood samples for the measurement of plasma cholesterol, HDL cholesterol, triglyceride, and HbA(1c) were collected. A daily glycemic profile was performed on a day in which the participants had consumed a standard menu representative of their treatment diet (HF or LF). RESULTS: Of the 63 study subjects, 29 in the HF group (91%) and 25 in the LF group (81%) completed the study Compared with the LF diet, the HF diet after 24 weeks decreased both mean daily blood glucose concentrations (P < 0.05) and number of hypoglycemic events (P < 0.01). When compliance to diet was taken into account, 83% of the subjects on the HF diet and 88% on the LF diet were compliant. In this subgroup, compared with the LF diet, the HF diet significantly reduced mean daily blood glucose concentrations (P < 0.001), HbA(1c) (P < 0.05), and number of hypoglycemic events (P < 0.01). CONCLUSIONS: In type 1 diabetic patients, an HF diet is feasible in the long term and, compared with an LF diet, improves glycemic control and reduces the number of hypoglycemic events. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Cohort_Studies_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_I_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Diabetic_Diet_MeSH P_Dietary_Carbohydrates_MeSH P_Dietary_Fiber_MeSH M_Energy_Intake_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH S_prevention_&_control_MeSH Hypoglycemia_prevention_&_control_MeSH M_Insulin_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Patient_Compliance_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 11030470 ----K I ----T Nateglinide. ----A Nateglinide is a novel D-phenylalanine derivative that inhibits ATP-sensitive K+ channels in pancreatic beta-cells in the presence of glucose and thereby stimulates the prandial release of insulin. Nateglinide reduces fasting and mealtime blood glucose levels in animals, healthy volunteers, and patients with type 2 (non-insulin-dependent) diabetes mellitus, and produces prompt prandial insulin responses with return to baseline insulin levels between meals. In randomised, double-blind 24-week studies in patients with type 2 diabetes, oral nateglinide 120 mg 3 times daily before meals improved glycaemic control significantly relative to placebo. Nateglinide 120 mg plus metformin 500 mg, both 3 times daily, conferred greater glycaemic improvement than either drug given alone, and nateglinide 60 or 120 mg 3 times daily plus metformin 1 g twice daily was superior to metformin plus placebo. Nateglinide 120 mg 3 times daily significantly reduced hyperglycaemia relative to placebo in a 16-week double-blind study in patients with type 2 diabetes mellitus. Combination therapy with troglitazone 600 mg daily produced significantly better glycaemic control than either drug given as monotherapy. Mild hypoglycaemia was the most frequently reported adverse event (1.3% of patients) after treatment with nateglinide 120 mg 3 times daily in a 16-week clinical study. No clinically significant abnormalities in laboratory results, ECGs, vital signs or physical examination findings have been noted in patients taking the drug. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Clinical_Trials_MeSH M_Cyclohexanes_MeSH S_administration_&_dosage_MeSH Cyclohexanes_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH S_pharmacology_MeSH Cyclohexanes_pharmacology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypercalcemia_MeSH S_drug_therapy_MeSH Hypercalcemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Pancreas_MeSH S_drug_effects_MeSH Pancreas_drug_effects_MeSH S_physiology_MeSH Pancreas_physiology_MeSH M_Phenylalanine_MeSH S_administration_&_dosage_MeSH Phenylalanine_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH S_pharmacology_MeSH Phenylalanine_pharmacology_MeSH ****** 11031747 ----K E ----T [Pharmacological properties of nateglinide, rapid-onset/short-duration insulinotropic agent, in the treatment of type 2 diabetes] ----A An early defect in Type 2 diabetes is the loss of acute insulin release after food intake, which causes prolonged elevation of postprandial glucose levels. Suppressing postprandial hyperglycemia is considered to be very important for preventing diabetic complications. Sulfonylureas are well-known insulin secretagogues and have been widely used in the treatment of Type 2 diabetes. These agents, however, do not appear to be able to ameliorate impairment of the first phase of insulin secretion and postprandial hyperglycemia. Nateglinide, which is a derivative of D-phenylalanine, is a non-sulfonylurea insulin secretagogue. Although the in vitro insulin-releasing effect of nateglinide is similar to that of sulfonylureas, its hypoglycemic effect is more rapid and short lasting. The in vivo unique pharmacodynamic profile of nateglinide is likely to result from its rapid absorption and elimination. This novel antidiabetic agent has made it possible to compensate for the impaired first phase insulin response and thus suppresses postprandial hyperglycemia. In clinical trials, nateglinide reduced prandial glucose excursion and improved early phase of insulin release dose-dependently after 12 weeks treatment. Nateglinide is a highly physiologic mealtime glucose regulator, which rapidly increases insulin secretion when taken before meals, mimicking early-phase insulin release lost in patients with Type 2 diabetes. ----P Journal_Article Review Review_Literature ----M M_Animals_MeSH M_Cyclohexanes_MeSH S_pharmacology_MeSH Cyclohexanes_pharmacology_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_pharmacology_MeSH Phenylalanine_pharmacology_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH ****** 11060717 ----K I ----T Pharmacology and clinical experience with repaglinide. ----A Repaglinide (NovoNorm((R))) is a novel oral antidiabetic agent, the first of a new class of insulin secretagogues known as the prandial glucose regulators to be approved for use in patients with Type 2 diabetes. Prandial glucose regulation is aimed at restoring the first-phase insulin response that follows consumption of a meal, which is missing in patients with Type 2 diabetes. After repaglinide administration, the resulting insulin profile reflects that of healthy individuals more closely, providing tighter glycaemic control and reducing the risk of hypoglycaemic events. Repaglinide is quickly absorbed and rapidly eliminated through biliary excretion, making it suitable for use in patients with renal impairment. It appears in the bloodstream within 15 to 30 min of dosing, stimulating short-term insulin release from the pancreatic beta-cells by binding to a unique site on the beta-cell membrane. Rapid elimination ensures that postprandial insulin levels quickly return to preprandial levels as the high prandial glucose level subsides. Repaglinide is given on a 'one meal, one tablet; no meal, no tablet' basis. It is particularly effective in patients who have not previously been treated with an oral antidiabetic agent, significantly reducing glycosylated haemoglobin (HbA(1c)) levels by 1.6%. It also offers increased mealtime flexibility and safety, compared with other oral antidiabetic agents. As a result of the short plasma half-life and lack of accumulation of repaglinide with repeated dosing, the risk of between-meal and nocturnal hypoglycaemia is substantially reduced compared with other oral antidiabetic agents. Repaglinide acts synergistically with metformin, consistently improving glycaemic control in patients who were insufficiently controlled by metformin alone. Results from recent studies have shown similar synergistic effects with neutral protamine Hagedorn (NPH)-insulin or troglitazone. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Carbamates_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Eating_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Piperidines_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH ****** 11060747 ----K E ----T Insulin sensitiser drugs. ----A Insulin resistance is the predominant early pathological defect in Type 2 diabetes. As well as being a risk factor for the development of Type 2 diabetes, insulin resistance is also associated with increased cardiovascular risk and other metabolic disturbances including visceral adiposity, hyperinsulinaemia, impaired glucose tolerance, hypertension and dyslipidaemia [1-4]. The newest approach to oral antidiabetic therapy is to target improvements in insulin sensitivity at muscle, adipose tissue and hepatic level. This results in improvements in glycaemic control and other features of the insulin resistance syndrome, with potential long-term benefits in preventing/delaying the onset of diabetic complications and macrovascular disease. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH M_Insulin_Resistance_MeSH S_physiology_MeSH Insulin_Resistance_physiology_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH ****** 11070748 ----K E ----T The effect of oral hypoglycaemic agents on dyslipidaemia in Nigerian patients with newly diagnosed non-insulin dependent diabetes mellitus--a prospective study. ----A Thirty-five patients with non-insulin dependent diabetes (NIDDM) were treated and followed up for 24 weeks. Six of whom were managed with diet and/or metformin, nine received glibenclamide, twelve had a combination of metformin and glibenclamide, while the remaining eight patients received metformin and/or some other type of sulphonylurea (chlorpropamide or glipizide). By an analysis of variance, the different drug regimes showed equivalent glycaemic controlling effects, but the influence on dyslipidaemia was variable within the treatment groups, while these changes were insignificant between the groups. It is thus concluded that commonly used oral hypoglycaemic agents do not adversely affect plasma lipid levels in Nigerian patients with NIDDM. ----P Journal_Article ----M M_Administration__Oral_MeSH M_African_Continental_Ancestry_Group_MeSH M_Analysis_of_Variance_MeSH M_Chlorpropamide_MeSH S_therapeutic_use_MeSH Chlorpropamide_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_diagnosis_MeSH Diabetes_Mellitus__Type_II_diagnosis_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_blood_MeSH Hyperlipidemia_blood_MeSH S_complications_MeSH Hyperlipidemia_complications_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Nigeria_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11092289 ----K I ----T Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. ----A OBJECTIVE: To evaluate the efficacy and tolerability of nateglinide and metformin alone and in combination in type 2 diabetic patients inadequately controlled by diet, focusing on changes in HbA1c, fasting plasma glucose (FPG), and mealtime glucose excursions. RESEARCH DESIGN AND METHODS: In this randomized double-blind study, patients with an HbA1c level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172). HbA1c and FPG were evaluated regularly, and plasma glucose levels were determined after Sustacal challenge at weeks 0, 12, and 24. Hypoglycemia and other adverse events were recorded. RESULTS: At study end point, HbA1c was reduced from baseline with nateglinide and metformin but was increased with placebo (-0.5, -0.8, and +0.5%, respectively; P < or = 0.0001). Changes in FPG followed the same pattern (-0.7, -1.6, and +0.4 mmol/l; P < or = 0.0001). Combination therapy was additive (HbA1c -1.4% and FPG -2.4 mmol/l; P < or = 0.01 vs. monotherapy). After Sustacal challenge, there was a greater reduction in mealtime glucose with nateglinide monotherapy compared with metformin monotherapy or placebo (adjusted area under the curve [AUC]0-130 min -2.1, -1.1, and -0.6 mmol x h(-1) x l(-1); p < or = 0.0001). An even greater effect was observed with combination therapy (AUC0-130 min -2.5 mmol x h(-1) x l(-1); P < or = 0.0001 vs. metformin and placebo). All regimens were well tolerated. CONCLUSIONS: Nateglinide and metformin monotherapy each improved overall glycemic control but by different mechanisms. Nateglinide decreased mealtime glucose excursions, whereas metformin primarily affected FPG. In combination, nateglinide and metformin had complementary effects, improving HbA1c, FPG, and postprandial hyperglycemia. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cyclohexanes_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Eating_MeSH M_Ethnic_Groups_MeSH M_Fasting_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_United_States_MeSH ****** 11136298 ----K I ----T Effect of rifampicin on the pharmacokinetics and pharmacodynamics of glimepiride. ----A AIMS: To study the effects of rifampicin on the pharmacokinetics and pharmaco-dynamics of glimepiride, a new sulphonylurea antidiabetic drug. METHODS: In this randomised, two-phase cross-over study, 10 healthy volunteers were treated for 5 days with 600 mg rifampicin or placebo once daily. On day 6, a single oral dose of 1 mg glimepiride was administered. Plasma glimepiride and blood glucose concentrations were measured up to 12 h. RESULTS: Rifampicin decreased the mean area under the plasma concentration-time curve of glimepiride by 34% (P < 0.001) and the mean elimination half-life by 25% (P < 0.05). No significant differences in the blood glucose response to glimepiride were observed between the placebo and rifampicin phases. However, symptomatic hypoglycaemia occurred only during the placebo phase. CONCLUSIONS: The effects of rifampicin on the pharmacokinetics of glimepiride suggest that rifampicin induced the CYP2C9-mediated metabolism of glimepiride and thereby slightly increased its systemic clearance. Because the interaction was modest and did not significantly alter the glucose-lowering effect of glimepiride in healthy volunteers, it is probably of limited clinical significance. However, in some patients the hypoglycaemic effect of glimepiride may be reduced during concomitant treatment with rifampicin. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Antibiotics__Antitubercular_MeSH S_pharmacology_MeSH Antibiotics__Antitubercular_pharmacology_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cross-Over_Studies_MeSH M_Drug_Interactions_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Male_MeSH M_Rifampin_MeSH S_pharmacology_MeSH Rifampin_pharmacology_MeSH M_Sulfonylurea_Compounds_MeSH S_blood_MeSH Sulfonylurea_Compounds_blood_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11185672 ----K E ----T Pharmacokinetics and bioavailability of a metformin/glyburide tablet administered alone and with food. ----A Two randomized crossover studies were conducted to evaluate the pharmacokinetics (including food effect) of fixed-combination metformin/glyburide tablets. Pharmacokinetics and bioavailability of two strengths (500 mg/2.5 mg and 500 mg/5 mg) of metformin/glyburide tablets were assessed relative to coadministered metformin and glyburide tablets in study 1. The effect of a high-fat meal on the bioavailability of a metformin/glyburide (500 mg/5 mg) tablet was assessed relative to the fasted condition in study 2. The fixed combination metformin/glyburide tablets showed bioequivalence for the metformin component with the reference metformin tablet and comparable bioavailability for the glyburide component with the reference glyburide tablet. Food does not appear to affect the bioavailability of either component to an appreciable extent. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adolescent_MeSH M_Adult_MeSH M_Biological_Availability_MeSH M_Cross-Over_Studies_MeSH M_Female_MeSH M_Food-Drug_Interactions_MeSH M_Glyburide_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Male_MeSH M_Metformin_MeSH S_pharmacokinetics_MeSH Metformin_pharmacokinetics_MeSH M_Tablets_MeSH ****** 11116534 ----K E ----T Hypoglycemic, diuretic and hypocholesterolemic effect of winter cherry (Withania somnifera, Dunal) root. ----A Hypoglycemic, diuretic and hypocholesterolemic effects of roots of W. somnifera (ashvagandha) were assessed on human subjects. Six mild NIDDM subjects and six mild hypercholesterolemic subjects were treated with the powder of roots of W. somnifera for 30 days. Suitable parameters were studied in the blood and urine samples of the subjects along with dietary pattern before and at the end of treatment period. Decrease in blood glucose was comparable to that of an oral hypoglycemic drug. Significant increase in urine sodium, urine volume, significant decrease in serum cholesterol, triglycerides, LDL (low density lipoproteins) and VLDL (very low density lipoproteins) cholesterol were observed indicating that root of W. somnifera is a potential source of hypoglycemic, diuretic and hypocholesterolemic agents. Clinical observations revealed no adverse effects. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Anticholesteremic_Agents_MeSH S_adverse_effects_MeSH Anticholesteremic_Agents_adverse_effects_MeSH S_pharmacology_MeSH Anticholesteremic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Anticholesteremic_Agents_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Capsules_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diuresis_MeSH S_drug_effects_MeSH Diuresis_drug_effects_MeSH M_Diuretics_MeSH S_adverse_effects_MeSH Diuretics_adverse_effects_MeSH S_pharmacology_MeSH Diuretics_pharmacology_MeSH S_therapeutic_use_MeSH Diuretics_therapeutic_use_MeSH M_Human_MeSH M_Hypercholesterolemia_MeSH S_drug_therapy_MeSH Hypercholesterolemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Middle_Aged_MeSH M_Natriuresis_MeSH S_drug_effects_MeSH Natriuresis_drug_effects_MeSH M_Plant_Extracts_MeSH S_adverse_effects_MeSH Plant_Extracts_adverse_effects_MeSH S_pharmacology_MeSH Plant_Extracts_pharmacology_MeSH S_therapeutic_use_MeSH Plant_Extracts_therapeutic_use_MeSH M_Plant_Roots_MeSH S_chemistry_MeSH Plant_Roots_chemistry_MeSH M_Plants__Medicinal_MeSH S_chemistry_MeSH Plants__Medicinal_chemistry_MeSH M_Potassium_MeSH S_analysis_MeSH Potassium_analysis_MeSH M_Powders_MeSH M_Sodium_MeSH S_analysis_MeSH Sodium_analysis_MeSH M_Solanaceae_MeSH S_chemistry_MeSH Solanaceae_chemistry_MeSH ****** 11129129 ----K I ----T Management of type 2 diabetes mellitus and cardiovascular risk: lessons from intervention trials. ----A Although the diagnosis of type 2 (noninsulin-dependent) diabetes mellitus is made when blood glucose levels exceed values which increase the risk of microvascular complications, macrovascular disease is the major complication of type 2 diabetes mellitus. Both epidemiological and prospective data have demonstrated that treatment of hyperglycaemia is markedly effective in reducing the risk of microvascular disease but is less potent in reducing that of myocardial infarction, stroke and peripheral vascular disease. Treatment of other cardiovascular risk factors, although by definition less prevalent than hyperglycaemia, appears to be more effective in preventing macrovascular disease than treatment of hyperglycaemia. In recent years, data from intervention trials have suggested that greater benefits with respect to the prevention of macrovascular disease can be achieved by effective treatment of hypertension and hypercholesterolaemia, and by the use of small doses of aspirin (acetylsalicylic acid) than by treating hyperglycaemia alone. On the other hand, the UK Prospective Diabetes Study (UKPDS), which examined the impact of intensive glucose and blood pressure (BP) control on micro- and macrovascular complications, is the only intervention trial to include only patients with type 2 diabetes mellitus. The UKPDS data, the epidemic increase in the number of patients with type 2 diabetes mellitus and their high cardiovascular risk have, however, initiated several new trials addressing, in particular, the possible benefits of treatment of the most common form of dyslipidaemia (high serum triglyceride and low high density lipoprotein cholesterol levels) in these patients. Type 2 diabetes mellitus is thus a disease associated with a high vascular risk, where the majority of patients need, and are likely to benefit from, pharmacological treatment of several cardiovascular risk factors provided treatment targets have not been achieved by life-style modification. ----P Journal_Article Review Review__Tutorial ----M M_Antihypertensive_Agents_MeSH S_therapeutic_use_MeSH Antihypertensive_Agents_therapeutic_use_MeSH M_Cardiovascular_Diseases_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_complications_MeSH Hyperlipidemia_complications_MeSH S_prevention_&_control_MeSH Hyperlipidemia_prevention_&_control_MeSH M_Hypertension_MeSH S_complications_MeSH Hypertension_complications_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Intervention_Studies_MeSH M_Life_Style_MeSH M_Platelet_Aggregation_Inhibitors_MeSH S_therapeutic_use_MeSH Platelet_Aggregation_Inhibitors_therapeutic_use_MeSH M_Risk_Assessment_MeSH ****** 11130936 ----K I ----T Recent advances in the pharmacologic management of diabetes mellitus. ----A The importance of glucose control in reducing the complications of diabetes mellitus has been clearly demonstrated. The emergency physician routinely is expected to treat a wide range of problems related to this disease, including making the initial diagnosis of type 2 and occasionally type 1 diabetes. Also common are patients with poorly controlled diabetes. The recent introduction of new classes of agents to lower blood glucose, especially in type 2 diabetes, should improve the control in this category of patient and reduce the complication rate. Some of these agents, such as troglitazone, have potentially fatal complications and require careful monitoring. Emergency physicians should be aware of the common complications of these drugs because patients can present to the ED with them. Hypoglycemia, a common cause of 911 calls and emergency visits, is not a side effect of either metformin or acarbose. Insulin lispro has improved postprandial glycemic control for type 1 and some insulin-requiring type 2 diabetics. Hypoglycemia is less of a risk with insulin lispro, and quality of life is better with this rapidly acting insulin. Newer methods of insulin delivery, such as continuous subcutaneous infusion, have greatly improved glucose control, given greater freedom to patients, and reduced the risks of hypoglycemia. ----P Journal_Article Review Review__Tutorial ----M M_Acarbose_MeSH S_adverse_effects_MeSH Acarbose_adverse_effects_MeSH S_therapeutic_use_MeSH Acarbose_therapeutic_use_MeSH M_Administration__Oral_MeSH M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Chromans_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus_MeSH S_drug_therapy_MeSH Diabetes_Mellitus_drug_therapy_MeSH M_Emergencies_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Overdose_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 11194240 ----K E ----T Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. ----A OBJECTIVE: Because a pseudonormal pattern of ventricular filling has never been considered in studies that reported a prevalence of left ventricular diastolic dysfunction (LVDD) between 20 and 40%, our aim was to more completely evaluate the prevalence of LVDD in subjects with diabetes. RESEARCH DESIGN AND METHODS: We studied 46 men with type 2 diabetes who were aged 38-67 years; without evidence of diabetic complications, hypertension, coronary artery disease, congestive heart failure, or thyroid or overt renal disease; and with a maximal treadmill exercise test showing no ischemia. LVDD was evaluated by Doppler echocardiography, which included the use of the Valsalva maneuver and pulmonary venous recordings to unmask a pseudonormal pattern of left ventricular filling. RESULTS: LVDD was found in 28 subjects (60%), of whom 13 (28%) had a pseudonormal pattern of ventricular filling and 15 (32%) had impaired relaxation. Systolic function was normal in all subjects, and there was no correlation between LVDD and indexes of metabolic control. CONCLUSIONS: LVDD is much more common than previously reported in subjects with well-controlled type 2 diabetes who are free of clinically detectable heart disease. The high prevalence of this phenomenon in this high-risk population suggests that screening for LVDD in type 2 diabetes should include procedures such as the Valsalva maneuver and pulmonary venous recordings to unmask a pseudonormal pattern of ventricular filling. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH P_Diastole_MeSH M_Echocardiography_MeSH M_Exercise_Test_MeSH M_Human_MeSH M_Laser-Doppler_Flowmetry_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Pulmonary_Veins_MeSH M_Support__Non-U_S__Gov't_MeSH M_Valsalva_Maneuver_MeSH M_Ventricular_Dysfunction__Left_MeSH S_etiology_MeSH Ventricular_Dysfunction__Left_etiology_MeSH S_physiopathology_MeSH Ventricular_Dysfunction__Left_physiopathology_MeSH ****** 11194214 ----K I ----T Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes. ----A OBJECTIVE: This double-blind randomized placebo-controlled parallel group study assessed the efficacy and safety (with particular regard to body weight and hypoglycemia) of repaglinide when used in a flexible mealtime dosing regimen in a situation close to everyday clinical practice. RESEARCH DESIGN AND METHODS: A total of 408 patients with type 2 diabetes considered poorly controlled by diet, but without a history of previous antidiabetic medication, were randomized to receive 0.5 mg repaglinide at mealtimes (increased to 1 mg after 4 weeks depending on blood glucose response) or placebo for 16 weeks. Patients were free to choose a flexible meal pattern, adjusting the dosing schedule from two to four preprandial doses per day in accordance with a "one meal, one dose; no meal, no dose" principle. Additional snacks were not a requirement of the treatment schedule. RESULTS: Treatment with repaglinide significantly improved glycemic control with respect to baseline and placebo, reducing HbA1c by 1.14% from baseline and fasting plasma glucose by 1.8 mmol/l. Improvement in glycemic control was independent of the meal pattern adopted by patients, including those most commonly taking two or four meals daily, with no correlation between meal pattern and risk of hypoglycemia. The improvement in glycemic control was also independent of degree of obesity and age < or =65 or >65 years. There was no significant body weight increase in the repaglinide group. CONCLUSIONS: Mealtime dosing with repaglinide is effective in improving overall glycemic control in type 2 diabetic patients for which control is suboptimal using diet alone. Patients are able to vary their meal pattern from a conventional regimen of three meals daily without compromising control or increasing the risk of adverse events. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diet_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH P_Food_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Placebos_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11194245 ----K I ----T Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo. ----A OBJECTIVE: This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects. RESEARCH DESIGN AND METHODS: Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose. RESULTS: Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 microU x ml(-1) x min(-1), respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose. CONCLUSIONS: In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adolescent_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Body_Weight_MeSH M_Carbamates_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Cyclohexanes_MeSH S_administration_&_dosage_MeSH Cyclohexanes_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH S_pharmacology_MeSH Cyclohexanes_pharmacology_MeSH M_Female_MeSH P_Food_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Kinetics_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_administration_&_dosage_MeSH Phenylalanine_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH S_pharmacology_MeSH Phenylalanine_pharmacology_MeSH M_Piperidines_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH M_Placebos_MeSH M_Time_Factors_MeSH ****** 11200947 ----K I ----T Impairment of early insulin response after glucose load, rather than insulin resistance, is responsible for postprandial hyperglycemia seen in obese type 2 diabetes: assessment using nateglinide, a new insulin secretagogue. ----A The insulin secretory pattern as a phenotype of type 2 diabetes is an impairment in the rapid, pulsatile secretion of insulin in response to a rise in blood glucose after meal-intake. The restoration of endogenous rapid insulin secretion after oral glucose load was established for the first time by using nateglinide, which is a newly developed insulin secretagogue, in obese patients with type 2 diabetes mellitus. It was clearly demonstrated that with nateglinide, serum insulin levels were quickly raised, and glycemic response curves were almost normalized with the same amount of insulin secretion during 180 min. Therefore, the lack of rapid, pulsatile secretion of insulin in response to glycemic rise after oral glucose load, rather than insulin resistance, is responsible for postprandial glycemic response in obese type 2 diabetes patients. ----P Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Cyclohexanes_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Glucose_MeSH S_diagnostic_use_MeSH Glucose_diagnostic_use_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH S_physiopathology_MeSH Hyperglycemia_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH P_Insulin_Resistance_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Obesity_MeSH S_complications_MeSH Obesity_complications_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Postprandial_Period_MeSH ****** 11200307 ----K I ----T Beneficial and detrimental effects of intensive glycaemic control, with emphasis on type 2 diabetes mellitus. ----A Diabetes mellitus is a major health problem in the world. Several clinical trials have shown that some of the major complications of diabetes mellitus can be partially prevented or delayed by intensive glycaemic control. However, there are benefits and risks in aiming for near normal blood glucose levels. Intensive glycaemic control delays the onset and progression of retinopathy, nephropathy and neuropathy. Epidemiological and observational studies have shown that cardiovascular events may be correlated with the severity and duration of diabetes mellitus, but major randomised trials have only shown weak and nonsignificant benefits of intensive glycaemic management in decreasing event rates. A modest improvement in lipid profile results from blood glucose control although, in the majority of cases, not enough to reach current targets. Detrimental effects of intensive glycaemic control include bodyweight gain and hypoglycaemia. Controversial issues in the management of patients with diabetes mellitus include the unproven increase in cardiovascular morbidity from sulphonylureas and hyperinsulinaemia, and the still unknown long term effects of newer oral antihyperglycaemic agents alone or in combination with traditional therapies (such as sulphonylureas and metformin). It is important to individualise management in setting glycaemic goals. Control of cardiovascular risk factors through blood pressure and lipid control and treatment with aspirin (acetylsalicylic acid) and ACE inhibitors have consistently shown benefits in the prevention of both macro- and microvascular complications in patients with diabetes mellitus; these measures deserve priority. ----P Journal_Article Review Review_Literature ----M M_Blindness_MeSH S_etiology_MeSH Blindness_etiology_MeSH S_prevention_&_control_MeSH Blindness_prevention_&_control_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Cardiovascular_Diseases_MeSH S_etiology_MeSH Cardiovascular_Diseases_etiology_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hyperinsulinism_MeSH S_chemically_induced_MeSH Hyperinsulinism_chemically_induced_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH M_Kidney_Failure__Chronic_MeSH S_etiology_MeSH Kidney_Failure__Chronic_etiology_MeSH S_prevention_&_control_MeSH Kidney_Failure__Chronic_prevention_&_control_MeSH M_Male_MeSH M_Risk_MeSH M_Weight_Gain_MeSH S_drug_effects_MeSH Weight_Gain_drug_effects_MeSH S_physiology_MeSH Weight_Gain_physiology_MeSH ****** 11460818 ----K E ----T Oral antidiabetic treatment in patients with coronary disease: time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up. ----A BACKGROUND: A sulfonylurea--usually glyburide--plus metformin constitute the most widely used oral antihyperglycemic combination in clinical practice. Both medications present undesirable cardiovascular effects. The issue whether the adverse effects of each of these pharmacologic agents may be additive and detrimental to the prognosis for coronary patients has not yet been specifically addressed. HYPOTHESIS: This study was designed to examine the survival in type 2 diabetics with proven coronary artery disease (CAD) receiving a combined glyburide/metformin antihyperglycemic treatment over a long-term follow-up period. METHODS: The study sample comprised 2,275 diabetic patients, aged 45-74 years, with proven CAD, who were screened but not included in the bezafibrate infarction prevention study. In addition, 9,047 nondiabetic patients with CAD represented a reference group. Diabetics were divided into four groups on the basis of their therapeutic regimen: diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a combination of the latter two (n = 253). RESULTS: The diabetic groups presented similar clinical characteristics upon recruitment. Crude mortality rate after a 7.7-year follow-up was lower in nondiabetics (14 vs. 31.6%, p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%), 324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients (43.9%) on combined treatment (p<0.000001). Time-related mortality was almost equal for patients on metformin and on combined therapy over an intermediate follow-up period of 4 years (survival rates 0.80 and 0.79, respectively). The group on combined treatment presented the worst prognosis over the long-term follow-up, with a time-related survival rate of 0.59 after 7 years, versus 0.68 and 0.70 for glyburide and metformin, respectively. After adjustment to variables for prognosis, the use of the combined treatment was associated with an increased hazard ratio (HR) for all-cause mortality of 1.53 (95% confidence interval [CI] 1.20-1.96), whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02-1.45) and HR 1.26 (95% CI 0.81-1.96), respectively. Conclusions: We conclude that after a 7.7-year follow-up, monotherapy with either glyburide or metformin in diabetic patients with CAD yielded a similar outcome and was associated with a modest increase in mortality. However, time-related mortality was markedly increased when a combined glyburide/metformin treatment was used. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Coronary_Disease_MeSH S_complications_MeSH Coronary_Disease_complications_MeSH S_mortality_MeSH Coronary_Disease_mortality_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Survival_Analysis_MeSH M_Time_Factors_MeSH ****** 11214781 ----K I ----T Effects and pharmacokinetics of oral glibenclamide and glipizide in Caucasian and Chinese patients with type-2 diabetes. ----A The effects and kinetics of oral glibenclamide (Gb) and glipizide (Gz) were studied in Caucasian and Chinese patients (ten in each group) with type-2 diabetes. In randomised order, 2.5 mg Gb, 2.5 mg Gz or placebo was given orally before the administration of 75 g oral glucose. Concentrations of insulin and proinsulin were determined using radioimmunoassay (RIA) without cross-reactivities, and sulphonylurea concentrations were determined using high-performance liquid chromatography (HPLC). There were no significant interethnic differences in Gb or Gz effects whether on glucose, insulin or proinsulin/insulin ratio at any time point. Following Gz, however, Chinese patients had greater increments of serum proinsulin at 10-30 min compared with Caucasians. Apart from the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of Gz being higher among the Chinese, no significant interethnic differences in pharmacokinetics were found. It appears that the same dosage principles could be used for Caucasian and Chinese patients with type-2 diabetes when Gb or Gz are prescribed. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Asian_Continental_Ancestry_Group_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_European_Continental_Ancestry_Group_MeSH M_Female_MeSH M_Glipizide_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glucose_Tolerance_Test_MeSH M_Glyburide_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Half-Life_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11168335 ----K I ----T Near-normoglycaemic remission in African-Americans with Type 2 diabetes mellitus is associated with recovery of beta cell function. ----A AIMS: To prospectively determine the frequency of remission and possible mechanism of beta cell recovery in non-Whites with Type 2 diabetes mellitus in the setting of intensive glycaemic regulation using pharmacological agents. METHODS: Twenty-six consecutive, newly diagnosed African-American, Type 2 diabetic patients presenting primarily for severe hyperglycaemia (31.0+/-12.8 mmol/l) were followed for at least 1 year. Initial hospitalization included treatment with insulin, fluids and electrolytes. Outpatient intensive glycaemic regulation included insulin or glibenclamide, diabetes education and diet that altered nutrient content. Plasma glucose and C-peptide responses to an oral glucose tolerance test and HbA1c were measured at < 14, 15-56 and 57-112 days after presentation. Remission was defined as a HbA1c < or = 6.3% and fasting plasma glucose < 6.9 mmol/l, 3 months after discontinuing all pharmacological agents. RESULTS: Eleven of 26 patients (42.3%) developed remission after a mean of 83 days of pharmacological treatment and remained in remission during follow-up for 248-479 days; one relapsed after 294 days. Fifteen patients who did not develop a remission and were followed for 168-468 days, required continuing pharmacological therapy to be well-controlled. (mean HbA1c = 7.1%). There was no significant difference in age, sex, plasma glucose at presentation, initial glycaemic regulation, final body mass index, magnitude of weight change or pharmacological agents used for treatment between the two groups. Plasma C-peptide response to oral glucose was initially (< 14 days) suppressed in all subjects and subsequently increased. The increase was significantly greater in those who underwent a remission than those who did not. Neither significant weight loss nor severe hypoglycaemia was observed in either group during intensive treatment. CONCLUSIONS: Forty-two per cent of newly diagnosed, unselected African-Americans with Type 2 diabetes, treated intensively using pharmacological agents, education and diet developed near-normoglycaemic remission. Remission was associated with a greater recovery of glucose-stimulated insulin secretion suggesting that therapies directed at promoting beta cell recovery and preservation are potentially useful approaches to the treatment of Type 2 diabetes mellitus. ----P Journal_Article ----M M_African_Americans_MeSH P_African_Continental_Ancestry_Group_MeSH M_Aged_MeSH M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH S_secretion_MeSH C-Peptide_secretion_MeSH M_Combined_Modality_Therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Diabetic_Diet_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH P_Hyperglycemia_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_physiopathology_MeSH Islets_of_Langerhans_physiopathology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_New_York_City_MeSH M_Patient_Education_MeSH M_Prospective_Studies_MeSH M_Time_Factors_MeSH ****** 11220549 ----K E ----T Using dose-response characteristics of therapeutics agents for treatment decisions in type 2 diabetes. ----A OBJECTIVE: We have shown that a positive family history of diabetes, and the variables of general and central obesity are independent risk factors for type 2 diabetes in our population. This study was done to evaluate whether a familial predisposition to diabetes resulted in a tendency for adverse anthropometric and haemodynamic profiles in south Indian non-diabetic subjects. METHODS: The analysis was carried out on 2463 subjects (M: F, 1196: 1267) with normal glucose tolerance (NGT). The study subjects were selected from population surveys for diabetes. Details of age, sex, family history of diabetes, body mass index (b.m.i.), waist-to-hip ratio (WHR) and blood pressure were recorded. Serum cholesterol and triglycerides were estimated. RESULTS: A positive family history of diabetes was present in 24.7% of our subjects. Mean b.m.i. and percentage of obesity were significantly higher in families with a positive family history (group 2) vs. families with no family history (group 1). Subjects in group 2 had a higher 2-h plasma glucose (p < 0.001) and higher prevalence of hypertension (chi2 = 6.91, p = 0.0086). Factor analysis with principle components analysis (PCA) showed that a family history of diabetes clustered with WHR in men, and with b.m.i. and WHR in women. The b.m.i. formed a different domain with blood pressure in both sexes. WHR and b.m.i. clustered with cholesterol and triglycerides in another domain. CONCLUSIONS: In this population, general and central obesity are associated with a family history of diabetes. A family history of diabetes may increase the risk of hypertension and hyperlipidaemia indirectly through its connection with b.m.i. ----P Journal_Article Review Review__Tutorial ----M M_Acarbose_MeSH S_therapeutic_use_MeSH Acarbose_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Therapy__Combination_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 11225747 ----K E ----T Leptin concentrations are related to glycaemic control, but do not change with short-term oral antidiabetic therapy in female patients with type 2 diabetes mellitus. ----A This study evaluated the relation of leptin with glycaemic control and the effect of 14 days of diet, or diet combined with gliclazide, glipizide-GITS or metformin treatment, on leptin concentration in 51 female patients with type 2 diabetes mellitus. Leptin levels were similar both at baseline and after treatment in diabetic and control groups. Diabetic patients with basal fasting plasma glucose (FPG) < 10 mmol/l or with basal postprandial plasma glucose (PPPG) < 13.9 mmol/l had significantly higher leptin levels than diabetic patients with basal FPG > or = 10 mmol/l or with basal PPPG > or = 13.9 mmol/l (19.6+/-8.7 vs. 13.65+/-5.4 microg/l, p < 0.05; and 20.2+/-7.9 vs. 12.9+/-5.2 microg/l, p < 0.05, respectively). Mode of treatment did not influence leptin levels. Delta leptin showed a weak correlation with basal FPG (r = 0.346; p < 0.05), basal and post-treatment PPPG (r = 0.335, p < 0.05 and r = 0.325, p < 0.05, respectively) and a moderate correlation with post-treatment FPG (r = 0.391, p < 0.01). In conclusion, leptin level is not affected by the presence of type 2 diabetes mellitus and by short-term treatment with diet or oral antidiabetic drugs but is directly related to glycaemic control in female patients with type 2 diabetes mellitus. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Diet_MeSH M_Fasting_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Leptin_MeSH S_blood_MeSH Leptin_blood_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Reference_Values_MeSH M_Regression_Analysis_MeSH ****** 11225164 ----K I ----T FDA approves nateglinide for treatment of type 2 diabetes. ----A ----P News ----M M_Cyclohexanes_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Approval_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_United_States_MeSH M_United_States_Food_and_Drug_Administration_MeSH ****** 11273476 ----K E ----T Serum insulin assay: an important therapeutic tool in management of freshly diagnosed type 2 diabetes mellitus. ----A OBJECTIVES: The study was performed to see that, whether metabolic control and response to treatment in freshly diagnosed patients of type 2 diabetes mellitus is affected by primary pathology (hyperinsulinemia/inappropriate insulin secretion). METHODS: One hundred and eight freshly diagnosed patients of type 2 diabetes mellitus with age range from 30-65 years were followed for a period of three months. The blood glucose, serum triglyceride, and serum insulin levels were determined in each patient. Patients were found to have either higher or normal to low serum insulin values at fasting, and accordingly patients were distributed into two groups; group one (normal to low initial fasting serum insulin level i.e. < or = 30 microU/ml) and group two (high fasting serum insulin level i.e. > or = 30 microU/ml). Each group was further divided into two subgroups A and B. Subgroup A was treated with glipizide and B with metformin. RESULTS: Diabetic patients who had fasting hyperinsulinemia (n = 53, 100%) had blood pressure > or = 140/90 at the time of presentation. Patients who had fasting serum insulin within normal range only 30% (n = 17) had hypertension. Patients of group one had good recovery from hyperglycemia and reduction in triglyceride values when treated with sulphonylurea (subgroup A) as compared to patients treated with biguanide (subgroup B). On the contrary patients of group two showed poor glycemic control, increase in blood pressure and rise in serum triglyceride titre when treated with sulphonylurea (subgroup A) while in the same group biguanide effectively produced euglycemia with normalization of blood pressure and decrease in triglyceride levels (subgroup B). CONCLUSION: Assessment of initial serum insulin levels is helpful guide to decide about the type of oral hypoglycemic agent to be used in freshly diagnosed patients to type 2 diabetes mellitus. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diagnosis_MeSH Diabetes_Mellitus__Type_II_diagnosis_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glipizide_adverse_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH M_Middle_Aged_MeSH M_Treatment_Outcome_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 11228758 ----K E ----T Effects of antihyperglycaemic therapies on proinsulin and relation between proinsulin and cardiovascular risk factors in type 2 diabetes. ----A AIM: To assess the effect of oral antihyperglycaemic therapy on fasting proinsulin and the relation between proinsulin levels and cardiovascular risk factors in type 2 diabetes. METHODS: One hundred and sixty-five patients with type 2 diabetes, fasting blood glucose concentration (FBG) > or = 6.7 mmol/l, were recruited from five diabetes outpatient clinics in primary health care. Diet and antihyperglycaemic medication, aiming at FBG < 6.7 mmol/l, was maintained for 6 months after completed dose titration in a randomized, double-blind, double-dummy trial with metformin (M), glibenclamide (G) and primary combination of both drugs (MG). The study compared M, G and MG in low dose (MGL) and also different high-dose regimens, i.e. G added to M (M/G), M added to G (G/M) and primary combination (MGH). Outcome measures were fasting proinsulin, glycaemia, body mass index, blood pressure, lipids, insulin and C-peptide. RESULTS: Lower proinsulin levels were found when therapy was initiated with metformin (M vs. G, p = 0.013 and M/G vs. G/M, p = 0.033). M and G were equally effective on glucose levels. In the group as a whole FBG decreased from (mean +/- s.d.) 10.2 +/- 2.7 to 7.0 +/- 1.2 mmol/l with no change in proinsulin. Proinsulin was associated with cardiovascular risk factors, linking high proinsulin to an atherogenic risk marker profile. Mean proinsulin change from baseline was inconsistently associated with markers of insulin resistance. Meal-stimulated glucose (net AUC) decreased after treatment only in those with low baseline proinsulin levels. CONCLUSION: It may be advantageous to initiate oral antihyperglycaemic therapy with metformin rather than with sulphonylurea. High proinsulin levels are associated with an atherogenic-risk marker profile and an impaired therapeutic postprandial glucose response after treatment in patients with type 2 diabetes. Proinsulin change after therapy is inconsistently associated with markers of insulin resistance and unrelated to fasting blood glucose reduction. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH M_Body_Mass_Index_MeSH M_Cardiovascular_Diseases_MeSH S_epidemiology_MeSH Cardiovascular_Diseases_epidemiology_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Diet_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Observer_Variation_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH M_Risk_Factors_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 11232737 ----K I ----T Management of type 2 diabetes mellitus in the elderly: special considerations. ----A The principles of managing type 2 diabetes mellitus in the elderly are no different from those in younger patients, but the priorities and therapeutic strategies need to be cautiously individualised. The objectives of treatment are to improve glycaemic control in a stepwise approach that involves nonpharmacological methods including diet and exercise, and pharmacological therapy including mixtures of oral antihyperglycaemic agents alone or in combination with insulin. Although the goals of treatment may be the same for elderly and younger patients, certain aspects of type 2 diabetes in the elderly require special consideration. Treatment decisions are influenced by age and life expectancy, comorbid conditions and severity of the vascular complications. Adherence to dietary therapy, physical activity, and medication regimens may be compromised by comorbid conditions and psychosocial limitations. Drug-induced hypoglycaemia has been the main consideration and the most serious potential complication. In addition, the long term macrovascular and microvascular complications of type 2 diabetes are a source of significant morbidity and mortality. Indeed, vascular and neuropathic complications are already present at the time of diagnosis in a significant number of patients, and the impact of improved diabetes control depends on the age and life expectancy of the patient. Age-related changes in pharmacokinetics and the potential for adverse effects and drug interactions should also be considered when choosing appropriate pharmacological therapy. In general, a conservative and stepwise approach to the treatment of the elderly patient with type 2 diabetes is suggested; treatment may be initiated with monotherapy, followed by early intervention with a combination of oral agents including a sulphonylurea as a foundation insulin secretagogue in addition to a supplemental insulin sensitiser. Insulin therapy is eventually required if significant hyperglycaemia [glycosylated haemoglobin (HbA1c) >8%] persists despite oral combination therapy. Combination therapy with evening insulin and a long-acting sulphonylurea such as glimepiride is an effective strategy to improve hyperglycaemia in the elderly patient with type 2 diabetes in whom polypharmacy with oral agents is unsuccessful. In addition, such a regimen is simple to follow for the patient who may not be able to adhere to a more complicated insulin regimen. Hyperglycaemia in the elderly can be managed well with practical intervention and a straightforward treatment plan to enhance compliance. Optimal glycaemic control should be possible for every patient if treatment is individualised; however, strict glycaemic control may not be achievable in all patients or even desirable in many elderly patients. ----P Journal_Article Review Review__Tutorial ----M M_Aged_MeSH P_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Therapy__Combination_MeSH P_Geriatrics_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 11257323 ----K E ----T The short-term effect of a switch from glibenclamide to metformin on blood pressure and microalbuminuria in patients with type 2 diabetes mellitus. ----A BACKGROUND: Renal hyperfiltration and albuminuria have a deleterious effect on kidney function. Therefore, we studied the effect of metformin on blood pressure, renal hemodynamics, and microalbuminuria in type 2 diabetic patients. METHODS: A clinical trial was designed in type 2 diabetic patients with incipient nephropathy. All patients were below the age of 65, normotensive, and without evidence of malignant, hepatic, or cardiovascular disorders. They were randomly allocated to receive glibenclamide or metformin. At baseline and 12 weeks thereafter we measured body mass index (BMI), serum insulin, blood glucose, lipid profile, glycosylated hemoglobin, blood pressure, glomerular filtration rate, renal plasma flow, and urine albumin. RESULTS: We studied 23 patients in the glibenclamide group and 28 in the metformin group. There was no difference in baseline variables between the groups. Metabolic control was obtained in both groups. In the metformin group, all the following variables decreased: microalbuminuria was reduced by a mean of 24.2 mg/day (p = 0.008); systolic and diastolic blood pressure by a mean of 5.3 mmHg (p = 0.002) and 3.93 mmHg (p = 0.009), respectively; insulin levels by an average of 11.8 microIU/mL (p = 0.001), and total cholesterol levels and triglycerides by an average of 0.45 and 0.18 mmol/L, respectively. Insulin resistance measured by the homeostasis model decreased more in the metformin group than in the glibenclamide group. Patients treated with glibenclamide had an increase in HDL cholesterol of 0.082 mmol/L (p = 0.01). CONCLUSIONS: Metformin significantly decreased the urine albumin excretion rate with none of the expected changes in renal hemodynamics, probably due to its favorable effects on blood pressure, lipid profile, metabolic control, and insulin resistance. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Albuminuria_MeSH S_drug_therapy_MeSH Albuminuria_drug_therapy_MeSH S_etiology_MeSH Albuminuria_etiology_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Body_Mass_Index_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_urine_MeSH Diabetes_Mellitus__Type_II_urine_MeSH M_Diabetic_Nephropathies_MeSH S_drug_therapy_MeSH Diabetic_Nephropathies_drug_therapy_MeSH S_physiopathology_MeSH Diabetic_Nephropathies_physiopathology_MeSH S_urine_MeSH Diabetic_Nephropathies_urine_MeSH M_Female_MeSH M_Glomerular_Filtration_Rate_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Insulin_Resistance_MeSH M_Kidney_MeSH S_drug_effects_MeSH Kidney_drug_effects_MeSH S_physiopathology_MeSH Kidney_physiopathology_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Renal_Circulation_MeSH S_drug_effects_MeSH Renal_Circulation_drug_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH ****** 11277315 ----K E ----T Insulin release form isolated, human islets after acute or prolonged exposure to glimepiride. ----A ----P Letter ----M M_Adult_MeSH M_Female_MeSH M_Glucose_MeSH S_administration_&_dosage_MeSH Glucose_administration_&_dosage_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_analysis_MeSH Insulin_analysis_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11289470 ----K E ----T Role of common sequence variants in insulin secretion in familial type 2 diabetic kindreds: the sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1alpha genes. ----A OBJECTIVE: We have demonstrated high heritability of insulin secretion measured as acute insulin response to glucose times insulin sensitivity (disposition index). Furthermore, we showed that obese normoglycemic family members of a type 2 diabetic proband failed to compensate for the insulin resistance of obesity by increasing insulin secretion. In this study, we tested the primary hypotheses that previously described variants in the pancreatic sulfonylurea receptor gene (SUR1 or ABCC8), glucokinase (GCK) gene, or hepatocyte nuclear factor 1alpha (TCF1 or HNF1alpha) gene contribute to the inherited deficiencies of insulin secretion and beta-cell compensation to insulin resistance, as well as the secondary hypotheses that these variants altered insulin sensitivity. RESEARCH DESIGN AND METHODS: We typed 124 nondiabetic members of 26 familial type 2 diabetic kindreds who had undergone tolbutamide-modified intravenous glucose tolerance tests for two variants of the ABCC8 (sulfonylurea) gene, two variants of the GCK gene, and one common amino acid variant in the TCF1 (HNF1alpha) gene. All family members were classified as normal or having impaired glucose tolerance based on oral glucose tolerance testing. We used minimal model analysis to calculate the insulin sensitivity index (S1) and glucose effectiveness (SG), and acute insulin response to glucose was calculated as the mean insulin excursion above baseline during the first 10 min after the glucose bolus. Disposition index (DI), a measure of beta-cell compensation for insulin sensitivity, was calculated as insulin sensitivity times acute insulin response. Effects of polymorphisms were determined using mixed effects models that incorporated family membership and by a likelihood analysis that accounted for family structure through polygenic inheritance. RESULTS: An intronic variant of the ABCC8 gene just upstream of exon 16 was a significant determinant of both DI and an analogous index based on acute insulin response to tolbutamide. Surprisingly, heterozygous individuals showed the lowest indexes, whereas the DI in the two homozygous states did not differ significantly. Neither the exon 18 variant nor the variants in the GCK and TCF1 genes were significant in this model. However, combined genotypes of ABCC8 exon 16 and 18 variants again significantly predicted both indexes of glucose and tolbutamide-stimulated insulin secretion. Unexpectedly, a variant in the 3' untranslated region of the GCK gene interacted significantly with BMI to predict insulin sensitivity. CONCLUSIONS: The exon 16 variant of the ABCC8 gene reduced beta-cell compensation to the decreased insulin sensitivity in the heterozygous state. This may explain the observation from several groups of an association of the ABCC8 variants in diabetes and is consistent with other studies showing a role of ABCC8 variants in pancreatic beta-cell function. However, our study focused on individuals from relatively few families. Ascertainment bias, family structure, and other interacting genes might have influenced our unexpected result. Additional studies are needed to replicate our observed deficit in beta-cell compensation in individuals heterozygous for ABCC8 variants. Likewise, the role of the GCK 3' variant in the reduced insulin sensitivity of obesity will require further study. ----P Journal_Article ----M M_Diabetes_Mellitus__Type_II_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH M_Female_MeSH M_Genotype_MeSH M_Glucokinase_MeSH S_genetics_MeSH Glucokinase_genetics_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Insulin_Resistance_MeSH M_Islets_of_Langerhans_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Male_MeSH M_Obesity_MeSH S_genetics_MeSH Obesity_genetics_MeSH S_physiopathology_MeSH Obesity_physiopathology_MeSH M_Potassium_Channels_MeSH S_genetics_MeSH Potassium_Channels_genetics_MeSH M_Receptors__Drug_MeSH S_genetics_MeSH Receptors__Drug_genetics_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Transcription_Factors_MeSH S_genetics_MeSH Transcription_Factors_genetics_MeSH P_Variation_(Genetics)_MeSH ****** 11289484 ----K E ----T Blood pressure does not rise before the onset of microalbuminuria in children followed from diagnosis of type 1 diabetes. Oxford Regional Prospective Study Group. ----A OBJECTIVE: To examine whether a rise in blood pressure could be detected before the onset of microalbuminuria (MA) in a cohort of children followed from diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: The Oxford Regional Prospective Study is an incident cohort study of children with type 1 diabetes aged (mean +/- SD) 9.8 +/- 3.7 years at diagnosis. Subjects were assessed annually from diagnosis, with measurement of HbA1c, arterial blood pressure (random zero), and three urine samples for estimation of the albumin/creatinine ratio. During follow-up, 63 of 494 children developed MA at one or more annual assessments and were designated as cases for a nested case-control study. Each case was matched for sex and age at diagnosis with two normoalbuminuric control subjects. Blood pressure (BP) data were compared at corresponding years of diabetes duration. RESULTS: Cases with MA were similar to normoalbuminuric control subjects with respect to age and BMI, but they had higher mean HbA1c levels (mean difference 1.1%, P < 0.001). In the years before the onset of MA, the diastolic BP standard deviation score (SDS) was significantly higher than zero in cases (mean 0.49, P < 0.001) and in control subjects (0.50, P < 0.001). No difference could be detected between cases and control subjects before the onset of MA in either systolic or diastolic BP (mean difference systolic -1.2 mmHg [95% CI -4.7 to 2.7], mean difference diastolic 0.1 mmHg [-2.4 to 2.6]). However, within the cases, the onset of MA was associated with elevations in systolic and diastolic BP SDSs (F = 16.1, P < 0.001; and F = 18.0, P < 0.001). BMI, but not HbA1c, was associated with systolic and diastolic BP SDSs in the subjects with MA (F = 0.6, P = 0.4; and F = 12.3, P = 0.001). However, the association of BP with MA remained signifcant for systolic BP (P = 0.001) and for diastolic BP (P < 0.001) after adjusting for BMI. CONCLUSIONS: A rise in systemic BP cannot be detected before the first appearance of MA in children with type 1 diabetes. BP rises concurrently with the onset of MA and is also closely related to BMI. ----P Journal_Article Multicenter_Study ----M P_Albuminuria_MeSH M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH P_Blood_Pressure_MeSH M_Body_Mass_Index_MeSH M_Child_MeSH M_Cohort_Studies_MeSH M_Creatinine_MeSH S_urine_MeSH Creatinine_urine_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_I_physiopathology_MeSH S_urine_MeSH Diabetes_Mellitus__Type_I_urine_MeSH M_Diastole_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypertension_MeSH S_epidemiology_MeSH Hypertension_epidemiology_MeSH M_Male_MeSH M_Reference_Values_MeSH M_Support__Non-U_S__Gov't_MeSH M_Systole_MeSH M_Time_Factors_MeSH ****** 11301562 ----K E ----T Lipid and lipoprotein responses to oral combined hormone replacement therapy in normolipemic obese women with controlled type 2 diabetes mellitus. ----A This study investigated the effects of oral combined hormone replacement therapy (OCHRT) on lipid concentrations and subpopulation distribution of lipoproteins in nine postmenopausal women with type 2 diabetes mellitus and moderate glycemic control. After 16 weeks of continuous daily therapy of conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg, the mean concentration of high-density lipoprotein (HDL) cholesterol showed a statistically significant increase of 16.7%, predominantly in the HDL2 subfraction. No statistically significant changes in mean concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, very low-density lipoprotein (VLDL) triglycerides, apolipoprotein A1, or apolipoprotein B were evident. Likewise, no changes were found in the average diameter of VLDL, LDL, or HDL particles; triglyceride concentrations of VLDL subfractions; cholesterol concentrations of LDL subfractions; or chemical composition of plasma LDL. These findings lend further support to the use of OCHRT in postmenopausal women with diabetes to decrease their risk for coronary artery disease. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH P_Estrogen_Replacement_Therapy_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Lipoproteins_MeSH S_blood_MeSH Lipoproteins_blood_MeSH M_Middle_Aged_MeSH M_Obesity_MeSH S_blood_MeSH Obesity_blood_MeSH M_Particle_Size_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 11305519 ----K I ----T Hemodynamic, metabolic and hormonal responses to oral glibenclamide in patients with cirrhosis receiving glucose. ----A BACKGROUND: In patients with cirrhosis, glucose may induce splanchnic and renal vasodilation. Since the antidiabetic sulfonylurea glibenclamide is known to induce splanchnic and renal vasoconstriction in portal hypertensive animals, this drug may inhibit glucose-induced hemodynamic responses in patients with cirrhosis. The aim of the present study was to investigate, in patients with cirrhosis, the short-term effects of glibenclamide on hemodynamic and humoral responses to glucose. METHODS: Patients were randomly assigned to receive either glibenclamide (5-mg tablet) or a placebo. All patients received an infusion of 10% glucose (62.5 ml/h for 12 h) that was started at the same time as glibenclamide or placebo administration. Studies were performed prior to and 90 min after glibenclamide or placebo. RESULTS: Glibenclamide (i.e. glibenclamide plus glucose) significantly increased plasma insulin concentrations and glycemia while placebo (i.e. glucose alone) significantly increased glycemia but did not change plasma insulin levels. Glibenclamide did not significantly change the hepatic venous pressure gradient while this value was significantly increased following glucose alone. Glibenclamide did not significantly change renal blood flow and glomerular filtration rate while glucose alone significantly increased renal blood flow without affecting the glomerular filtration rate. Glibenclamide significantly decreased cardiac index while glucose alone did not change this value. CONCLUSIONS: In patients with cirrhosis receiving glucose, glibenclamide blunted glucose-induced splanchnic and renal vasodilation. In addition, glibenclamide per se induced a decrease in cardiac index. These findings should be taken into account when glibenclamide is administered to patients with cirrhosis and type 2 diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Female_MeSH M_Glucose_MeSH S_administration_&_dosage_MeSH Glucose_administration_&_dosage_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH M_Hemodynamic_Processes_MeSH S_drug_effects_MeSH Hemodynamic_Processes_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Infusions__Intravenous_MeSH M_Insulin_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Liver_MeSH S_drug_effects_MeSH Liver_drug_effects_MeSH S_metabolism_MeSH Liver_metabolism_MeSH M_Liver_Cirrhosis_MeSH S_physiopathology_MeSH Liver_Cirrhosis_physiopathology_MeSH M_Liver_Function_Tests_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Probability_MeSH M_Reference_Values_MeSH M_Respiratory_Function_Tests_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH ****** 11315840 ----K 2 ----T Sulfonylurea treatment of type 2 diabetic patients does not reduce the vasodilator response to ischemia. ----A OBJECTIVE: Sulfonylureas block the activation of vascular potassium-dependent ATP channels and impair the vasodilating response to ischcmia in nondiabetic individuals, but it is not know whether this occurs in type 2 diabetic patients under chronic treatment with these drugs. Glimepiride, a new sulfonylurea, apparently has no cardiovascular interactions. The aim of our study was to compare the effect of the widely used compound glibenclamide, the pancreas-specific glimepiride, and diet treatment alone on brachial artery response to acute forearm ischemia. RESEARCH DESIGN AND METHODS: Brachial artery examination was performed by a high-resolution ultrasound technique on 20 type 2 diabetic patients aged mean +/- SD) 67 +/- 2 years and on 18 nondiabetic patients matched for age, hypertension, and dislipidemia. Diabetic subjects underwent three separate evaluations at the end of each 8-week treatment period, during which they received glibenclamide, glimepiride, or diet alone according to crossover design. Scans were obtained before and after 4.5 min of forearm ischemia. Postischemic vasodilation and hyperemia were expressed as percent variations in vessel diameter and blood flow. RESULTS: Postischemic vasodilation and hyperemia were, respectively, 5.42 +/- 0.90 and 331 +/- 38% during glibenclamide, 5.46 +/- 0.69 and 326 +/- 28% during glimepiride, and 5.17 +/- 0.64 and 357 +/- 35% during diet treatment (NS). These results were similar to those found in the nondiabetic patients (6.44 +/- 0.68 and 406 +/- 42%, NS). CONCLUSIONS: In type 2 diabetic patients, the vasodilating response to forearm ischemia was the same whether patients were treated with diet treatment alone or with glibenclamide or glimepiride at blood glucose-lowering equipotent closes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Pressure_MeSH M_Brachial_Artery_MeSH S_physiology_MeSH Brachial_Artery_physiology_MeSH S_physiopathology_MeSH Brachial_Artery_physiopathology_MeSH S_ultrasonography_MeSH Brachial_Artery_ultrasonography_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Diet_MeSH M_Female_MeSH M_Forearm_MeSH S_blood_supply_MeSH Forearm_blood_supply_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_complications_MeSH Hyperlipidemia_complications_MeSH S_physiopathology_MeSH Hyperlipidemia_physiopathology_MeSH M_Hypertension_MeSH S_complications_MeSH Hypertension_complications_MeSH S_physiopathology_MeSH Hypertension_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Ischemia_MeSH S_physiopathology_MeSH Ischemia_physiopathology_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Reference_Values_MeSH M_Regional_Blood_Flow_MeSH S_drug_effects_MeSH Regional_Blood_Flow_drug_effects_MeSH S_physiology_MeSH Regional_Blood_Flow_physiology_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11315844 ----K I ----T Combination therapies with insulin in type 2 diabetes. ----A ----P Journal_Article Review Review__Tutorial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_epidemiology_MeSH Hypoglycemia_epidemiology_MeSH S_prevention_&_control_MeSH Hypoglycemia_prevention_&_control_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_MEDLINE_MeSH M_Weight_Gain_MeSH ****** 11315848 ----K E ----T Postprandial blood glucose. American Diabetes Association. ----A ----P Consensus_Development_Conference Journal_Article Review Review_Literature ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus_MeSH S_blood_MeSH Diabetes_Mellitus_blood_MeSH S_physiopathology_MeSH Diabetes_Mellitus_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus_therapy_MeSH M_Fasting_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_blood_MeSH Hyperglycemia_blood_MeSH P_Postprandial_Period_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11336617 ----K E ----T Clinical review of glimepiride. ----A This article reviews the pharmacological and clinical aspects of glimepiride, the latest second-generation sulfonylurea for treatment of Type 2 diabetes mellitus (DM). Glimepiride therapy ameliorates the relative insulin secretory deficit found in most patients with Type 2 DM. It is a direct insulin secretagogue; indirectly, it also increases insulin secretion in response to fuels such as glucose. Its action to augment insulin secretion requires binding to a high affinity sulfonylurea receptor, which results in closure of ATP-sensitive potassium channels in the beta-cells of the pancreas. The question has been raised whether insulin secretagogues by acting on vascular or myocardial potassium channels may prevent ischaemic preconditioning, a physiological adaptation that could affect the outcome of coronary heart disease, but there is evidence against this concern being applicable to glimepiride. Glimepiride's antihyperglycaemic efficacy is equal to other secretagogues. It has pharmacokinetic properties that make it less prone to cause hypoglycaemia in renal dysfunction than some other insulin secretagogues, particularly glyburide (also known as glibenclamide in Europe). Its convenient once daily dosing may enhance compliance for diabetic patients who often also require medications for other co-morbid conditions, such as hypertension, hyperlipidaemia and cardiac disease. Glimepiride is approved for monotherapy, for combination with metformin and with insulin. Clinically, its reduced risk of hypoglycaemia makes it preferable to some other insulin secretagogues when attempting to achieve recommended glycaemic control (haemoglobin A(1c) (HgbA(1c)) 7%). Using suppertime neutral protamine Hagedorn (NPH) and regular insulin with morning glimepiride in overweight diabetic patients achieves glycaemic goals more quickly than insulin alone and with lower insulin doses. ----P Journal_Article Review Review__Tutorial ----M M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 11353879 ----K E ----T 24-hour glycemic profile in type 2 diabetic patients treated with gliclazide modified release once daily. ----A OBJECTIVES: In type 2 diabetes, the primary and secondary prevention of long-term micro- and macrovascular complications requires a control of blood glucose levels 24 hours a day. The present study was undertaken to assess the effect of a new formulation of gliclazide administered once daily, gliclazide modified release, on plasma glucose levels over 24 hours. MATERIAL AND METHODS: In 21 type 2 diabetic patients previously treated by diet alone or oral antidiabetic agents, glycemic profile (8 am, 10 am, 12 am, 2 pm, 5 pm, 8 pm, 10 pm, 3 am and 8 am), overall glycemic control, acceptability, and compliance with treatment were assessed before and after a 10-week treatment with gliclazide modified release, (30-60 mg), given once daily at breakfast. RESULTS: The results indicate a significant decrease in plasma glucose levels at all points of the cycle. Mean plasma glucose levels over 24 hours and mean plasma glucose levels during the fasting and the postprandial periods were significantly improved after treatment. In previous drug-naive patients, decrease in HbA1C was observed (1.0 +/- 1.1%, P=0.022). The acceptability was good, with no hypoglycemic events, and a high compliance with treatment was also observed. CONCLUSION: We can therefore conclude that gliclazide modified release, given once daily at breakfast, is effective over 24 hours in reducing plasma glucose levels in type 2 diabetes. This once-daily administration should lead to an optimal patient compliance with treatment. ----P Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH P_Circadian_Rhythm_MeSH M_Delayed-Action_Preparations_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Patient_Compliance_MeSH M_Research_Design_MeSH ****** 11375357 ----K I ----T Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes. ----A OBJECTIVE--This study compared the effects of nateglinide, glyburide, and placebo on postmeal glucose excursions and insulin secretion in previously diet-treated patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--This randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks. Glucose, insulin, and C-peptide profiles during liquid meal challenges were measured at weeks 0 and 8. At weeks -1 and 7, 19-point daytime glucose and insulin profiles, comprising three solid meals, were measured. RESULTS--During the liquid-meal challenge, nateglinide reduced the incremental glucose area under the curve (AUC) more effectively than glyburide ( = -4.94 vs. -2.71 mmol. h/l, P < 0.05), whereas glyburide reduced fasting plasma glucose more effectively than nateglinide ( = -2.9 vs. -1.0 mmol/l, respectively, P < 0.001). In contrast, C-peptide induced by glyburide was greater than that induced by nateglinide ( = +1.83 vs. +0.95 nmol. h/l, P < 0.01), and only glyburide increased fasting insulin levels. During the solid meal challenges, nateglinide and glyburide elicited similar overall glucose control ( 12-h incremental AUC = -13.2 vs. -15.3 mmol. h/l), but the insulin AUC induced by nateglinide was significantly less than that induced by glyburide ( 12-h AUC = +866 vs. +1,702 pmol. h/l, P = 0.01). CONCLUSIONS--This study demonstrated that nateglinide selectively enhanced early insulin release and provided better mealtime glucose control with less total insulin exposure than glyburide. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Aged_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Cyclohexanes_MeSH S_adverse_effects_MeSH Cyclohexanes_adverse_effects_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Diet_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_adverse_effects_MeSH Phenylalanine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Placebos_MeSH M_Postprandial_Period_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH M_Single-Blind_Method_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 11376359 ----K E ----T The effects of inorganic chromium and brewer's yeast supplementation on glucose tolerance, serum lipids and drug dosage in individuals with type 2 diabetes. ----A OBJECTIVE: To study the effects of supplementation with organic and inorganic chromium on glucose tolerance, serum lipids, and drug dosage in type 2 diabetes patients, in the hope of finding a better and more economical method of control. METHODS: Seventy eight type 2 diabetes patients were divided randomly into two groups and given Brewer's yeast (23.3ug Cr/day), and CrCl3 (200ug Cr/day) sequentially with placebo in between, in a double blind cross-over design of four stages, each lasting 8 weeks. At the beginning and end of each stage, subjects were weighed, their dietary data and drug dosage recorded, and blood and urine samples were collected for analysis of glucose (fasting and 2 hour post 75g glucose load) fructosamine, triglycerides, total and HDL-cholesterol, and serum and urinary chromium. RESULTS: Both supplements caused a significant decrease in the means of glucose (fasting and 2 hour post glucose load), fructosamine and triglycerides. The means of HDL-cholesterol, and serum and urinary chromium were all increased. The mean drug dosage decreased slightly (and significantly in case of Glibenclamide) after both supplements and some patients no longer required insulin. No change was noted in dietary intakes or Body Mass Index. A higher percentage of subjects responded positively to Brewer's yeast chromium, which was retained more by the body, with effects on fructosamine, triglycerides, and HDL-cholesterol maintained in some subjects when placebo followed it, and mean urinary chromium remaining significantly higher than zero time mean. CONCLUSION: Chromium supplementation gives better control of glucose and lipid variables while decreasing drug dosage in type 2 diabetes patients. A larger scale study is needed to help decide on the convenient chemical form, and dosage required to achieve optimal response. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Chlorides_MeSH S_administration_&_dosage_MeSH Chlorides_administration_&_dosage_MeSH M_Chromium_Compounds_MeSH S_administration_&_dosage_MeSH Chromium_Compounds_administration_&_dosage_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH P_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH P_Saccharomyces_cerevisiae_MeSH M_Treatment_Outcome_MeSH ****** 11394726 ----K I ----T Matching treatment to pathophysiology in type 2 diabetes. ----A BACKGROUND: Because type 2 diabetes is a progressive condition, >50% of all patients whose disease is initially controlled with diet and exercise will eventually need single or multiple pharmacologic agents to maintain adequate glycemic control. Although current treatment standards require that combination therapy be instituted only after the failure of monotherapy, the results of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study suggest that aggressive initial treatment is crucial to slowing the evolution of long-term complications associated with this disease. OBJECTIVES: This article reviews the diagnosis and classification of type 2 diabetes, describes the multiple defects in glucose metabolism associated with the disease, and discusses the various pharmacologic options for achieving glycemic control in these patients. METHODS: The information in this review was compiled through a search of MEDLINE. Search terms included but were not limited to type 2 diabetes and antihyperglycemic agents. In addition, abstracts were identified using the Web sites of diabetes-related professional organizations. RESULTS: Two pathophysiologic mechanisms, insulin resistance and impaired insulin secretion, are usually present at diagnosis in type 2 diabetes. Several studies have shown that combination therapy with antihyperglycemic agents having different mechanisms of action provides greater efficacy than treatment with single agents. CONCLUSIONS: Current research suggests that early aggressive treatment with combination therapy achieves glycemic control at lower doses and with fewer side effects than monotherapy with either component. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_diagnosis_MeSH Diabetes_Mellitus__Type_II_diagnosis_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Glucose_Intolerance_MeSH S_physiopathology_MeSH Glucose_Intolerance_physiopathology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin_Resistance_MeSH S_physiology_MeSH Insulin_Resistance_physiology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11402628 ----K E ----T The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic beta-cell function in response to glucose loading in individuals with non-insulin-dependent diabetes mellitus. ----A In the first report (Journal of Clinical Pharmacology 2000; 40:647-654), it was shown that ingestion of 120 mg of Ginkgo biloba extract (EGb 761) daily for 3 months by normal glucose-tolerant individuals caused a significant increase in pancreatic beta-cell insulin and C-peptide response, measured as the area under the curve (AUC0-->120) during a 2-hour standard (75 g) oral glucose tolerance test (OGTT). This follow-up study was designed to determine the effect of the same Ginkgo biloba treatment on glucose-stimulated pancreatic beta-cell function in non-insulin-dependent diabetes mellitus (NIDDM) subjects. In diet-controlled subjects (fasting plasma glucose [FPG], 117 +/- 16 mg/dl; fasting plasma insulin [FPI], 29 +/- 8 microU/ml; n = 6), ingestion of Ginkgo biloba produced no significant effect on the insulin AUC0-->120 (193 +/- 53 vs. 182 +/- 58 microU/ml/h, before and after ingesting Ginkgo biloba, respectively). In hyperinsulinemic NIDDM subjects taking oral hypoglycemic medications (n = 6) (FPG 143 +/- 48 mg/dl; FPI 46 +/- 13 microU/ml), ingestion of Ginkgo biloba caused blunted plasma insulin levels from 30 to 120 minutes during the OGTT, leading to a reduction of the insulin AUC0-->120 (199 +/- 33 vs. 147 +/- 58 microU/ml/h, before and after Ginkgo biloba, respectively). The C-peptide levels increased, and so the AUC0-->120 did not parallel the insulin AUC0-->120, creating a dissimilar insulin/C-peptide ratio indicative of an enhanced hepatic extraction of insulin relative to C-peptide. Thus, in pancreatic beta-cells that are already maximally stimulated, ingestion of Ginkgo biloba may cause a reduction in plasma insulin levels. Only in NIDDM subjects with pancreatic exhaustion (FPG 152 +/- 46 mg/dl; FPI 16 +/- 8 microU/ml; n = 8), who also took oral hypoglycemic agents, did Ginkgo biloba ingestion significantly increase pancreatic beta-cell function in response to glucose loading (insulin AUC0-->120 increased from 51 +/- 29 to 98 +/- 20 microU/ml/h, p < 0.0001), paralleled by a C-peptide AUC0-->120 increase from 7.2 +/- 2.8 to 13.7 +/- 6.8 (p < 0.0001). Whether this increase is due to "resuscitation" of previously exhausted islets or increased activity of only the remaining functional islets is unclear. However, not even in this group did increased pancreatic beta-cell activity cause a reduction of blood glucose during the OGTT. It is concluded that ingestion of Ginkgo biloba extract by an NIDDM subject may increase the hepatic metabolic clearance rate of not only insulin but also the hypoglycemic agents. The result is reduced insulin-mediated glucose metabolism and elevated blood glucose. ----P Clinical_Trial Journal_Article ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Diet_MeSH M_Female_MeSH P_Ginkgo_biloba_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_metabolism_MeSH Islets_of_Langerhans_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH P_Phytotherapy_MeSH M_Plant_Extracts_MeSH S_administration_&_dosage_MeSH Plant_Extracts_administration_&_dosage_MeSH S_adverse_effects_MeSH Plant_Extracts_adverse_effects_MeSH S_pharmacology_MeSH Plant_Extracts_pharmacology_MeSH S_therapeutic_use_MeSH Plant_Extracts_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Vasodilator_Agents_MeSH S_administration_&_dosage_MeSH Vasodilator_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Vasodilator_Agents_adverse_effects_MeSH S_pharmacology_MeSH Vasodilator_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Vasodilator_Agents_therapeutic_use_MeSH ****** 11410214 ----K E ----T Lessons from the glitazones: a story of drug development. ----A Troglitazone, the first in the thiazolidinedione class of oral hypoglycaemic agents, was launched in the USA in March, 1997. It reached Europe later that year, only to be withdrawn within weeks on the grounds of liver toxicity. Meanwhile it went on to generate sales of over $2 billion in the USA, and caused at least 90 cases of liver failure (70 resulting in death or transplantation) before it was withdrawn in March, 2000. Rosiglitazone and pioglitazone reached the US market in 1999 as first-line agents to be used alone or in combination with other drugs, but in Europe the same dossiers were used one year later to apply for a limited licence as second-line agents restricted to oral combination therapy. How should we use the glitazones? And how did they achieve blockbuster status without any clear evidence of advantage over existing therapy? ----P Journal_Article Review Review__Tutorial ----M M_Adverse_Drug_Reaction_Reporting_Systems_MeSH M_Chromans_MeSH S_administration_&_dosage_MeSH Chromans_administration_&_dosage_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Approval_MeSH S_legislation_&_jurisprudence_MeSH Drug_Approval_legislation_&_jurisprudence_MeSH M_Drug_Therapy__Combination_MeSH M_Europe_MeSH M_Hepatitis__Toxic_MeSH S_etiology_MeSH Hepatitis__Toxic_etiology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Liver_Failure_MeSH S_chemically_induced_MeSH Liver_Failure_chemically_induced_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH P_Thiazolidinediones_MeSH M_United_States_MeSH ****** 11423506 ----K I ----T Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166). ----A OBJECTIVE: This randomized crossover double-blind placebo-controlled study aimed to assess the efficacy of nateglinide (A-4166), a novel phenylalanine-derived insulin secretagogue, in type 2 diabetic subjects while fasting and 5 min before a standard meal. RESEARCH DESIGN AND METHODS: A single dose of nateglinide (60, 120, or 180 mg) or placebo was given to eight diet-treated overnight-fasted type 2 diabetic patients and to seven patients 5 min before a standard breakfast. Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min. RESULTS: The time-averaged 180-min postdose mean decrease in fasting plasma glucose concentration was greater after nateglinide (1.8 mmol/l; 95% CI 1.5-2.0) than after placebo (0.7 mmol/l; 95% CI 0.3-1.2) (P < 0.001). Hypoglycemia did not develop in any of the subjects. Insulin concentrations increased 1.5-, 1.8-, and 1.9-fold with the 60-, 120-, and 180-mg doses, respectively (P < 0.001), peaking approximately 30 min after the dose. Nateglinide concentrations peaked after approximately 30 min, decreasing to 21% of peak by 180 min. In the meal test, the mean increase (2.9 mmol/l, 2.3-3.6) in plasma glucose over 180 min after placebo was reduced by 1.8 mmol/l (P < 0.001) with the two higher doses of nateglinide. CONCLUSIONS: A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia. Administered 5 min before a meal, nateglinide reduced the postprandial glucose excursion by 64%. With its rapid onset and short duration of action, nateglinide is a promising oral prandial therapy in type 2 diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Cyclohexanes_MeSH S_blood_MeSH Cyclohexanes_blood_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_blood_MeSH Phenylalanine_blood_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Postprandial_Period_MeSH ****** 11448655 ----K E ----T Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. ----A PURPOSE: To evaluate the efficacy and tolerability of pioglitazone in combination with a sulfonylurea in the treatment of type 2 diabetes mellitus. SUBJECTS AND METHODS: This 16-week, double-blind study included patients on a stable regimen of a sulfonylurea for > or = 30 days and with a glycosylated hemoglobin (HbA1C) level > or = 8.0%. Patients were randomly assigned to receive once daily pioglitazone 15 mg (n = 184), pioglitazone 30 mg (n = 189), or placebo plus sulfonylurea (n = 187). RESULTS: Patients receiving pioglitazone + sulfonylurea had significant (P < 0.05) decreases from baseline in HbA1C and fasting plasma glucose levels compared with patients treated with placebo + sulfonylurea. As compared with placebo, HbA1C decreased by 0.9% (95% confidence interval [CI]: 0.06% to 1.2%) with pioglitazone 15 mg and 1.3% (CI: 1% to 1.6%) with 30 mg pioglitazone; fasting plasma glucose levels decreased by 39 mg/dL (95% CI: 27 to 52 mg/dL) with pioglitazone 15 mg and by 58 mg/dL (95% CI: 46-70 mg/dL) with 30 mg pioglitazone. Both pioglitazone + sulfonylurea groups had significant (P < 0.05) mean percent decreases in triglyceride levels (17%, 95% CI: 6% to 27% for 15 mg; 26%, 95% CI: 16% to 36% for 30 mg) and increases in high-density lipoprotein cholesterol levels (6%, 95% CI: 1% to 11% for 15 mg; 13%, CI: 8% to 18% for 30 mg) compared with placebo + sulfonylurea. There were small but statistically significant mean percent increases in low-density lipoprotein cholesterol levels in all groups. Pioglitazone was well tolerated, and the rates of adverse events were similar in all groups. CONCLUSION: In patients with type 2 diabetes, pioglitazone plus sulfonylurea significantly improves HbA1C and fasting plasma glucose levels with beneficial effects on serum triglyceride and HDL-cholesterol levels. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH M_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH P_Thiazolidinediones_MeSH M_Time_Factors_MeSH M_Treatment_Outcome_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_United_States_MeSH ****** 11449877 ----K I ----T Nateglinide. ----A The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, interactions, and dosage of nateglinide are reviewed. Nateglinide is an oral hypoglycemic agent approved for use alone or in combination with metformin as an adjunct to diet and exercise for the treatment of type 2 diabetes mellitus. Nateglinide, an amino acid derivative of D-phenylalanine, stimulates the secretion of insulin by binding to the ATP potassium channels in pancreatic beta cells. The result is an increase in beta-cell calcium influx, which leads to rapid, short-lived insulin release. The drug is rapidly and completely absorbed in the small intestine. The estimated bioavailability is 72%. Nateglinide is highly bound to plasma proteins, is metabolized extensively by the liver, and has an elimination half-life of 1.4 hours. Several clinical trials of nateglinide, alone and in combination with other oral hypoglycemic agents, have found the drug to be safe, effective, and well tolerated. The most common adverse effects are nausea, diarrhea, dizziness, and lightheadedness. There is a potential for interactions between nateglinide and medications affected by the cytochrome P-450 isoenzyme system. Dosage regimens ranging from 60 to 240 mg have been evaluated. The maximum effective dosage is 120 mg taken 10 minutes before meals three times a day. Nateglinide is an alternative to second-generation sulfonylureas for the treatment of type 2 diabetes mellitus. Additional comparative trials are needed to fully elucidate nateglinide's role. ----P Journal_Article Review Review__Tutorial ----M M_Biological_Availability_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH P_Cyclohexanes_MeSH S_adverse_effects_MeSH Cyclohexanes_adverse_effects_MeSH S_metabolism_MeSH Cyclohexanes_metabolism_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Half-Life_MeSH M_Human_MeSH P_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH P_Phenylalanine_MeSH S_adverse_effects_MeSH Phenylalanine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_metabolism_MeSH Phenylalanine_metabolism_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Randomized_Controlled_Trials_MeSH ****** 11450504 ----K E ----T Mechanisms of acute and chronic hypoglycemic action of gliclazide. ----A An extrapancreatic effect of sulfonylureas has been postulated. However, in vivo results have been disputed because the amelioration of insulin action that follows sulfonylurea may represent the relief from glucose toxicity rather than a direct effect of the drug. Therefore, we studied the hypoglycemic action of gliclazide acutely and after 2 months of therapy in seven type 2 diabetic patients. All patients received a 240-minute i.v. glucose infusion with [3-3H]glucose. In a random order, 160 mg gliclazide (study 1) or placebo (study 2) was given orally before glucose infusion. Finally, the effect of 160 mg gliclazide was reassessed after a two-month treatment with the same sulfonylurea (80 mg t.i.d.). Basal plasma glucose, insulin, C-peptide and endogenous glucose production (EGP) were similar before the two initial studies. During glucose infusion, EGP was more suppressed after gliclazide in spite of comparable increase in plasma insulin and C-peptide. After the two-month therapy, basal plasma glucose levels and HbA1c were lower while plasma insulin and C-peptide were higher with respect to baseline (p < 0.05). Gliclazide further reduced plasma glucose, the incremental area above baseline, and EGP during glucose infusion, while plasma insulin and C-peptide achieved higher plateaus (p < 0.05). When data were pooled, plasma glucose concentration and EGP correlated both in the basal state (r = 0.71) and during the last hour of glucose infusion (r = 0.84; both p < 0.05). These data suggest that gliclazide enhances the suppression of EGP induced by insulin and that this effect is greater with chronic treatment because of concomitant improvement of insulin secretion. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acute_Disease_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Chronic_Disease_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Gliclazide_MeSH S_adverse_effects_MeSH Gliclazide_adverse_effects_MeSH M_Gluconeogenesis_MeSH M_Glucose_Clamp_Technique_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH S_physiopathology_MeSH Hypoglycemia_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Kinetics_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Regression_Analysis_MeSH M_Time_Factors_MeSH M_Tritium_MeSH ****** 11467343 ----K E ----T Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. ----A Alpha-Lipoic acid (LA) is a disulfide compound that is produced in small quantities in cells, and functions naturally as a co-enzyme in the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase mitochondrial enzyme complexes. In pharmacological doses, LA is a multifunctional antioxidant. LA has been used in Germany for over 30 years for the treatment of diabetes-induced neuropathy. In patients with type 2 diabetes, recent studies have reported that intravenous (i.v.) infusion of LA increases insulin-mediated glucose disposal, whereas oral administration of LA has only marginal effects. If the limitations of oral therapy can be overcome, LA could emerge as a safe and effective adjunctive antidiabetic agent with insulin sensitizing activity. ----P Journal_Article Review Review__Academic ----M M_Administration__Oral_MeSH M_Antioxidants_MeSH S_administration_&_dosage_MeSH Antioxidants_administration_&_dosage_MeSH S_therapeutic_use_MeSH Antioxidants_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Neuropathies_MeSH S_drug_therapy_MeSH Diabetic_Neuropathies_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Infusions__Intravenous_MeSH M_Insulin_MeSH S_physiology_MeSH Insulin_physiology_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Oxidative_Stress_MeSH M_Thioctic_Acid_MeSH S_administration_&_dosage_MeSH Thioctic_Acid_administration_&_dosage_MeSH S_therapeutic_use_MeSH Thioctic_Acid_therapeutic_use_MeSH ****** 11472451 ----K I ----T Comparison between repaglinide and glipizide in Type 2 diabetes mellitus: a 1-year multicentre study. ----A AIMS: To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes. METHODS: Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily. RESULTS: Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively). CONCLUSIONS: Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Carbamates_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Nephropathies_MeSH S_epidemiology_MeSH Diabetic_Nephropathies_epidemiology_MeSH M_Diabetic_Neuropathies_MeSH S_epidemiology_MeSH Diabetic_Neuropathies_epidemiology_MeSH M_Diabetic_Retinopathy_MeSH S_epidemiology_MeSH Diabetic_Retinopathy_epidemiology_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Glipizide_MeSH S_adverse_effects_MeSH Glipizide_adverse_effects_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH ****** 11473038 ----K I ----T Acute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetes. ----A The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 +/- 2 years, BMI 27.5 +/- 1.1 kg/m(2), fasting plasma glucose 9.8 +/- 0.8 mmol/l, HbA(1c) 7.5 +/- 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40-80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means +/- SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 +/- 0.9 vs. 7.8 +/- 0.6 mmol/l; placebo, 10.0 +/- 0.8 vs. 11.0 +/- 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 +/- 12.0 vs. 61.0 +/- 17.0 pmol. l(-1). pulse(-1); placebo, 36.1 +/- 8.4 vs. 30.3 +/- 7.4 pmol. l(-1). pulse(-1), P = 0.047; 5 weeks-elevated: gliclazide vs. placebo, 49.7 +/- 13.3 vs. 37.1 +/- 9.5 pmol. l(-1). pulse(-1), P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 +/- 2.2 vs. 16.7 +/- 4.3 pmol. l(-1). pulse(-1); placebo, 5.9 +/- 0.9 vs. 7.2 +/- 0.9 pmol. l(-1). pulse(-1), P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 +/- 2.5 vs. 9.4 +/- 2.1 pmol. l(-1). pulse(-1), P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between individual values for the acute improvement of regularity, as measured by ApEn, and the decrease in fasting plasma glucose during short-term (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coarse ApEn, respectively). In conclusion, the sulfonylurea agent gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity. The data suggest a possible relationship between the improvement in short-term glycemic control and the acute improvement of regularity of the in vivo insulin release process. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Entropy_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 11473078 ----K I ----T Utilization of oral hypoglycemic agents in a drug-insured U.S. population. ----A OBJECTIVE: Clinical trials provide information regarding the safety and efficacy of medications used to manage type 2 diabetes but do not elucidate drug effectiveness in a typical managed care environment. The aim of this study was to characterize "real-world" drug utilization patterns from both a prescriber and a patient perspective. RESEARCH DESIGN AND METHODS: We conducted a retrospective analysis of a large administrative pharmacy claims database, using data on continuously pharmacy benefit-eligible members prescribed oral hypoglycemic agents (OHAs). RESULTS: The 12-month persistence rate for the OHA cohort was low, ranging from 31% for alpha-glucosidase inhibitors to 60% for metformin; compliance rates varied between 70 and 80%. During the first 12 months of therapy, 36% of the patients remaining on therapy at 12 months had one or more therapy modifications. The mean number of therapy changes increased with the length of patient follow-up, with more than half of all patients experiencing at least one therapy change over the duration of follow-up. CONCLUSIONS: These findings document the wide variation in utilization patterns associated with pharmacological management of type 2 diabetes, suggesting that opportunity exists to optimize its pharmacological management. ----P Journal_Article ----M M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Cohort_Studies_MeSH M_Databases_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH M_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Enzyme_Inhibitors_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_economics_MeSH Hypoglycemic_Agents_economics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insurance__Pharmaceutical_Services_MeSH S_utilization_MeSH Insurance__Pharmaceutical_Services_utilization_MeSH M_Longitudinal_Studies_MeSH M_Managed_Care_Programs_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Retrospective_Studies_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Time_Factors_MeSH M_United_States_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 11475269 ----K I ----T Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes. ----A BACKGROUND: The pharmacodynamics and dose-response relationship of repaglinide, a novel oral hypoglycemic agent, were evaluated in steady-state treatment of patients with type 2 diabetes. METHODS: Efficacy of repaglinide (0.25 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) was compared to that of placebo in a double-blind, randomized, parallel-group, 4-week dose-response clinical trial in 143 patients. Repaglinide was administered 15 minutes before meals (breakfast, lunch, and dinner). Efficacy of repaglinide therapy was assessed by measuring changes from baseline in mean levels of blood glucose (BGmean), fasting serum glucose (FSG), and mean levels of serum insulin (INSmean). RESULTS: Blood concentrations of repaglinide were proportional to the dose administered. INSmean values increased in all repaglinide treatment groups (by 6.7 to 12.9 microU/mL). All doses of repaglinide significantly decreased values of BGmean and FSG as compared with the placebo group. BGmean values stabilized between the second and third week of repaglinide treatment. A well-defined dose-response relationship was observed for BGmean and FSG values. All doses of repaglinide were well tolerated, and there were no serious adverse events. CONCLUSIONS: These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Carbamates_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Ethnic_Groups_MeSH M_Fasting_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Placebos_MeSH M_Support__Non-U_S__Gov't_MeSH M_United_States_MeSH ****** 11475233 ----K E ----T [Hypoglycemic treatment of type 2 diabetes] ----A BACKGROUND: Hyperglycaemia in type 2 diabetes results from reduced beta-cell function and insulin resistance. The treatment of type 2 diabetes must be targeted against both conditions to reduce symptoms of hyperglycaemia and the risk of diabetic late complications. MATERIAL AND METHODS: In this review we cover the recent scientific documentation from long term studies on treatment effects. We also discuss the different treatments available. RESULTS: Recent clinical trials have shown that lowering blood glucose levels over time significantly reduces development of microvascular complications in type 2 diabetes. There are several treatment options available which make adequate blood glucose control possible in patients with type 2 diabetes. INTERPRETATION: A reduction in the development of microvascular complications in type 2 diabetes is an achievable goal. ----P Journal_Article Review Review__Tutorial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Diabetic_Diet_MeSH M_Drug_Therapy__Combination_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH M_Insulin_Resistance_MeSH M_Reference_Values_MeSH ****** 11496727 ----K E ----T [Pharma-clinics. Medication of the month. Repaglinide (NovoNorm)] ----A Repaglinide (NovoNorm) is an antidiabetic oral agent of the new glinide class with insulinotropic activity. Its action on insulin secretion is more rapid and shorter than that of sulphonylurea compounds. Thanks to these properties, repaglinide is able to better control postprandial hyperglycaemia and is associated with a lower risk of delayed hypoglycaemic episodes. It is indicated for the treatment of type 2 (non-insulin-dependent) diabetes mellitus as monotherapy, after diet failure, or in combination with metformin, when the biguanide is insufficient. NovoNorm is commercialized as tablets of 0.5, 1 and 2 mg, to be taken just before each meal. Initial dosis should be 0.5 mg before meal in diabetic patients on diet alone or 1 mg before meal in patients already receiving an hypoglycaemic agent. If necessary, the dosis should be progressively increased, depending on the individual response, up to 4 mg before meal (maximal daily dosage of 16 mg), in order to optimize blood glucose control. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Carbamates_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Piperidines_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Postprandial_Period_MeSH ****** 11520304 ----K E ----T Differences in pharmacotherapy and in glucose control of type 2 diabetes patients in two neighbouring towns: a longitudinal population-based study. ----A AIM: To compare prescribing, dosage and blood glucose levels in patients with type 2 diabetes in two communities with differences in anti-hyperglycaemic drug utilization. METHODS: A retrospective longitudinal (1984-1994) population-based study in two neighbour towns in southern Sweden. The mean prescribed daily dose was expressed as a fraction of the Defined Daily Dose (DDD) for each drug. RESULTS: In town A, prescribing of oral agents and insulin was predominantly made by one specialized diabetes clinician, while in town B it was spread among several different general practitioners and one specialist. Altogether 44 636 medical visits by 2348 patients were identified. In each town, about 40% of the patients were treated without anti-hyperglycaemic drugs, about 40% with oral agents and about 20% with insulin. However, there were pronounced between-town differences in dosage and glucose control. The mean prescribed daily dose of sulphonylurea monotherapy decreased gradually from approximately 0.7 to approximately 0.5 DDD in town B but remained approximately 0.8 DDD in town A. The proportion of patients on both sulphonylurea and metformin increased substantially in town A but not in town B. In these patients, the mean prescribed daily dose of sulphonylurea exceeded 1.0 DDD in both towns, although it decreased with time in town B. The mean prescribed daily dose of insulin increased from 1.05 to 1.2 DDD in town A but remained virtually unchanged at 0.95 DDD in town B. The mean fasting blood glucose was lower in town A than in town B both overall (7.7 vs. 8.8 mmol/l), in those treated without any anti-hyperglycaemic drugs (7.2 vs. 8.1 mmol/l), in those on sulphonylurea monotherapy (8.3 vs. 9.7 mmol/l) and in those treated with insulin (8.1 vs. 10.2 mmol/l). CONCLUSIONS: Glucose control in routine care was better when most patients were treated by a diabetes specialist and were exposed to more intense pharmacotherapy. ----P Journal_Article ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Chlorpropamide_MeSH S_therapeutic_use_MeSH Chlorpropamide_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Longitudinal_Studies_MeSH M_Male_MeSH M_Retrospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Sweden_MeSH M_Time_Factors_MeSH M_Urban_Population_MeSH ****** 11525087 ----K E ----T [Repaglinide, potentially a therapeutic improvement for diabetes mellitus type 2] ----A In about 25% of type 2 diabetes patients, good diabetes control is not attainable with oral blood-glucose lowering drugs. Furthermore, in many people with diabetes the disease deteriorates, despite the use of blood-glucose lowering medication, due to the decline of the pancreatic beta cells. The development of new drugs, such as repaglinide, is therefore important. Repaglinide is an insulin secretion enhancer with a different mechanism of action to the sulphonylureas, which means it does not continuously stimulate insulin secretion. The tablets should be taken with each meal. After oral ingestion repaglinide is resorbed quickly, with a half-life of between 30 minutes to an hour. In clinical trials repaglinide has been found to be equally effective as glibenclamide. Repaglinide has been found to be particularly effective in sulphonylurea-naive patients. Skipping the meal plus tablet combination results in less frequent hypoglycaemic symptoms compared to glibenclamide. Repaglinide results in greater reductions in postprandial glucose levels than glibenclamide. It does not affect insulin resistance. Long-term data are lacking, both with regard to efficacy and side effects. Repaglinide deserves a place in the diabetes treatment of newly-diagnosed type 2 diabetes patients who are well-informed about their disease, as well as in patients with renal failure. It should also be considered for patients whose diabetes is poorly controlled on metformin monotherapy. ----P Journal_Article Review Review__Tutorial ----M M_Carbamates_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_English_Abstract_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_prevention_&_control_MeSH Hypoglycemia_prevention_&_control_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Piperidines_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Therapeutic_Equivalency_MeSH ****** 11529585 ----K E ----T Effects of improved glycaemic control on endothelial function in patients with type 2 diabetes. ----A BACKGROUND: Patients with type 2 diabetes have abnormal endothelial function but it is not certain whether improvements in glycaemic control will improve endothelial function. AIMS: To examine the effects of short-term improved glycaemic control on endothelial function in patients with inadequately regulated type 2 diabetes mellitus. METHODS: Forty-three patients with type 2 diabetes and glycosylated haemoglobin (HbA1c) > 8.9% were randomized to either improved glycaemic control (IC) n = 21 or usual glycaemic control (UC) n = 22 for 20 weeks. Using high-resolution B-mode ultrasound, brachial artery flow-mediated dilatation (FMD) and glyceryl trinitrate-mediated dilatation (GTN-D) were measured at baseline and 20 weeks later. RESULTS: After 20 weeks, HbA1c was significantly lower in IC versus UC (IC 8.02 +/- 0.25% versus UC 10.23 +/- 0.23%, P < 0.0001) but changes in FMD and GTN-D were not different between the groups (FMD at baseline and week 20 IC 5.1 +/- 0.56% versus 4.9 +/- 0.56% and UC 4.2 +/- 0.51% versus 3.1 +/- 0.51%; P = 0.23: GTN-D IC 12.8 +/- 1.34% versus 10.4 +/- 1.32% and UC 13.7 +/- 1.2% versus 12.7 +/- 1.23%; P = 0.39). In the IC group weight increased by 3.2 +/- 0.8 kg after 20 weeks compared to 0.02 +/- 0.70 kg in UC (P = 0.003). Blood pressure and serum lipid concentrations did not change in either group. CONCLUSIONS: Short-term reduction of HbA1c levels did not appear to affect endothelial function in patients with type 2 diabetes and previously poorly regulated glycaemic control. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Brachial_Artery_MeSH S_ultrasonography_MeSH Brachial_Artery_ultrasonography_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Endothelium__Vascular_MeSH S_drug_effects_MeSH Endothelium__Vascular_drug_effects_MeSH S_physiopathology_MeSH Endothelium__Vascular_physiopathology_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Nitroglycerin_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH M_Treatment_Outcome_MeSH ****** 11534426 ----K E ----T [Objectives and therapeutic strategy in type 2 diabetes mellitus] ----A United Kingdom Prospective Diabetes Study (UKPDS) has demonstrated definitively that patients with type 2 diabetes mellitus (DM) benefit from intensive blood glucose control, because it diminishes the risk to develop microvascular complications. The therapeutic targets in the type 2 DM have been modified in order to reduce the risk of these complications. However, aggressive treatment may be disastrous for patients with microvascular complications and/or an increased risk of hypoglycemic unawareness, and neither it would be advised in older patients or with short life expectancy. The available drugs for treatment of type 2 DM offer many options for achieving these therapeutic targets, based on the need of the individual patient. In this job we review the targets in the metabolic control of type 2 DM and their backgrounds, and we describe briefly the therapeutic strategy recommended for reaching these targets, with special attention to the new oral antidiabetic agents (repaglinide and thiazolidinediones). ----P Journal_Article Review Review__Tutorial ----M M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hyperinsulinism_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_Resistance_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH ****** 11547217 ----K E ----T Endothelial dysfunction and type 2 diabetes. Part 2: altered endothelial function and the effects of treatments in type 2 diabetes mellitus. ----A Coronary artery, cerebrovascular and peripheral vascular disease, are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy. Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. The endothelium is a major organ involved by cardiovascular risk factors, such as hypercholesterolemia, hypertension, inflammation, ageing, postmenopausal status, and smoking. Changes in endothelium function may lead to the coronary artery circulation being unable to cope with the increased metabolism of myocardial muscle independently of a reduced coronary artery diameter. The way endothelial function is altered in diabetic patients is not yet fully understood, but the loss of normal endothelial function could be involved in the pathogenesis of diabetic angiopathy, as endothelial dysfunction is associated with diabetic microangiopathy and macroangiopathy. Finally, recent reports indicate that an improved metabolic control in diabetic patients, whatever the treatment used, is associated with near normalization or restoration of normal endothelial function. ----P Journal_Article Review Review__Academic ----M M_Animals_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_physiopathology_MeSH Diabetic_Angiopathies_physiopathology_MeSH M_Diabetic_Diet_MeSH M_Endothelium__Vascular_MeSH S_physiopathology_MeSH Endothelium__Vascular_physiopathology_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_physiopathology_MeSH Hyperglycemia_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Oxidative_Stress_MeSH ****** 11553186 ----K E ----T Intramuscular injection of insulin lispro or soluble human insulin: pharmacokinetics and glucodynamics in Type 2 diabetes. ----A AIM: The aim of the study was to compare the pharmacokinetics and glucodynamics of insulin lispro and soluble human insulin following intramuscular (i.m.) injection in patients with Type 2 diabetes with secondary failure of sulphonylureas. METHODS: Single 15-U i.m. doses of insulin lispro or soluble human insulin were administered to 16 patients in a two-way, randomized, crossover design. Glucodynamic and pharmacokinetic parameters were determined over 6 h after insulin injection using clamp techniques. RESULTS: Insulin C(max) was significantly higher (971 +/- 217 vs. 659 +/- 141 pmol/l, P < 0.001) and T(max) was significantly shorter (46.9 +/- 27 vs. 94.7 +/- 50.1 min, P = 0.002) with insulin lispro. Glucose infusion rate (GIR) curves showed clear separation 20 min after injection and were significantly greater for insulin lispro during the 40-60, 60-80 and 80-100-minute time intervals. Total glucose infused was only approximately 5% larger with insulin lispro during the 6-h follow-up, due to lower insulinaemia at later time points. The glucose R(max) and TR(max) were not statistically different between insulin treatments. CONCLUSION: This study shows that i.m. injection of insulin lispro is followed by its more rapid absorption, which results in stronger metabolic effect in the first 2 h when compared with soluble human insulin under the same test conditions. Diabet. Med. 18, 562-566 (2001) ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Injections__Intramuscular_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_blood_MeSH Insulin_blood_MeSH S_pharmacokinetics_MeSH Insulin_pharmacokinetics_MeSH M_Least-Squares_Analysis_MeSH M_Middle_Aged_MeSH ****** 11553190 ----K I ----T Beta-cell function evaluated by HOMA as a predictor of secondary sulphonylurea failure in Type 2 diabetes. ----A BACKGROUND AND AIMS: Secondary failure to oral hypoglycaemic agents, a common evolution of long-standing Type 2 diabetes, is usually assessed by non-standardized indices requiring fine clinical assessment, including hyperglycaemia resistant to maximum doses of sulphonylureas despite appropriate diet and follow-up. The goal of this study was to evaluate if HOMA, a modelized plasma insulin/glucose ratio allowing simple evaluation of residual insulin secretion and sensitivity, is a better predictor of the insulin requiring stage than clinical indices. MATERIALS AND METHODS: HOMA was measured in 84 Type 2 diabetic patients aged 58 +/- SD 6 years, with diabetes duration 11 +/- 4 years, hospitalized because of hyperglycaemia resistant to maximal doses of sulphonylureas (e.g. glibenclamide > or = 15 mg/day), with no apparent external reason for hyperglycaemia. Despite reinforced appropriate diet recommendations, 62 of these patients remained hyperglycaemic (insulin-requiring group). RESULTS: Age, duration of diabetes, body mass index (BMI) and HOMA value for insulin sensitivity (71 +/- 6% vs. 76 +/- 7%, normal values 59-161%) were comparable in the two groups. HbA(1c) was higher (10.0 +/- 0.2% vs. 8.3 +/- 0.3%, P < 0.001) and HOMA insulin secretion values lower (25 +/- 2% vs. 43 +/- 6%, normal values 70-150%, P < 0.01) in the insulin-requiring group. Of the following potential predictors: HbA(1c) > 8%, duration of diabetes > or = 10 years, HbA(1c) combined with diabetes duration, insulin sensitivity < or = 40%, insulin secretion < or = 20%, the latter showed the best positive predictivity (86% patients with low insulin secretion were insulin-requiring). CONCLUSIONS: (i) HOMA is a simple and good predictor of the insulin-requiring stage in Type 2 diabetes mellitus; (ii) this stage of diabetes is characterized by a further decline of insulin secretion rather than of insulin sensitivity. Diabet. Med. 18, 584-588 (2001) ----P Journal_Article ----M M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Calibration_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Predictive_Value_of_Tests_MeSH M_Sensitivity_and_Specificity_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Treatment_Failure_MeSH ****** 11560198 ----K E ----T A review of rosiglitazone in type 2 diabetes mellitus. ----A The thiazolidinedione rosiglitazone maleate works primarily to improve insulin sensitivity in muscle and adipose tissue. It may have additional pharmacologic effects, however, as its main target is peroxisome proliferator-activated receptor-gamma. Data using the homeostasis model assessment and proinsulin:insulin ratio in patients with type 2 diabetes mellitus suggest that rosiglitazone may have the potential to sustain or improve beta-cell function. In these patients the drug reduces fasting plasma glucose, glycosylated hemoglobin, insulin, and C-peptide. In clinical trials, rosiglitazone monotherapy significantly reduced glycosylated hemoglobin by 1.5% compared with placebo and led to significant improvements in glycemic control when given in combination with metformin, sulfonylureas, or insulin. A dosage of 4 mg twice/day significantly reduced fasting plasma glucose levels and produced comparable reductions in glycosylated hemoglobin compared with glyburide. Rosiglitazone has a low risk of gastrointestinal side effects and hypoglycemia, reduced insulin demand, potential sparing effects on beta-cells, and favorable drug interaction profile. Adverse events of clinical significance are edema, anemia, and weight gain. Premarketing data indicate no significant difference in liver enzyme elevations for rosiglitazone, placebo, or active controls. Another drug in the thiazolidinedione class, troglitazone, was associated with idiosyncratic hepatotoxicity and was removed from the market. Therefore, until long-term data are available for rosiglitazone, liver enzyme monitoring is recommended. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_chemistry_MeSH Hypoglycemic_Agents_chemistry_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_chemistry_MeSH Thiazoles_chemistry_MeSH S_pharmacokinetics_MeSH Thiazoles_pharmacokinetics_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 11563410 ----K I ----T The effect of food on the oral bioavailability and the pharmacodynamic actions of the insulinotropic agent nateglinide in healthy subjects. ----A Nateglinide (Starlix, SDZ DJN 608 or A-4166), a new insulinotropic agent, is intended to be administered prior to a meal in order to improve early insulin release in non-insulin-dependent diabetes mellitus patients. The effects of a meal on the oral bioavailability and pharmacodynamic actions of nateglinide were investigated. Twelve healthy male subjects completed this randomized, single-dose, four-way crossover study in which each subject received a 60 mg dose of nateglinide 10 minutes before the start of and immediately after a high-fat breakfast meal. In addition, each subject received a single 30 and 60 mg dose of nateglinide underfasting conditions. Plasma and urine concentrations of nateglinide were determined by an HPLC method while plasma glucose and insulin concentrations were measured by standard immunoassay methods. Compared to the fasted state, administration of nateglinide 10 minutes before the meal was associated with an increase in the rate of absorption (12% increase in Cmax and 52% decrease in tmax), while there was no significant effect on the extent of absorption (AUC). Alternatively, when nateglinide was given after the meal, a food effect was observed that was characterized by a decrease in the rate of absorption: 34% decrease in Cmax and a 22% increase in tmax but no significant effect on AUC. Nateglinide was rapidly eliminated with plasma t 1/2 = 1.4 hours. Its plasma renal clearance, 20.7 ml/min, appears to be due mostly to active tubular secretion. However, only 13% to 14% of the dose is recovered as nateglinide in the urine. The 30 and 60 mg tablets were dose proportional in terms of both AUC and Cmax; both tmax and t 1/2 were dose independent. Regardless of timing, the combination of a meal and nateglinide produced a larger increase in insulin levels than did nateglinide alone. Meal-related glucose excursions were eliminated when nateglinide was taken prior to the meal. Thus, the rapid onset/short duration stimulation of insulin release by nateglinide should allow good control of prandial hyperglycemia while limiting exposure to hyperinsulinemia. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Analysis_of_Variance_MeSH M_Biological_Availability_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cross-Over_Studies_MeSH M_Cyclohexanes_MeSH S_blood_MeSH Cyclohexanes_blood_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH S_pharmacology_MeSH Cyclohexanes_pharmacology_MeSH S_urine_MeSH Cyclohexanes_urine_MeSH M_Dietary_Fats_MeSH S_pharmacokinetics_MeSH Dietary_Fats_pharmacokinetics_MeSH M_Fasting_MeSH S_physiology_MeSH Fasting_physiology_MeSH P_Food-Drug_Interactions_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_urine_MeSH Hypoglycemic_Agents_urine_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_blood_MeSH Phenylalanine_blood_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH S_pharmacology_MeSH Phenylalanine_pharmacology_MeSH S_urine_MeSH Phenylalanine_urine_MeSH ****** 11569941 ----K E ----T CLX-0901 (Calyx Therapeutics). ----A Calyx Therapeutics is developing the insulin sensitizer, CLX-0901, as an antidiabetic agent. CLX-0901 is the synthetic analog of CLX-0900 which was originally isolated from a plant source. Phase I and toxicological studies indicate that the compound is safe and well tolerated [363764]. As of March 2001, phase II studies had commenced [402737]. Other antidiabetics being investigated by Calyx include CLX-0301, CLX-0921, CLX-0940, CLX-0100 and CLX-0101 [376032]. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_contraindications_MeSH Hypoglycemic_Agents_contraindications_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH S_toxicity_MeSH Hypoglycemic_Agents_toxicity_MeSH M_Insulin_Resistance_MeSH M_Stilbenes_MeSH S_pharmacokinetics_MeSH Stilbenes_pharmacokinetics_MeSH S_pharmacology_MeSH Stilbenes_pharmacology_MeSH S_therapeutic_use_MeSH Stilbenes_therapeutic_use_MeSH S_toxicity_MeSH Stilbenes_toxicity_MeSH M_Structure-Activity_Relationship_MeSH ****** 11574430 ----K I ----T Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes. ----A OBJECTIVE: Insulin and glucose levels in response to premeal insulin lispro or repaglinide were evaluated in adult patients with cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia. RESEARCH DESIGN AND METHODS: Seven patients with CFRD were fed 1,000-kcal liquid mixed meals. Three study conditions were administered in random order on separate mornings: 1) no premeal diabetes medication, 2) insulin lispro, 0.1 unit/kg body wt premeal and 3) repaglinide 1 mg premeal. Glucose and insulin levels were measured every 20 min for 5 h. RESULTS: Fasting insulin and glucose levels were normal in patients with CFRD, but the peak glucose level was elevated. Insulin lispro significantly decreased the peak glucose level (P = 0.0004) and the 2-h (P = 0.001) and 5-h (P < 0.0001) glucose area under the curve (AUC). Repaglinide significantly decreased the 5-h glucose AUC (P = 0.03). Neither drug completely normalized cystic fibrosis glucose excursion at the doses used for this study. Insulin lispro significantly increased the 5-h insulin AUC (P = 0.04). CONCLUSIONS: In response to subcutaneous insulin lispro, postprandial glucose excursion was significantly diminished and insulin secretion was enhanced compared with a control meal in which no medication was given to patients with CFRD. The oral agent repaglinide resulted in lesser corrections in these parameters. Neither drug completely normalized glucose or insulin levels, suggesting that the doses chosen for this study were suboptimal. Placebo-controlled longitudinal studies comparing the effectiveness of repaglinide and insulin on glucose metabolic control as well as overall nutrition and body weight are needed to help determine optimal medical treatment of CFRD. ----P Journal_Article ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Cystic_Fibrosis_MeSH S_complications_MeSH Cystic_Fibrosis_complications_MeSH M_Diabetes_Mellitus_MeSH S_blood_MeSH Diabetes_Mellitus_blood_MeSH S_etiology_MeSH Diabetes_Mellitus_etiology_MeSH M_Female_MeSH M_Food_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_etiology_MeSH Hypoglycemia_etiology_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 11574434 ----K E ----T Postchallenge hyperglycemia in a national sample of U.S. adults with type 2 diabetes. ----A OBJECTIVE: Postchallenge hyperglycemia (PCH) is known to contribute to suboptimal glycemic control in adults with non-insulin-requiring type 2 diabetes. The objective of this study was to estimate the prevalence of PCH among individuals with diabetes. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (1988-1994) in adults aged 40-74 years with diabetes who were not using insulin (i.e., they used oral hypoglycemics or received no pharmacological therapy). Each respondent underwent a standard 75-g oral glucose tolerance test. PCH was defined as a 2-h glucose level >or=200 mg/dl. RESULTS: Overall, PCH was present in 74% of those with diagnosed diabetes. Although it was present in virtually all (99%) of the diabetic adults under suboptimal glycemic control (HbA(1c) >or=7.0%), PCH was also common (39%) among those under optimal control (HbA(1c) <7.0%). Likewise, among sulfonylurea users, PCH was present in 99% of those under suboptimal control and in 63% of those under good control. Similar patterns were observed in those with undiagnosed diabetes. Isolated PCH (2-h glucose >or=200 mg/dl and fasting glucose <126 mg/dl) was present in 9.8% of the adults with diagnosed diabetes. CONCLUSIONS: These data suggest that PCH is common among diabetic adults in the U.S., even in the setting of "optimal" glycemic control and sulfonylurea use. Interventions designed to lower postprandial glucose excursions may help improve overall glycemic control in the general population of U.S. adults with diabetes. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Cross-Sectional_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Fasting_MeSH M_Food_MeSH P_Glucose_Tolerance_Test_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH P_Hyperglycemia_MeSH S_epidemiology_MeSH Hyperglycemia_epidemiology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Kinetics_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11577798 ----K I ----T Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. ----A Repaglinide, a carbamoylmethyl benzoic acid derivative, is the first of a new class of oral antidiabetic agents designed to normalise postprandial glucose excursions in patients with type 2 diabetes mellitus. Like the sulphonylureas, repaglinide reduces blood glucose by stimulating insulin release from pancreatic beta-cells, but differs from these and other antidiabetic agents in its structure, binding profile, duration of action and mode of excretion. In clinical trials of up to 1-year's duration, repaglinide maintained or improved glycaemic control in patients with type 2 diabetes mellitus. In comparative, 1-year, double-blind, randomised trials (n = 256 to 544), patients receiving repaglinide (0.5 to 4mg before 3 daily meals) achieved similar glycaemic control to that in patients receiving glibenclamide (glyburide) < or = 15 mg/day and greater control than patients receiving glipizide < or = 15 mg/day. Changes from baseline in glycosylated haemoglobin and fasting blood glucose levels were similar between patients receiving repaglinide and glibenclamide in all studies; however, repaglinide was slightly better than glibenclamide in reducing postprandial blood glucose in I short term study (n = 192). Patients can vary their meal timetable with repaglinide: the glucose-lowering efficacy of repaglinide was similar for patients consuming 2, 3 or 4 meals a day. Repaglinide showed additive effects when used in combination with other oral antidiabetic agents including metformin, troglitazone, rosiglitazone and pioglitazone, and intermediate-acting insulin (NPH) given at bedtime. In 1-year trials, the most common adverse events reported in repaglinide recipients (n = 1,228) were hypoglycaemia (16%), upper respiratory tract infection (10%), rhinitis (7%), bronchitis (6%) and headache (9%). The overall incidence of hypoglycaemia was similar to that recorded in patients receiving glibenclamide, glipizide or gliclazide (n = 597) [18%]; however, the incidence of serious hypoglycaemia appears to be slightly higher in sulphonylurea recipients. Unlike glibenclamide, the risk of hypoglycaemia in patients receiving repaglinide was not increased when a meal was missed in 1 trial. In conclusion, repaglinide is a useful addition to the other currently available treatments for type 2 diabetes mellitus. Preprandial repaglinide has displayed antihyperglycaemic efficacy at least equal to that of various sulphonylureas and is associated with a reduced risk of serious hypoglycaemia. It is well tolerated in a wide range of patients, including the elderly, even if a meal is missed. Furthermore, glycaemic control is improved when repaglinide is used in combination with metformin. Thus, repaglinide should be considered for use in any patient with type 2 diabetes mellitus whose blood glucose cannot be controlled by diet or exercise alone, or as an adjunct in patients whose glucose levels are inadequately controlled on metformin alone. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Aging_MeSH S_metabolism_MeSH Aging_metabolism_MeSH M_Animals_MeSH M_Biological_Availability_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH P_Carbamates_MeSH S_metabolism_MeSH Carbamates_metabolism_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Interactions_MeSH M_Half-Life_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH P_Hypoglycemic_Agents_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Intestinal_Absorption_MeSH M_Metabolic_Clearance_Rate_MeSH P_Piperidines_MeSH S_metabolism_MeSH Piperidines_metabolism_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH ****** 11585005 ----K I ----T Nateglinide: a new rapid-acting insulinotropic agent. ----A The United Kingdom Prospective Diabetes Study has shown that tight glycaemic control significantly reduces microvascular complications in Type 2 diabetes, but the effects on macrovascular complications were less impressive and did not reach statistical significance. Epidemiological studies have shown that post-prandial hyperglycaemia, rather than fasting hyperglycaemia, is more closely related to cardiovascular complications. It is, therefore, possible that previous studies may have overlooked the possible benefits of tight control of post-prandial hyperglycaemia as an important factor in reducing the cardiovascular mortality. Nateglinide is a novel D-phenylalanine derivative that inhibits ATP-sensitive K+ channels in pancreatic beta-cells in the presence of glucose and thereby restores first phase insulin response in patients with Type 2 diabetes. This helps in reducing post-prandial glucose excursion. Combination studies with metformin have shown it to be effective in controlling hyperglycaemia. While metformin reduces the basal plasma glucose, nateglinide helps in controlling post-prandial peaks. Nateglinide provides a new therapeutic option for treating Type 2 diabetes by specifically targeting post-prandial hyperglycaemia. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Clinical_Trials_MeSH M_Cyclohexanes_MeSH S_pharmacology_MeSH Cyclohexanes_pharmacology_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Guidelines_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Microcirculation_MeSH S_drug_effects_MeSH Microcirculation_drug_effects_MeSH M_Molecular_Structure_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_pharmacology_MeSH Phenylalanine_pharmacology_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Postprandial_Period_MeSH ****** 11678967 ----K I ----T Glibenclamide improves postprandial hypertriglyceridaemia in type 2 diabetic patients by reducing chylomicrons but not the very low-density lipoprotein subfraction levels. ----A AIM: There are scarce data dealing with the degree of postprandial lipaemia after sulphonylurea administration. The aim of this study was to examine the effect of acute glibenclamide administration on postprandial lipaemia in Type 2 diabetic patients. METHODS: Eight randomly selected Type 2 diabetic individuals, aged 43-65 years (mean, 54 years), who had never received any anti-diabetic drug, were included in the study. Each patient was given a 485 kcal mixed meal (45% fat, 40% carbohydrate and 15% protein) twice on separate days after an overnight fast: once with placebo and once with 5 mg glibenclamide, per os, in a random order. The two tests were performed with an interval of 7 days. Venous blood samples were drawn just before and 2 h, 4 h and 6 h after meal consumption. Total triglyceride levels in plasma, in chylomicrons (CM), in CM-deficient plasma, in very low-density lipoprotein (VLDL) subfractions (VLDL-1, VLDL-2) and in intermediate-density lipoprotein (IDL) were determined. Free fatty acid (FFA) and total cholesterol levels in plasma, as well as high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels in CM-deficient plasma, were also measured. Finally, serum glucose, insulin and C-peptide concentrations were measured in each sample. RESULTS: As expected there was a significant decrease in postprandial glycaemia after glibenclamide administration compared to placebo (mean area under the curve values: AUC = 53.3 +/- 18.2 and 69.1 +/- 21.6 mm/h, P = 0.00009). In addition, the mean AUC values of insulin and C-peptide were significantly greater after drug administration. The AUC values of total plasma triglyceride and of CM triglyceride following glibenclamide administration were significantly lower compared to placebo, while the AUC values of postprandial triglyceride in CM-deficient plasma and of postprandial triglyceride in VLDL-1, VLDL-2 and IDL were not different after drug administration compared to placebo. Finally, no significant differences were noted in the AUC values of total cholesterol, LDL cholesterol, HDL cholesterol and plasma FFA levels after glibenclamide administration. CONCLUSIONS: These results demonstrate that glibenclamide administration improves postprandial hypertriglyceridaemia acutely by reducing postprandial triglycerides of intestinal origin. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Chylomicrons_MeSH S_blood_MeSH Chylomicrons_blood_MeSH M_Coronary_Disease_MeSH S_prevention_&_control_MeSH Coronary_Disease_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypertriglyceridemia_MeSH S_blood_MeSH Hypertriglyceridemia_blood_MeSH S_drug_therapy_MeSH Hypertriglyceridemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipoproteins__VLDL_MeSH S_blood_MeSH Lipoproteins__VLDL_blood_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH S_physiology_MeSH Postprandial_Period_physiology_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 11678974 ----K I ----T Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients. ----A AIM: To compare the effect of glimepiride in combination with metformin with monotherapy of each drug on glycaemic control in Type 2 diabetic patients. DESIGN AND METHODS: Randomized, double-blind, double-dummy, parallel-group multicentre study conducted in France. Type 2 diabetic patients aged 35-70 years inadequately controlled by metformin monotherapy 2550 mg daily for at least 4 weeks were randomized to either metformin, glimepiride or metformin and glimepiride. RESULTS: Three hundred and seventy-two patients aged 56 +/- 8 years were treated for 5 months. Combination treatment was significantly more efficient in controlling HbA1c (% change + 0.07 +/- 1.20 for metformin, + 0.27 +/- 1.10 for glimepiride, -0.74 +/- 0.96 for combination treatment, P < 0.001), fasting blood glucose (FBG) (mmol/l change + 0.8 +/- 0.4 for metformin, + 0.7 +/- 3.1 for glimepiride and -1.8 +/- 2.2 for combination treatment, P < 0.001) and post-prandial blood glucose (PPBG) (mmol/l change + 1.1 +/- 5.9 for metformin, + 0.1 +/- 5.1 for glimepiride and -2.6 +/- 3.9 for combination treatment, P < 0.001) than either glimepiride or metformin alone. There was no significant difference between metformin or glimepiride monotherapy with respect to the change in HbA1c or FBG; however, glimepiride was significantly more effective than metformin in reducing PPBG. The incidence of symptomatic hypoglycaemia was higher in the combination group than in either monotherapy group (P = 0.039). CONCLUSIONS: Addition of glimepiride to metformin in Type 2 diabetic patients inadequately controlled by metformin alone resulted in superior glycaemic control compared with glimepiride or metformin monotherapy. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Research_Design_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11679464 ----K I ----T Effects of sibutramine in obese female subjects with type 2 diabetes and poor blood glucose control. ----A OBJECTIVE: In this study, we evaluated the efficacy of sibutramine in combination with hypoglycemic drugs in obese type 2 diabetic women whose glucose levels were poorly regulated. RESEARCH DESIGN AND METHODS: Female patients with type 2 diabetes, poorly controlled glucose levels, and HbA(1c) >8% were randomly assigned to one of two groups. In addition to their prescribed hypoglycemic agents (maximum doses of sulfonylureas and metformin), one group (n = 30) received a placebo twice daily for 6 months and the other (n = 30) received sibutramine 10 mg b.i.d. for the same period. RESULTS: One patient in the sibutramine group was excluded during the study period because of hypertension; thus, a total of 29 data sets were analyzed for this group. In the placebo group, five patients had to be excluded because of low treatment efficacy, leaving a total of 25 who completed the study. Comparing the changes that occurred over 6 months in the sibutramine and placebo groups, the former showed significantly greater reductions in fasting blood glucose (P < 0.0001), second-hour postprandial blood glucose (P < 0.0001), insulin resistance (P < 0.0001), waist circumference (P < 0.0001), BMI (P < 0.0001), HbA(1c) (P < 0.0001), diastolic blood pressure, pulse rate, uric acid levels, and all elements of the lipid profile except HDL cholesterol and apolipoprotein A1. CONCLUSIONS: The addition of sibutramine to oral hypoglycemic therapy resulted in significant weight loss and improvement in metabolic parameters in this patient group. Sibutramine is an effective adjunct to oral hypoglycemic therapy in obese women with type 2 diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Appetite_Depressants_MeSH S_therapeutic_use_MeSH Appetite_Depressants_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Cyclobutanes_MeSH S_therapeutic_use_MeSH Cyclobutanes_therapeutic_use_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Obesity_in_Diabetes_MeSH S_blood_MeSH Obesity_in_Diabetes_blood_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH M_Placebos_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_Weight_Loss_MeSH S_drug_effects_MeSH Weight_Loss_drug_effects_MeSH ****** 11692183 ----K E ----T Genetic variability of the SUR1 promoter in relation to beta-cell function and Type II diabetes mellitus. ----A AIMS/HYPOTHESIS: We aimed to examine the promoter of SUR1 for genetic variation and to determine if variants were associated with Type II (non-insulin-dependent) diabetes mellitus or measures of beta-cell function. METHODS: We examined 465 bp upstream of the ATG site in 46 Type II diabetic patients and 15 glucose tolerant control subjects by SSCP-heteroduplex analysis. RESULTS: We identified an a --> t substitution 437 bp upstream of the ATG site. The allelic frequency was similar in 455 unrelated Type II diabetic patients and in 203 glucose tolerant control subjects matched for age (0.036, [95 % CI 0.019-0.053] vs 0.034 [95 % CI 0.009-0.059]; p = 0.92). Among the glucose tolerant subjects there were no differences between non-carriers (n = 189) and carriers (n = 14) of the variant in fasting values or 30 min values of plasma glucose and serum insulin during an oral glucose tolerance test. In a study of 233 glucose tolerant offspring of and spouses to Danish Caucasian Type II diabetic patients, non-carriers (n = 193) and carriers (n = 37) of the -437 a/t polymorphism did not differ in glucose or tolbutamide stimulated insulin response during an intravenous glucose tolerance test with intravenous tolbutamide injection [AUCs-insulin (0-8) min, 2290 +/- 1660 vs 2308 +/- 1935 pmol/l x min and AUCs-insulin(20-30 min), 3113 +/- 2033 vs. 3393 +/- 2830 pmol/l x min, respectively]. CONCLUSION/INTERPRETATION: We have identified a novel a/t polymorphism of the SUR1 gene promoter which is not associated with Type II diabetes mellitus or measures of beta-cell function. Previous reported non-functional variants of SUR1 associated with Type II diabetes mellitus still need to be accounted for. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Alleles_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_DNA_Mutational_Analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Gene_Frequency_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Islets_of_Langerhans_MeSH S_physiopathology_MeSH Islets_of_Langerhans_physiopathology_MeSH M_Kinetics_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Polymorphism_(Genetics)_MeSH M_Polymorphism__Single-Stranded_Conformational_MeSH M_Potassium_Channels_MeSH S_genetics_MeSH Potassium_Channels_genetics_MeSH P_Promoter_Regions_(Genetics)_MeSH M_Support__Non-U_S__Gov't_MeSH M_Tolbutamide_MeSH S_diagnostic_use_MeSH Tolbutamide_diagnostic_use_MeSH P_Variation_(Genetics)_MeSH ****** 11716156 ----K E ----T Medical care from childhood to adulthood in type 1 and type 2 diabetes. ----A Diabetes mellitus comprises a heterogeneous group of diseases that have in common the development of macro- and microvascular complications. It is now possible to identify subjects at high risk of Type 1 or Type 2 diabetes, especially in the patient's family members. Preventive interventions are quickly becoming available, and can help delay the onset of the disease and thereby reduce complications in these subjects. Furthermore the correct etiological diagnosis of diabetes is fundamental in providing the best treatment for the patient. Maturity-onset diabetes of the young (MODY) syndrome should be suspected in cases of a subtle onset of diabetes and autosomal dominant inheritance. Mitochondrial DNA mutations should be considered when a diabetic patient also suffers from deafness or if there is a family history of this combination in the mother side of the family. Atypical diabetes has to be identified by the physician to avoid mistakes when the patient enters the non-insulin-dependent phase. In the case of Wolfram's syndrome a gene analysis for each family member should be performed to identify heterozygote subjects. Recently, many discoveries in genetics help us better understand the pathogenesis of the diseases and diagnose the monogenic form of diabetes more easily. If all family members are followed in the same center, clues from the family history are readily available for differential diagnosis and preventive interventions can be established more effectively. ----P Journal_Article Review Review__Tutorial ----M M_Adolescent_MeSH M_Adult_MeSH M_Autoantibodies_MeSH S_blood_MeSH Autoantibodies_blood_MeSH M_Child_MeSH M_Child__Preschool_MeSH M_DNA__Mitochondrial_MeSH S_analysis_MeSH DNA__Mitochondrial_analysis_MeSH P_Diabetes_Mellitus__Type_I_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_I_etiology_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_I_genetics_MeSH S_immunology_MeSH Diabetes_Mellitus__Type_I_immunology_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_I_prevention_&_control_MeSH P_Diabetes_Mellitus__Type_II_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH S_immunology_MeSH Diabetes_Mellitus__Type_II_immunology_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_II_prevention_&_control_MeSH M_Human_MeSH M_Infant_MeSH M_Infant__Newborn_MeSH ****** 11715152 ----K E ----T [Thiazolidinediones--a new class of oral antidiabetics] ----A Two members of the group, thiazolidinediones, have been approved for the treatment of type 2 diabetes mellitus. These novel oral antihyperglycaemic agents reduce insulin resistance through binding to and activation of the nuclear receptor, PPAR gamma, with subsequent effects on the glucose and lipid homoeostasis. The compounds will probably exhibit beneficial effects on other facets of the metabolic syndrome. Their effectiveness on glycaemic control appears comparable, as assessed by the literature available. HbA1c is lowered by 1.0 to 1.5%. Both drugs are approved for combination therapy with either metformin or sulphonylureas, not as monotherapy or in combination with insulin. Disturbed heart function (NYHA I-IV) is a contra-indication. In contrast to troglitazone, there is so far no evidence of liver toxicity. In spite of the limited literature, it is anticipated that the present class of oral hypoglycaemic agents will turn out to be an important contribution to improving the metabolic control of patients with type 2 diabetes, if the safety profile remains unchanged in long-term studies. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Human_MeSH P_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_chemistry_MeSH Hypoglycemic_Agents_chemistry_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Insulin_Resistance_MeSH M_Receptors__Cytoplasmic_and_Nuclear_MeSH S_drug_effects_MeSH Receptors__Cytoplasmic_and_Nuclear_drug_effects_MeSH S_genetics_MeSH Receptors__Cytoplasmic_and_Nuclear_genetics_MeSH P_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_chemistry_MeSH Thiazoles_chemistry_MeSH S_pharmacokinetics_MeSH Thiazoles_pharmacokinetics_MeSH ****** 11724081 ----K E ----T Prescribing patterns and therapeutic implications for diabetic hypertension in Bahrain. ----A OBJECTIVE: To determine drug prescription patterns and the extent of conformity with World Health Organization/international Society of Hypertension (WHO/ISH) guidelines in diabetic hypertension. DESIGN: Retrospective prescription-based survey. SETTING: Seven primary-care health centers, comprising approximately one-third of primary-care health centers in Bahrain. PATIENTS: Patients with type 2 diabetes and hypertension. MAIN OUTCOME MEASURE: The prescribing pattern of antihypertensive and antidiabetic drugs. RESULTS: Among a study sample of 1,463 patients with type 2 diabetes and hypertension, antidiabetic agents were prescribed as monotherapy in the following descending order: glyburide, gliclazide, insulin, and metformin. As combinations, sulfonylureas plus metformin was most popular, followed by metformin plus insulin, and sulfonylureas plus insulin. Sulfonylurea and metformin with insulin was rarely used. There was no significant difference in prescribing of glyburide and metformin between the elderly and young middle-aged diabetic patients; many patients older than 65 years were treated with a beta-blocker along with a long-acting sulfonylurea. Both as monotherapy and in overall use, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium-channel blockers were most often prescribed. Among 35.5% patients treated with antihypertensive combinations, various two- and three-drug combinations of beta-blockers, ACE inhibitors, calcium-channel blockers, and diuretics were often used. The proportion of patients taking atenolol 100 mg/d was higher with combination regimens. Hydrochlorothiazide 25 mg or equivalent thiazide diuretics were extensively used. CONCLUSIONS: The prescribing pattern of antihypertensives in diabetic hypertension differs in many instances from WHO/ISH guidelines, especially regarding the choice of antihypertensive drugs and their combinations. The appropriateness of antidiabetic drug choice is questionable in relation to the antihypertensive used. ----P Journal_Article ----M M_Adrenergic_beta-Antagonists_MeSH S_therapeutic_use_MeSH Adrenergic_beta-Antagonists_therapeutic_use_MeSH M_Age_Factors_MeSH M_Angiotensin-Converting_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Angiotensin-Converting_Enzyme_Inhibitors_therapeutic_use_MeSH M_Antihypertensive_Agents_MeSH S_therapeutic_use_MeSH Antihypertensive_Agents_therapeutic_use_MeSH M_Bahrain_MeSH M_Diabetes_Mellitus_MeSH S_complications_MeSH Diabetes_Mellitus_complications_MeSH M_Diuretics__Thiazide_MeSH S_therapeutic_use_MeSH Diuretics__Thiazide_therapeutic_use_MeSH M_Drug_Combinations_MeSH M_Drug_Utilization_Review_MeSH M_Human_MeSH M_Hypertension_MeSH S_drug_therapy_MeSH Hypertension_drug_therapy_MeSH S_etiology_MeSH Hypertension_etiology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Prescriptions__Drug_MeSH M_Retrospective_Studies_MeSH ****** 11724096 ----K I ----T Nateglinide therapy for type 2 diabetes mellitus. ----A OBJECTIVE: To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of nateglinide. DATA SOURCES: Primary and review articles regarding nateglinide were identified by MEDLINE search (from 1966 to January 2001); abstracts were identified through the Institute for Scientific Information Web of Science (from 1995 to January 2001) and the American Diabetes Association; additional information was obtained from the nateglinide product information. STUDY SELECTION/DATA EXTRACTION: All articles and meeting abstracts identified from the data sources were evaluated and all information deemed relevant was included in this review. Much of the information was from abstracts or the product labeling, since few clinical studies have been published in the medical literature. DATA SYNTHESIS: Nateglinide is a novel nonsulfonylurea oral antidiabetic agent that stimulates insulin secretion from the pancreas. It has a rapid onset and short duration of action, allowing administration before a meal to reduce postprandial hyperglycemia. Improvement in glycemic control with nateglinide monotherapy has been demonstrated in patients not previously treated with antidiabetic medications. Greater improvement in glycemic control was observed when nateglinide was administered in combination with metformin. CONCLUSIONS: Nateglinide is similar to repaglinide, but has a quicker onset of action, quicker reversal, and does not usually require dosage titration. Based on the pharmacodynamics of nateglinide and repaglinide, nateglinide produces a more rapid postprandial increase in insulin secretion, and its duration of response is shorter than that of repaglinide. The risk of postabsorptive hypoglycemia should be lower than with either sulfonylureas or repaglinide. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Clinical_Trials_MeSH M_Cyclohexanes_MeSH S_adverse_effects_MeSH Cyclohexanes_adverse_effects_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Phenylalanine_MeSH S_adverse_effects_MeSH Phenylalanine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH ****** 11726007 ----K E ----T Glycemic control with Humalog Mix25 in type 2 diabetes inadequately controlled with glyburide. ----A BACKGROUND: Humalog Mix25 (Mix25) is a premixed insulin mixture of 25% insulin lispro and 75% neutral protamine lispro. OBJECTIVE: The aim of this study was to quantitate the improvement in glycemic control achieved with Mix25 versus the maximum dose of glyburide (GB) in patients with type 2 diabetes inadequately controlled with GB. METHODS: In this randomized, parallel, open-label comparative study, patients with type 2 diabetes received either Mix25 before the morning and evening meals for 4 months or GB 15 mg daily for 4 months. Glycemic control was assessed by glycosylated hemoglobin (HbA1c) measurements, 4-point self-monitored blood glucose profiles, and patient-reported hypoglycemia. Patients also completed a treatment satisfaction questionnaire at the end of the study. RESULTS: All 172 patients were white; 85 were randomized to receive Mix25. The mean age was 59.5 +/- 8.2 years, and 35.5% (61/172) were men. The mean body mass index was 27.2 kg/m2. The mean duration of type 2 diabetes was 10.2 +/- 6.6 years, and the mean duration of sulfonylurea treatment was 5.8 +/- 5.9 years. The mean HbA1c and fasting blood glucose levels were 10.07% +/- 1.4% and 11.6 +/- 2.8 mmol/L, respectively, in the glyburide group and 9.85% +/- 1.2% and 12.2 +/- 2.9 mmol/L, respectively, in the Mix25 group. There were no statistically significant differences between the treatment groups at baseline for any of the demographic or efficacy variables. At end point, mean HbA1c was significantly lower in the Mix25 group than in the GB group (Mix25, 8.5% +/- 1.3%; GB, 9.4% +/- 1.8%; P = 0.001). A larger decrease from baseline in HbA1c and in all self-monitored blood glucose values was observed in the Mix25 group: -1.4% versus -0.7% for HbA1c, P = 0.004; -2.8 mmol/L versus -1.1 mmol/L for fasting blood glucose, P < 0.01; -5.1 mmol/L versus -1.7 mmol/L for the morning 2-hour postprandial blood glucose, P < 0.001; -2.2 mmol/L versus -0.8 mmol/L for the evening preprandial blood glucose, P < 0.05; and -4.4 mmol/L versus -1.5 mmol/L for the evening 2-hour postprandial blood glucose, P < 0.001. Patients expressed more satisfaction with Mix25 than with GB, as measured by the weighted combined score on a treatment satisfaction questionnaire (2.0 +/- 1.3 vs 0.7 +/- 1.3). The mean hypoglycemia rate (events per patient per 30 days) was significantly higher in the Mix25 group at end point (Mix25, 0.30 +/- 0.53; GB, 0.05 +/- 0.20; P < 0.001). CONCLUSIONS: Compared with maximum-dose GB, twice-daily injections of Mix25 resulted in improved glycemic control and treatment satisfaction, and were associated with a predictably higher rate of hypoglycemia in this group of patients with type 2 diabetes who were inadequately controlled with maximum-dose GB. Although the inclusion of patients who were inadequately controlled with GB was intended to allow a comparison of the 2 treatments with respect to efficacy and tolerability in a real-life setting, a double-blind comparison in treatment-naive individuals may have resulted in a different outcome. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Body_Mass_Index_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Questionnaires_MeSH M_Treatment_Outcome_MeSH ****** 11728565 ----K I ----T Insulinotropic meglitinide analogues. ----A The loss of early-phase insulin secretion is an important and early event in the natural history of type 2 diabetes. Because a normal pattern of insulin secretion is essential for the effective control of postprandial metabolism, a rational basis for the development of agents that target early-phase insulin release exists. Conventional oral hypoglycaemic agents do not target, or adequately control, postprandial glycaemia. The emergence of new classes of oral agent with a more specific mode of action provides, for the first time, an opportunity to restore early-phase insulin release. One such drug class is the meglitinide analogues (repaglinide, nateglinide, and mitiglinide). These drugs are ideally suited for combination use with metformin. They could also prove effective in combination with a thiazolidinedione, a drug class that targets insulin resistance. Exogenous insulin is frequently required in the late management of type 2 diabetes. However, one hope for newer combinations of diabetic drugs is that the functional life of the beta cell can be extended, thereby delaying the need for insulin injections. ----P Journal_Article Review Review__Tutorial ----M M_Adult_MeSH M_Animals_MeSH M_Benzamides_MeSH S_therapeutic_use_MeSH Benzamides_therapeutic_use_MeSH M_Carbamates_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Cyclohexanes_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH P_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Piperidines_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Rats_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11735645 ----K E ----T Hepatotoxicity with thiazolidinediones: is it a class effect? ----A Decreased insulin sensitivity plays a major role in various human diseases. particularly type 2 diabetes mellitus, and is associated with a higher risk of atherosclerosis and cardiovascular complications. Thiazolidinediones, more commonly termed glitazones, are the first drugs to specifically target muscular insulin resistance. They have proven efficacy for reducing plasma glucose levels in patients with type 2 diabetes mellitus treated with diet alone, sulphonylureas, metformin or insulin. In addition, they are associated with some improvement of the cardiovascular risk profile. However, troglitazone, the first compound approved by the Food and Drug Administration in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozen deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to unique properties of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy with regard to blood glucose control in patients with type 2 diabetes mellitus as compared with troglitazone. In controlled clinical trials, the incidence of significant (> or =3 x upper limit of normal) increases in liver enzyme levels (ALT in particular) was similar with rosiglitazone or pioglitazone as compared with placebo, whereas troglitazone was associated with a 3-fold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only a few case reports of hepatotoxicity have been reported in patients treated with rosiglitazone until now, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. It should be mentioned that troglitazone, unlike pioglitazone and rosiglitazone, induces the cytochrome P450 isoform 3A4, which is partly responsible for its metabolism, and may be prone to drug interactions. Importantly enough, obesity, insulin resistance and type 2 diabetes mellitus are associated with liver abnormalities, especially non-alcoholic steatohepatitis, independent of any pharmacological treatment. This association obviously complicates the selection of patients who are good candidates for a treatment with glitazones as well as the monitoring of liver tests after initiation of therapy with any thiazolidinedione compound. While regular monitoring of liver enzymes is still recommended and more long term data are desirable, current evidence from clinical trials and postmarketing experience in the US supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone. ----P Journal_Article Review Review__Tutorial ----M M_Aged_MeSH M_Chromans_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH S_pharmacokinetics_MeSH Chromans_pharmacokinetics_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Hepatitis__Toxic_MeSH S_enzymology_MeSH Hepatitis__Toxic_enzymology_MeSH S_mortality_MeSH Hepatitis__Toxic_mortality_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Structure-Activity_Relationship_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_metabolism_MeSH Thiazoles_metabolism_MeSH S_pharmacokinetics_MeSH Thiazoles_pharmacokinetics_MeSH P_Thiazolidinediones_MeSH ****** 11763159 ----K E ----T Current and future treatment strategies for type 2 diabetes: the beta-cell as a therapeutic target. ----A Diabetes affects millions of people worldwide. The most common variants are type 1 diabetes with autoimmune destruction of the pancreatic beta-cells and type 2 diabetes with peripheral insulin resistance and beta-cell dysfunction. In spite of tremendous research, current pharmacological regimens are still sub-optimal for adequate blood glucose control. As a consequence, patients with diabetes are at significant risk for development of serious long-term complications, such as blindness and kidney disease. This review will discuss present and future strategies for the treatment of type 2 diabetes with a focus on the more recently recognized problems of beta-cell dysfunction and loss. The treatment strategies presented include promotion of beta-cell proliferation and differentiation by glucagon-like peptide 1 receptor agonists. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Drug_Delivery_Systems_MeSH S_methods_MeSH Drug_Delivery_Systems_methods_MeSH S_trends_MeSH Drug_Delivery_Systems_trends_MeSH M_Forecasting_MeSH M_Human_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_metabolism_MeSH Islets_of_Langerhans_metabolism_MeSH S_pathology_MeSH Islets_of_Langerhans_pathology_MeSH M_Sulfonylurea_Compounds_MeSH S_chemistry_MeSH Sulfonylurea_Compounds_chemistry_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 11763160 ----K E ----T Pramlintide (Amylin). ----A Pramlintide is a human amylin analog, under development by Amylin (originally in collaboration with Johnson & Johnson), as an adjunct with insulin for the potential prevention of complications of type I diabetes, and as a single agent for type II diabetes [279804], [295121], [305454]. In December 2000, Amylin submitted a US NDA seeking approval to market pramlintide as an adjunctive therapy for type 1 and 2 diabetics using insulin [392527]; the application was accepted for review by the FDA in January 2001 [396938], and was scheduled for review by the Endocrinologic and Metabolic Drugs Advisory Committee on July 26 2001 [408924]. In May 2001, Amylin submitted an MAA for pramlintide to the EMEA [411323] and in October 2001, Amylin received an approvable letter from the FDA for both Type I and insulin-using Type II diabetes; however, at this time, discussions with the FDA were ongoing regarding additional clinical work that was required before the NDA would be approved [425570]. ----P Journal_Article Review Review_Literature ----M M_Amyloid_MeSH S_chemical_synthesis_MeSH Amyloid_chemical_synthesis_MeSH S_pharmacology_MeSH Amyloid_pharmacology_MeSH S_therapeutic_use_MeSH Amyloid_therapeutic_use_MeSH M_Animals_MeSH M_Diabetes_Mellitus_MeSH S_drug_therapy_MeSH Diabetes_Mellitus_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_chemical_synthesis_MeSH Hypoglycemic_Agents_chemical_synthesis_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH ****** 11735640 ----K I ----T Orlistat: in the prevention and treatment of type 2 diabetes mellitus. ----A Orlistat is a nonsystemically acting gastric and pancreatic lipase inhibitor that limits the absorption of dietary fat. A retrospective pooled analysis of three 2-year, double-blind, randomised, placebo-controlled trials involving patients with obesity revealed that orlistat recipients were more likely to experience an improvement, and less likely to experience a deterioration, in glucose tolerance status than placebo recipients. In comparison with placebo, orlistat recipients had significantly greater reductions in glycosylated haemoglobin and fasting plasma glucose levels in large, double-blind, randomised, placebo-controlled studies of 24 to 52 weeks' duration involving patients with obesity and type 2 diabetes mellitus. In one such study, the dosage of concomitant sulphonylureas was able to be reduced in more orlistat than placebo recipients (43.2 vs 28.9%), with discontinuation of sulphonylurea therapy achieved in 11.7% of orlistat recipients. The most common adverse effects reported in orlistat recipients with type 2 diabetes mellitus relate to the gastrointestinal system and are similar to those reported in studies involving patients without type 2 diabetes mellitus. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Blood_Glucose_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_II_prevention_&_control_MeSH M_Enzyme_Inhibitors_MeSH S_adverse_effects_MeSH Enzyme_Inhibitors_adverse_effects_MeSH S_pharmacokinetics_MeSH Enzyme_Inhibitors_pharmacokinetics_MeSH S_pharmacology_MeSH Enzyme_Inhibitors_pharmacology_MeSH M_Gastrointestinal_Diseases_MeSH S_chemically_induced_MeSH Gastrointestinal_Diseases_chemically_induced_MeSH M_Hemoglobin_A__Glycosylated_MeSH M_Human_MeSH M_Lactones_MeSH S_adverse_effects_MeSH Lactones_adverse_effects_MeSH S_pharmacokinetics_MeSH Lactones_pharmacokinetics_MeSH S_pharmacology_MeSH Lactones_pharmacology_MeSH M_Obesity_MeSH S_complications_MeSH Obesity_complications_MeSH S_drug_therapy_MeSH Obesity_drug_therapy_MeSH M_Randomized_Controlled_Trials_MeSH M_Treatment_Outcome_MeSH ****** 11751665 ----K E ----T Post-stenotic coronary blood flow at rest is not altered by therapeutic doses of the oral antidiabetic drug glibenclamide in patients with coronary artery disease. ----A OBJECTIVE: To investigate whether blood flow in normal and post-stenotic coronary arteries is altered by therapeutic doses of the sulfonylurea agent glibenclamide. PATIENTS: 12 patients with a high grade stenosis of the left anterior descending coronary artery (n = 10) or left circumflex coronary artery (n = 2), and an angiographically normal corresponding left circumflex artery or left anterior descending artery, respectively. DESIGN: Two Doppler ultrasound wires were positioned in the "normal" and post-stenotic artery for simultaneous measurements of coronary blood flow velocity under baseline conditions and after intravenous glibenclamide, 0.05 mg/kg body weight. Local coronary blood flow was calculated from the average peak velocity and the cross sectional area derived from quantitative coronary angiographic analysis. Coronary flow reserve was determined after intracoronary injection of 30 microg adenosine and 12 mg papaverine. RESULTS: One hour after glibenclamide, serum insulin increased from (mean (SD)) 7.4 (2.0) to 44.8 (25.5) mU/l (p < 0.005), and C peptide from 1.4 (0.4) to 3.4 (1.2) ng/l (p = 0.005). In normal coronary arteries coronary flow reserve was 2.6 (0.4) after adenosine and 3.0 (0.4) after papaverine, while in post-stenotic arterial segments it was 1.2 (0.3) after adenosine (p = 0.005) and 1.3 (0.3) after papaverine (p = 0.005). There was no significant difference after glibenclamide. In non-stenotic arteries, average peak velocity (18.8 (5.2) cm/s) and calculated coronary blood flow (23.8 (10.7) ml/min) were not altered by glibenclamide (18.3 (5.2) cm/s and 22.8 (10.4) ml/min, respectively). In post-stenotic arteries, baseline average peak velocity was 13.3 (4.9) ml/min and coronary blood flow was 9.1 (3.0) ml/min, without significant change after glibenclamide (13.3 (5.2) cm/s, 9.0 (3.2) ml/min). CONCLUSIONS: Glibenclamide, 0.05 mg/kg intravenously, is effective in increasing serum insulin, suggesting a K(ATP) channel blocking effect in pancreatic beta cells. It does not compromise coronary blood flow and vasodilatation in response to adenosine and papaverine in post-stenotic and angiographically normal coronary arteries at rest. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Coronary_Angiography_MeSH M_Coronary_Circulation_MeSH S_drug_effects_MeSH Coronary_Circulation_drug_effects_MeSH M_Coronary_Stenosis_MeSH S_drug_therapy_MeSH Coronary_Stenosis_drug_therapy_MeSH S_pathology_MeSH Coronary_Stenosis_pathology_MeSH S_physiopathology_MeSH Coronary_Stenosis_physiopathology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_pathology_MeSH Diabetes_Mellitus__Type_II_pathology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Angiopathies_MeSH S_drug_therapy_MeSH Diabetic_Angiopathies_drug_therapy_MeSH S_pathology_MeSH Diabetic_Angiopathies_pathology_MeSH S_physiopathology_MeSH Diabetic_Angiopathies_physiopathology_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Peptides_MeSH S_blood_MeSH Peptides_blood_MeSH ****** 11772918 ----K E ----T Standards of medical care for patients with diabetes mellitus. ----A ----P Guideline Journal_Article Practice_Guideline ----M M_Diabetes_Mellitus_MeSH S_classification_MeSH Diabetes_Mellitus_classification_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus_prevention_&_control_MeSH S_therapy_MeSH Diabetes_Mellitus_therapy_MeSH M_Mass_Screening_MeSH M_Quality_Assurance__Health_Care_MeSH M_Societies__Medical_MeSH M_United_States_MeSH ****** 11790216 ----K E ----T Oral antihyperglycemic therapy for type 2 diabetes: scientific review. ----A CONTEXT: Care of patients with type 2 diabetes has been revolutionized throughout the past several years-first, by the realization of the importance of tight glycemic control in forestalling complications, and second, by the availability of several unique classes of oral antidiabetic agents. Deciphering which agent to use in certain clinical situations is a new dilemma facing the primary care physician. OBJECTIVE: To systematically review available data from the literature regarding the efficacy of oral antidiabetic agents, both as monotherapy and in combination. DATA SOURCES: A MEDLINE search was performed to identify all English-language reports of unique, randomized controlled clinical trials involving recently available oral agents for type 2 diabetes. Bibliographies were also reviewed to find additional reports not otherwise identified. STUDY SELECTION AND DATA EXTRACTION: Studies (63) were included in the analysis if they had a study period of at least 3 months; if each group contained at least 10 subjects at the study's conclusion; and if hemoglobin A(1c) was reported. When multiple dosages of a drug were tested, the results of the highest approved dosage were used. In placebo-controlled trials, hemoglobin A(1c) data are presented as the difference between the change in treated vs placebo subjects. DATA SYNTHESIS: Five distinct oral drug classes are now available for the treatment of type 2 diabetes. Compared with placebo treatment, most of these agents lower hemoglobin A(1c) levels approximately 1% to 2%. Equivalent efficacy is usually demonstrated when different agents are compared with one another in the same study population. When they are used in combination, there are additional glycemic benefits. Long-term vascular risk reduction has been demonstrated only with sulfonylureas and metformin. CONCLUSIONS: With few exceptions, the available oral antidiabetic agents are equally effective at lowering glucose concentrations. Their mechanisms of action are different, however, and as a result they appear to have distinct metabolic effects. These are reflected in their adverse effect profiles and their effect on cardiovascular risk, which may influence drug choice. ----P Journal_Article Review Review__Academic ----M M_Administration__Oral_MeSH M_Biguanides_MeSH S_therapeutic_use_MeSH Biguanides_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Diet_MeSH M_Drug_Therapy__Combination_MeSH M_Enzyme_Inhibitors_MeSH S_pharmacology_MeSH Enzyme_Inhibitors_pharmacology_MeSH M_Exercise_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_classification_MeSH Hypoglycemic_Agents_classification_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Randomized_Controlled_Trials_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 11790217 ----K E ----T Oral antihyperglycemic therapy for type 2 diabetes: clinical applications. ----A Oral agents are the mainstay of pharmacologic treatment for type 2 diabetes, and physicians now have a number of agents to choose from. However, more choices translate into more complex decision making. Many patients with diabetes have associated comorbidities, and most diabetic patients will require more than 1 agent to achieve good glycemic control. This article illustrates several of the pharmacologic approaches to type 2 diabetes through 4 situations that use principles of evidence-based medicine. The scenarios also highlight some of the difficulties in choosing the optimal pharmacologic treatment regimen for individual patients. Physicians should also recognize that type 2 diabetes is a multisystem disorder that requires multidisciplinary care, including education and ongoing counseling for effective patient self-management of the disease. Finally, patient preferences are a vital component of informed decision making for pharmacologic treatment of diabetes. ----P Case_Reports Journal_Article ----M M_Aged_MeSH M_Biguanides_MeSH S_therapeutic_use_MeSH Biguanides_therapeutic_use_MeSH M_Comorbidity_MeSH M_Decision_Making_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH M_Drug_Therapy__Combination_MeSH M_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Enzyme_Inhibitors_therapeutic_use_MeSH M_Evidence-Based_Medicine_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_economics_MeSH Hypoglycemic_Agents_economics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Patient_Education_MeSH M_Patient_Participation_MeSH M_Physician-Patient_Relations_MeSH M_Practice_Guidelines_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 11800292 ----K E ----T Glimepiride in type 2 diabetes mellitus Thai patients. ----A This study aimed to confirm the efficacy of glimepiride given once daily in the treatment of Thai type 2 diabetic patients and to find out the optimum dosage for Thai patients. The patients were enrolled at the diabetic clinics of 5 hospitals (Rajavithi, Chulalongkorn, Pramongkutklao, Siriraj and Theptarin Hospitals). All patients started glimepiride 1 mg once daily and escalated to 2, 3, 4 and until 6 mg every 4 weeks if fasting plasma glucose (FPG) exceeded 140 mg/dL. Subjects were 60 females and 29 males with an average age of 52.2 +/- 10.0 years. Mean BMI was 25.5 +/- 3.8 kg/m2. Fifty seven patients (64.0%) were drug naive and thirty two patients (36.0%) had been previously treated with oral hypoglycemic agents. Seventy three per cent of the drug naive and 37 per cent of the previously treated patients could be controlled with 1-2 mg of glimepiride once daily. At the twelfth week of treatment, mean fasting plasma glucose decreased from 224.6 to 156.6 mg/dL (30% reduction) and mean HbA1c decreased from 10.0 to 7.5 per cent (25% reduction). At the end of the study 49.4 per cent of the patients had HbA1c < 7.0 per cent, 21.3 per cent had HbA1c 7.0-8.0 per cent and 29.3 per cent had HbA1c > 8.0 per cent. Adverse events that were probably or possibly related to the drug were reported in 5 patients (5.6%). Three of them were hypoglycemia and two patients had skin rash. All hypoglycemic episodes were mild. Glimepiride was indicated to be safe. There were no clinically significant changes in clinical laboratory values, physical examinations and vital signs. In conclusion, glimepiride was efficacious and safe in type 2 diabetes Thai patients and 1-2 mg of glimepiride appeared to be a sufficient dose for most newly diagnosed type 2 diabetic patients. ----P Clinical_Trial Journal_Article Multicenter_Study ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thailand_MeSH M_Treatment_Outcome_MeSH ****** 11815505 ----K E ----T Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). ----A OBJECTIVE: To evaluate the efficacy of the addition of insulin when maximal sulfonylurea therapy is inadequate in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Glycemic control, hypoglycemia, and body weight were monitored over 6 years in 826 patients with newly diagnosed type 2 diabetes in 8 of 23 U.K. Prospective Diabetes Study (UKPDS) centers that used a modified protocol. Patients were randomly allocated to a conventional glucose control policy, primarily with diet (n = 242) or an intensive policy with insulin alone (n = 245), as in the main study. However, for patients randomized to an intensive policy with sulfonylurea (n = 339), insulin was added automatically if the fasting plasma glucose remained >108 mg/dl (6.0 mmol/l) despite maximal sulfonylurea doses. RESULTS: Over 6 years, approximately 53% of patients allocated to treatment with sulfonylurea required additional insulin therapy. Median HbA(1c) in the sulfonylurea +/- insulin group was significantly lower (6.6%, interquartile range [IQR] 6.0-7.6) than in the group taking insulin alone (7.1%, IQR 6.2-8.0; P = 0.0066), and significantly more patients in the sulfonylurea +/- insulin group had an HbA(1c) <7% (47 vs. 35%, respectively; P = 0.011). Weight gain was similar in the intensive therapy groups, but major hypoglycemia occurred less frequently over all in the sulfonylurea (+/- insulin) group compared with the insulin alone group (1.6 vs. 3.2% per annum, respectively; P = 0.017). CONCLUSIONS: Early addition of insulin when maximal sulfonylurea therapy is inadequate can significantly improve glycemic control without promoting increased hypoglycemia or weight gain. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Great_Britain_MeSH M_Hemoglobin_A__Glycosylated_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 11815507 ----K I ----T Optimizing insulin secretagogue therapy in patients with type 2 diabetes: a randomized double-blind study with repaglinide. ----A OBJECTIVE: Repaglinide, a novel antidiabetic agent that has a rapid onset and short duration of action, was developed for mealtime dosing. The purpose of this pharmacodynamic study was to validate a prandial regimen of repaglinide by comparing meal-related dosing with a regimen in which the same total daily dose was divided into only two doses at morning and evening meals. RESEARCH DESIGN AND METHODS: The study was a double-blind, randomized, parallel-group trial in 19 antidiabetic agent-naive subjects with type 2 diabetes (mean age 58 years, known duration of diabetes 3.5 years, HbA(1c) 7.3%, and BMI 32 kg/m(2)). Patients were randomly assigned to receive repaglinide either before each of the three main meals or before breakfast and before the evening meal. Patients in both groups received the same total daily dose of repaglinide. Twenty-four hour profiles of blood glucose, plasma insulin, and plasma C-peptide concentrations were measured at baseline and after 4 weeks of treatment. RESULTS: Repaglinide increased postprandial insulin levels and markedly reduced postprandial glucose levels relative to baseline in both groups. Significant reductions were also recorded in fasting blood glucose and HbA(1c) levels. The repaglinide regimen, in which a dose was taken before each main meal, was more effective in improving glycemic control (including postprandial glucose and HbA(1c) levels) than the same total dose of repaglinide divided into morning and evening mealtime doses. CONCLUSIONS: These data support the strategy of mealtime dosing with repaglinide. The improvements in glycemic control observed in these patients are encouraging. In addition to classic parameters of glycemic control, improvements in postprandial glucose excursions may prove to be important because postprandial hyperglycemia has been suggested to be an independent risk factor for cardiovascular disease in diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Eating_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH M_Postprandial_Period_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11824428 ----K 3 ----T Sibutramine: new preparation. Slight weight loss; but also a slight rise in blood pressure ... ----A (1) The reference treatment for achieving weight loss by obese patients is a combination of dietary measures, exercise and behavioural interventions. There is currently no drug treatment with demonstrated efficacy on the morbidity or mortality associated with excess body weight. (2) Sibutramine, a serotonin- and noradrenaline-reuptake inhibitor structurally related to the amphetamines has been granted marketing authorisation in France for the treatment of obesity and excess body weight in patients with associated risk factors. (3) The clinical file on sibutramine contains no trial focusing on morbidity or mortality end points. (4) According to comparative clinical trials, weight loss during a 6-12 month course of sibutramine is, on average, between 3 and 9 kg greater than that on placebo. Patients regain weight after sibutramine cessation. (5) Sibutramine has little or no benefit on blood sugar or lipid parameters. (6) The main known adverse effect of sibutramine is increased blood pressure. Sibutramine also has amphetamine-like side effects. (7) In practice, sibutramine currently has no place in the management of obesity. ----P Journal_Article ----M M_Appetite_MeSH S_drug_effects_MeSH Appetite_drug_effects_MeSH M_Appetite_Depressants_MeSH S_adverse_effects_MeSH Appetite_Depressants_adverse_effects_MeSH S_therapeutic_use_MeSH Appetite_Depressants_therapeutic_use_MeSH M_Clinical_Trials_MeSH M_Comparative_Study_MeSH P_Cyclobutanes_MeSH S_adverse_effects_MeSH Cyclobutanes_adverse_effects_MeSH S_therapeutic_use_MeSH Cyclobutanes_therapeutic_use_MeSH M_France_MeSH M_Human_MeSH M_Hypertension_MeSH S_chemically_induced_MeSH Hypertension_chemically_induced_MeSH M_Obesity_MeSH S_drug_therapy_MeSH Obesity_drug_therapy_MeSH M_Treatment_Outcome_MeSH ****** 11833837 ----K E ----T Comparative efficacy of preprandial or postprandial Humalog Mix75/25 versus glyburide in patients 60 to 80 years of age with type 2 diabetes mellitus. ----A BACKGROUND: Humalog Mix75/25 (Mix75/25) is a novel premixed insulin containing 75% neutral protamine lispro (an intermediate-acting insulin) and 25% insulin lispro. OBJECTIVE: The purpose of this study was to compare glycemic control and hypoglycemia rates with Mix75/25 versus glyburide, and with preprandial versus postprandial Mix75/25, in patients aged 60 to 80 years with type 2 diabetes mellitus and persistent hyperglycemia on sulfonylurea therapy. METHODS: In this open-label, 16-week, parallel-group study, patients were randomized to 1 of 2 treatments: glyburide 15 mg/d (or up to the maximum daily dose) or Mix75/25. The Mix75/25 group was randomly subdivided into preprandial (immediately before breakfast and dinner) and postprandial (within 15 minutes after the start of breakfast and dinner) injection subgroups. The primary outcomes were glycemic control and rate of hypoglycemia. RESULTS: A total of 143 patients were randomized; 127 completed the study. The change in glycosylated hemoglobin (HbA(1c)) from baseline to end point was significantly greater with Mix75/25 than with glyburide (mean +/- SEM, -1.14% +/- 0.18% vs -0.36% +/- 0.15%, P = 0.001). HbA(1c) changes with preprandial and postprandial Mix75/25 were not significantly different (-1.20% +/- 0.26% vs -1.08% +/- 0.26%, P = 0.748). Fasting blood glucose (BG), 2-hour postprandial BG, and mean daily BG reductions were greater with Mix75/25 than with glyburide (P < 0.001); preprandial and postprandial Mix75/25 administration did not differ significantly with respect to any of these BG variables. The hypoglycemia rate increased with Mix75/25 by 0.17 +/- 0.02 episodes per patient per 30 days, but there was no change with glyburide (P = 0.077). Body weight increased by 1.02 +/- 0.35 kg with Mix75/25 and decreased by 0.85 +/- 0.18 kg with glyburide (P < 0.001). CONCLUSIONS: Compared with glyburide, Mix75/25 significantly improved glycemic control in older patients with type 2 diabetes mellitus, could be administered after meals without compromising glycemic control, and was well tolerated. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_blood_MeSH Hypoglycemia_blood_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Patient_Acceptance_of_Health_Care_MeSH M_Postprandial_Period_MeSH S_physiology_MeSH Postprandial_Period_physiology_MeSH M_Recombinant_Proteins_MeSH S_therapeutic_use_MeSH Recombinant_Proteins_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH ****** 11837468 ----K E ----T Glibenclamide vs gliclazide in reducing oxidative stress in patients of noninsulin dependent diabetes mellitus--a double blind randomized study. ----A OBJECTIVE: Parameters of oxidative stress were quantitated in 50 patients with type 2 diabetes mellitus in uncontrolled state and after control using oral glibenclamide or gliclazide. The estimates were further compared between the two groups irrespective of drug used to evaluate the difference, if any. METHODS: The study was a double blind, uncontrolled, noncrossover and randomized trial. Fifty patients of uncontrolled type 2 diabetes were divided in to two groups. Group I (25 patients) received capsule A (glibenclamide) while Group II (25 patients) received capsule B (gliclazide). The parameters studied were Superoxide dismutase (SOD), malonyl-dialdehyde (MDA) and reduced glutathione (GSH). They were done at (a) uncontrolled stage (FBS--165 +/- 16.7 mg/dl, PP--240 +/- 30.1 mg/dl and HbA1--10.5 +/- 0.9% in group I and FBS--150 +/- 15.8 mg/dl, PP--246 +/- 29.1 mg/dl HbA1 10.6 +/- 0.8% in group II) and during controlled stage at 12 weeks (FBS--120 +/- 18.5 mg/dl, PP--180 +/- 19.1 mg/dl and HbA1--8.4 +/- 0.29% in group I and FBS--118 +/- 17.6 mg/dl, PP--176 +/- 20.1 mg/dl and HbA1--8.5 +/- 0.39% in group II patients). RESULTS: The significantly raised levels of MDA and SOD, and decreased levels of reduced glutathione (GSH) during uncontrolled stage of diabetes indicated free radical stress induced lipid peroxidation. The significant fall of MDA and SOD and increased levels of GSH in blood in both groups after control revealed beneficial effects of glycemic control on oxidative stress. The levels were not normalized and stayed higher than those in controls. On intergroup comparison; the control of diabetes with gliclazide (group II) showed improvement in oxidative stress (MDA, GSH) better (p < 0.001) than glibenclamide (group I). CONCLUSION: Oxidative stress in uncontrolled diabetes is decreased with glycemic control. The control of diabetes with gliclazide reduced oxidative stress more than glibenclamide, indicating higher antioxidant properties of gliclazide. Normalization of oxidative stress was not achieved. Further studies are required to see long-term effect of drug therapy in combating oxidative stress after achieving acceptable control of diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Oxidative_Stress_MeSH S_drug_effects_MeSH Oxidative_Stress_drug_effects_MeSH ****** 11837705 ----K E ----T Modeling the pharmacokinetics and pharmacodynamics of a unique oral hypoglycemic agent using neural networks. ----A PURPOSE: To develop a predictive population pharmacokinetic/ pharmacodynamic (PK/PD) model for repaglinide (REP), an oral hypoglycemic agent, using artificial neural networks (ANNs). METHODS: REP, glucose concentrations, and demographic data from a dose ranging Phase 2 trial were divided into a training set (70%) and a test set (30%). NeuroShell Predictor was used to create predictive PK and PK/PD models using population covariates: evaluate the relative significance of different covariates; and simulate the effect of covariates on the PK/PD of REP. Predictive performance was evaluated by calculating root mean square error and mean error for the training and test sets. These values were compared to naive averaging (NA) and randomly generated numbers (RN). RESULTS: Covariates found to have an influence on PK of REP include dose, gender. race, age, and weight. Covariates affecting the glucose response included dose, gender, and weight. These differences are not expected to be clinically significant. CONCLUSIONS: We came to the following three conclusions: 1) ANNs are more precise than NA and RN for both PK and PD; 2) the bias was acceptable for ANNs as compared with NA and RN; and 3) neural networks offer a quick and simple method for predicting, for identifying significant covariates, and for generating hypotheses. ----P Clinical_Trial Clinical_Trial__Phase_II Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Carbamates_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH P_Neural_Networks_(Computer)_MeSH M_Piperidines_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH M_Predictive_Value_of_Tests_MeSH ****** 11860348 ----K E ----T New trends in the development of oral antidiabetic drugs. ----A A large number of oral antidiabetic agents are available today. This article provides a short review of the pharmacology and some clinical aspects of various oral antidiabetic drugs. It focuses mainly on the newest developing drugs (therapy of the near future) and on the most commonly used older groups for the common approach of every-day practice (sulphonylureas). The primary goal of this review is to compare the electrophysiological effects of glibenclamide in isolated normal and streptozotocin induced diabetic rats and alloxan induced rabbits ventricular preparations, while on the other hand to differentiate the hypoglycaemic sulphonylureas (0.1-1000 mmol/kg) according to their cardiovascular activity in healthy and diabetic animals. In vitro (1-100 micromol/l) as well as chronically treated (5 mg/kg for 10 weeks) glibenclamide prolonged the action potential duration in normal but failed to affect it in diabetic ventricular preparations. Our results suggest that the sensitivity to glibenclamide of K(ATP) channels in diabetic ventricular fibers is drastically decreased. The effects of different sulphonylureas (tolbutamide, glibenclamide, gliclazide, glimepiride) on ventricular ectopic beats as well as the duration of ventricular fibrillation induced by 10 min ischemia/50 min reperfusion in healthy and diabetic rats were compared. Tolbutamide and gliclazide dose-dependently enhanced both parameters both in healthy and diabetic groups. Glibenclamide in healthy rats increased, while in diabetic rats it decreased the arrhythmogenicity. Glimepiride depressed the arrhythmogenicity in both healthy and diabetic animals. Glimepiride proved to dose-dependently enhance the myocardial tissue flow in dog in contrast to glibenclamide. These results confirm that glimepiride has less cardiovascular actions than other sulphonylureas. From the newest oral antidiabetics this review tries to emphasize the most important basic pharmacological properties, mechanism of action, therapeutic use. ----P Journal_Article Review Review__Academic ----M M_Administration__Oral_MeSH M_Animals_MeSH M_Carbohydrates_MeSH S_metabolism_MeSH Carbohydrates_metabolism_MeSH M_Diabetes_Mellitus_MeSH S_drug_therapy_MeSH Diabetes_Mellitus_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_Resistance_MeSH S_physiology_MeSH Insulin_Resistance_physiology_MeSH M_Intestinal_Absorption_MeSH S_drug_effects_MeSH Intestinal_Absorption_drug_effects_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11869171 ----K E ----T Vascular K(ATP) channel blockade by glibenclamide, but not by acarbose, in patients with Type II diabetes. ----A Glibenclamide inhibits the opening of vascular ATP-sensitive potassium (K(ATP)) channels, which represents a protective mechanism during ischaemia. This effect may imply harmful cardiovascular effects of glibenclamide when used under conditions of ischaemia in patients with Type II diabetes. Acarbose is not associated with effects on the cardiovascular system, because the drug is not absorbed from the bowel. Therefore we hypothesized that treatment of Type II diabetes patients with glibenclamide will impair the vasodilator function of K(ATP) opening, unlike treatment with acarbose. A double-blind randomized cross-over study in 12 patients with Type II diabetes was performed to compare the effects of glibenclamide with those of acarbose on the vasodilator responses to K(ATP) channel opening in the forearm vascular bed. The study consisted of two periods: 8 weeks of treatment with orally administered glibenclamide (10 mg x day(-1)) followed by 8 weeks of treatment with acarbose (300 mg x day(-1)), or vice versa. At the end of each treatment period, forearm blood flow (venous occlusion plethysmography) in response to intra-arterially administered diazoxide, acetylcholine and dipyridamole and to forearm ischaemia was measured. The diazoxide-mediated increase in the forearm blood flow ratio (infused/control arm) was significantly less pronounced after glibenclamide than after acarbose (290 +/- 58% and 561 +/- 101% respectively; P<0.0005). Forearm blood flow responses to acetylcholine, dipyridamole and forearm ischaemia were similar during glibenclamide and acarbose treatment. Thus, in patients with Type II diabetes mellitus, treatment with glibenclamide is associated with an attenuated response to K(ATP) opening as compared with treatment with acarbose. This implies that glibenclamide may affect defensive mechanisms under conditions of K(ATP) channel activation. ----P Journal_Article ----M M_Acarbose_MeSH S_therapeutic_use_MeSH Acarbose_therapeutic_use_MeSH M_Acetylcholine_MeSH S_pharmacology_MeSH Acetylcholine_pharmacology_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diazoxide_MeSH S_pharmacology_MeSH Diazoxide_pharmacology_MeSH M_Dipyridamole_MeSH S_pharmacology_MeSH Dipyridamole_pharmacology_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Forearm_MeSH S_blood_supply_MeSH Forearm_blood_supply_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Ischemia_MeSH S_physiopathology_MeSH Ischemia_physiopathology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Plethysmography_MeSH M_Potassium_Channel_Blockers_MeSH S_therapeutic_use_MeSH Potassium_Channel_Blockers_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Vasodilator_Agents_MeSH S_pharmacology_MeSH Vasodilator_Agents_pharmacology_MeSH ****** 11872684 ----K E ----T Effects of treatment with sulfonylurea drugs or insulin on ischemia-induced myocardial dysfunction in type 2 diabetes. ----A In patients with diabetes and coronary artery disease, the potential negative role of sulfonylurea drugs is under intensive investigation. We assessed the effects of treatment with glibenclamide or insulin on the extension of left ventricular myocardial dysfunction induced by acute ischemia. Nineteen consecutive patients with type 2 diabetes and coronary artery disease entered the study. Each patient was randomly assigned to either insulin or glibenclamide therapy. Treatment was crossed over after 12 weeks and maintained for another 12 weeks. At the end of each treatment, left ventricular myocardial function at rest and during dipyridamole infusion was studied by two-dimensional echocardiography under the same conditions of metabolic control. Glibenclamide or insulin treatment did not influence the rest values of left ventricular dimensions, left ventricular ejection fraction (LVEF), or wall motion score index (WMSI). Dipyridamole infusion, in patients receiving glibenclamide treatment, decreased LVEF (43 +/- 7 vs. 37 +/- 12%, P < 0.005) and increased WMSI (1.4 +/- 0.28 vs. 1.98 +/- 0.24, P < 0.001) compared with baseline values; during insulin treatment, LVEF (46 +/- 8 vs. 45 +/- 11%, NS) and WMSI (1.4 +/- 0.29 vs. 1.6 +/- 0.4, NS) did not change significantly. Peak stress LVEF was higher (45 +/- 11 vs. 37 +/- 12%, P < 0.001) and WMSI lower (1.6 +/- 0.4 vs. 1.98 +/- 0.24, P < 0.001) in patients receiving insulin. The results indicate that in patients with type 2 diabetes and coronary artery disease, ischemic myocardial dysfunction induced by dipyridamole infusion is less severe during treatment with insulin than with glibenclamide. Restitution of a preconditioning mechanism in insulin-treated patients may be the potential beneficial mechanism. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Dipyridamole_MeSH S_diagnostic_use_MeSH Dipyridamole_diagnostic_use_MeSH M_Echocardiography__Stress_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Heart_Ventricles_MeSH S_physiopathology_MeSH Heart_Ventricles_physiopathology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Myocardial_Diseases_MeSH S_prevention_&_control_MeSH Myocardial_Diseases_prevention_&_control_MeSH M_Myocardial_Ischemia_MeSH S_complications_MeSH Myocardial_Ischemia_complications_MeSH P_Treatment_Outcome_MeSH M_Ventricular_Dysfunction__Left_MeSH S_etiology_MeSH Ventricular_Dysfunction__Left_etiology_MeSH S_physiopathology_MeSH Ventricular_Dysfunction__Left_physiopathology_MeSH S_prevention_&_control_MeSH Ventricular_Dysfunction__Left_prevention_&_control_MeSH ****** 11874430 ----K E ----T Vascular effects of glibenclamide vs. glimepiride and metformin in Type 2 diabetic patients. ----A AIMS: Glibenclamide attenuates the protective responses to opening of vascular ATP-sensitive potassium (K(ATP)) channels during ischaemia. Therefore, glibenclamide treatment of Type 2 diabetes mellitus may have hazardous cardiovascular effects when used under conditions of ischaemia. Glimepiride and metformin seem to lack such characteristics. Based on these data, we hypothesized that, in contrast to glibenclamide, chronic treatment of Type 2 diabetic patients with glimepiride or metformin will not impair the vasodilator function of K(ATP) opening in vivo. METHODS: Two groups of 12 Type 2 diabetes mellitus patients participated in a double-blind randomized cross-over study consisting of two 8-week periods, in which treatment with orally administered glibenclamide (15 mg/day) was compared with either glimepiride or metformin (6 mg and 1500 mg/day, respectively). At the end of each treatment period, the increase in forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial administered diazoxide (K(ATP) opener), acetylcholine (endothelium-dependent vasodilator) and dipyridamole (adenosine-uptake blocker) and to forearm ischaemia was measured. RESULTS: There were no significant differences in vasodilator responses to diazoxide, acetylcholine, dipyridamole and forearm ischaemia after glibenclamide compared with glimepiride and metformin. CONCLUSIONS: Chronic treatment of Type 2 diabetes mellitus with glimepiride or metformin has similar effects on vascular K(ATP) channels compared with chronic glibenclamide treatment. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acetylcholine_MeSH S_pharmacology_MeSH Acetylcholine_pharmacology_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Flow_Velocity_MeSH S_drug_effects_MeSH Blood_Flow_Velocity_drug_effects_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Body_Mass_Index_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diazoxide_MeSH S_pharmacology_MeSH Diazoxide_pharmacology_MeSH M_Dipyridamole_MeSH S_pharmacology_MeSH Dipyridamole_pharmacology_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Forearm_MeSH S_blood_supply_MeSH Forearm_blood_supply_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Vasodilation_MeSH S_drug_effects_MeSH Vasodilation_drug_effects_MeSH ****** 11875249 ----K 5 ----T "A" is for amylin and amyloid in type 2 diabetes mellitus. ----A Amyloid deposits within the islet of the pancreas have been known for a century. In 1987, the islet amyloid precursor polypeptide (IAPP) amylin (a 37 amino acid) was discovered. Recently there has been an explosion of amylin's importance in the development of type 2 diabetes mellitus (T2DM). This review is intended to share what is understood about amylin derived amyloid and the role it plays in T2DM. Whether islet amyloid is an epiphenomenona, a tombstone, or a trigger it leaves an indelible footprint in greater that 70% of the patients with T2DM. There is current data supporting the damaging role of intermediate sized toxic amyloid particles to the beta cell resulting in a beta cell defect which contributes to a relative deficiency or loss of insulin secretion. Within the islet there is an intense redox stress which may be associated with the unfolding of amylin's native secondary structure compounding its amyloidogenic properties. In addition to the beta cell defect there may be an absorptive defect as a result of amyloid deposition in the basement membranes which form an envelope around the inta-islet capillary endothelium. We have an opportunity to change our current treatment modalities with newer medications and we should attempt to diagnose T2DM earlier and use these newer treatment strategies in combination to decrease glucotoxicity without elevating endogenous insulin and amylin. In the 21st century our goal should be to prevent remodeling, save the pancreatic islet, conquer islet amyloid, and amyloid diabetes. ----P Journal_Article Review Review__Tutorial ----M M_Amino_Acid_Sequence_MeSH M_Amyloid_MeSH S_chemistry_MeSH Amyloid_chemistry_MeSH S_classification_MeSH Amyloid_classification_MeSH S_physiology_MeSH Amyloid_physiology_MeSH S_ultrastructure_MeSH Amyloid_ultrastructure_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH S_pathology_MeSH Diabetes_Mellitus__Type_II_pathology_MeSH M_Human_MeSH M_Molecular_Sequence_Data_MeSH ****** 11884761 ----K 4 ----T Glucose tolerance, insulin secretion and insulin sensitivity in polycystic ovary syndrome. ----A ----P Editorial Review Review__Tutorial ----M M_Female_MeSH P_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH P_Insulin_Resistance_MeSH S_physiology_MeSH Insulin_Resistance_physiology_MeSH M_Polycystic_Ovary_Syndrome_MeSH S_blood_MeSH Polycystic_Ovary_Syndrome_blood_MeSH S_drug_therapy_MeSH Polycystic_Ovary_Syndrome_drug_therapy_MeSH S_physiopathology_MeSH Polycystic_Ovary_Syndrome_physiopathology_MeSH ****** 11894443 ----K E ----T Type 2 diabetes management: a comprehensive clinical review of oral medications. ----A Diabetes is a major and growing health problem in the US. An incredible array of different oral medications is now on the market. Clinicians should understand all these new medications and in which clinical picture they will work best. ----P Journal_Article Review Review__Tutorial ----M M_Benzamides_MeSH S_pharmacology_MeSH Benzamides_pharmacology_MeSH S_therapeutic_use_MeSH Benzamides_therapeutic_use_MeSH M_Carbamates_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Piperidines_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 11896745 ----K E ----T Alternative therapies for type 2 diabetes. ----A Type 2 diabetes is a chronic metabolic disease that has a significant impact on the health, quality of life, and life expectancy of patients, as well as on the health care system. Exercise, diet, and weight control continue to be essential and effective means of improving glucose homeostasis. However, lifestyle management measures may be insufficient or patient compliance difficult, rendering conventional drug therapies (i.e., oral glucose-lowering agents and insulin injection) necessary in many patients. In addition to adverse effects, drug treatments are not always satisfactory in maintaining euglycemia and avoiding late stage diabetic complications. As an alternative approach, medicinal herbs with antihyperglycemic activities are increasingly sought by diabetic patients and health care professionals. Commonly used herbs and other alternative therapies, less likely to have the side effects of conventional approaches for type 2 diabetes, are reviewed. ----P Journal_Article Review Review__Tutorial ----M M_Acupuncture_Therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Dietary_Supplements_MeSH M_Human_MeSH M_Hydrotherapy_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Phytotherapy_MeSH S_methods_MeSH Phytotherapy_methods_MeSH ****** 11903411 ----K E ----T Effects and serum levels of glibenclamide and its active metabolites in patients with type 2 diabetes. ----A OBJECTIVE: To study the effects and serum levels of glibenclamide (Gb) and its active metabolites in patients on chronic Gb medication on different daily doses. MATERIAL AND METHODS: Fifty patients with type 2 diabetes on regular Gb therapy (1.75-14.0 mg daily). Blood samples were taken immediately before and 90 min after regular Gb intake. A standardized breakfast was served 30 min after drug intake. Serum insulin and proinsulin levels were determined by ELISA methods without cross-reactivities. Serum drug levels were determined by HPLC. Fischer's R to Z-test (correlation coefficients) and paired Student t-tests were used when comparing values within the entire group and unpaired non-parametric Mann-Whitney tests were used when comparing high and low dose levels. A p-value < 0.05 was considered significant. RESULTS: There were significant correlations between daily Gb dose, on the one hand, and, on the other, HbAlc (r = 0.55), Delta-insulin (r = - 0.59) and Delta-proinsulin (r = - 0.52) levels. Significant correlations between Gb therapy duration and insulin (r = - 0.40) and proinsulin (r = - 0.34) secretion and between Gb dose and ratio proinsulin/insulin (RPI) at both time points (r = 0.32 and 0.30) were also found. The RPI was lower after Gb intake. In patients on > or = 10.5 mg steady state serum metabolite levels (Ml and Ml + M2) were higher (29(0-120) and 33 (0-120) ng/ml) than those of Gb itself (18(0-64) ng/ml). A great inter-subject variability in Gb levels at both time points was seen. CONCLUSIONS: Our results indicate that, in patients on chronic medication, Gb is capable of stimulating both insulin and proinsulin secretion; the effect on insulin release is relatively greater. The effect was more pronounced in patients on a low Gb dose, either because of less impaired beta-cells in those receiving low doses, or due to reduced sulphonylurea sensitivity in those on high dosage (down-regulation). In patients on a daily dose of 10.5 mg or more, serum metabolite levels of clinical relevance were demonstrated; the metabolites may contribute to hypoglycaemic events. ----P Journal_Article ----M M_Aged_MeSH M_Biotransformation_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_European_Continental_Ancestry_Group_MeSH M_Female_MeSH M_Glyburide_MeSH S_blood_MeSH Glyburide_blood_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Middle_Aged_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH S_secretion_MeSH Proinsulin_secretion_MeSH M_Support__Non-U_S__Gov't_MeSH M_Sweden_MeSH ****** 11903412 ----K E ----T The effects of intensive glycaemic control on body composition in patients with type 2 diabetes. ----A AIM: To examine the effects of improved glycaemic control over 20 weeks on the type and distribution of weight change in patients with type 2 diabetes who at baseline have poor glycaemic control. METHODS: Forty-three patients with type 2 diabetes and HbA1c > 8.9% were randomised to either intensive glycaemic control (IC) n = 21 or usual glycaemic control (UC) n = 22 for 20 weeks. Dual energy X-ray absorptiometry was used to assess the type and distribution of weight change during the study. RESULTS: After 20 weeks HbA1c was significantly lower in patients randomised to IC than UC (HbA1c IC 8.02 +/- 0.25% vs. UC 10.23 +/- 0.23%, p < 0.0001). In the IC group weight increased by 3.2 +/- 0.8 kg after 20 weeks (fat-free mass increased by 1.8 +/- 0.3 kg) compared to 0.02 +/- 0.70 kg in UC (p = 0.003). The gain in total body fat mass comprised trunk fat mass (IC 0.94 +/- 0.5 kg vs. UC 0.04 +/- 0.4 kg, p = 0.18) and peripheral fat mass (total body fat - trunk fat) (IC 0.71 +/- 0.32 kg vs. UC -0.21 +/- 0.28 kg, p = 0.04). Blood pressure and serum lipid concentrations did not change over time in either group. CONCLUSIONS: Intensive glycaemic control was associated with weight gain which was distributed in similar proportions between the central and peripheral regions and consisted of similar proportions of fat and fat-free mass. Blood pressure and serum lipid concentrations were not adversely affected. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adipose_Tissue_MeSH S_anatomy_&_histology_MeSH Adipose_Tissue_anatomy_&_histology_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH P_Body_Composition_MeSH S_physiology_MeSH Body_Composition_physiology_MeSH M_Body_Weight_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Densitometry__X-Ray_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Electrocardiography_MeSH M_Ethnic_Groups_MeSH M_Female_MeSH M_Human_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_New_Zealand_MeSH M_Support__Non-U_S__Gov't_MeSH M_Weight_Gain_MeSH ****** 11903417 ----K E ----T The NEPI antidiabetes study (NANSY). 1: short-term dose-effect relations of glimepiride in subjects with impaired fasting glucose. ----A AIM: NANSY is a randomised, placebo-controlled Swedish-Norwegian study which aims to include 2 x 1112 male and female subjects with impaired fasting glucose (IFG), to assess whether conversion to type 2 diabetes can be delayed by addition of sulphonylurea to dietary regulation and increased exercise. This pilot study was conducted to find the optimum dose of glimepiride in NANSY. METHODS: In a double blind trial in primary care 25 IFG subjects were in random order exposed to single doses and one-week treatments with 0 (placebo), 0.5, 1.0 and 2.0 mg glimepiride once daily. The optimum dose was assessed by measuring blood glucose during oral 75 g glucose tolerance test (OGTT), comparing fasting blood glucose, and the area under the blood glucose curve (AUC), and by monitoring hypoglycaemic events. RESULTS: With single doses, there was a clear dose-response relationship for the reduction in AUC, with a statistically significant difference only between placebo (mean 1981, 95% confidence intervals (CI) 1883-2078) and 2 mg glimepiride (mean 1763, 95% CI 1665-1861). However, following 1-week treatments, the only significant difference was between placebo (mean 1934, 95% CI 1856-2012) and 1 mg glimepiride (mean 1714, 95% CI 1637-1792). Correspondingly, the only statistically significant difference in fasting blood glucose day 7 was between placebo (5.87 mmol/l, 95% CI 5.68-6.05 mmol/l) and 1 mg glimepiride (5.42 mmol/l, 95% CI 5.21-5.62 mmol/l). Chemical hypoglycaemia was common but hypoglycaemic symptoms were rare and similar between the active doses, and easily countered by the subjects. CONCLUSIONS: The sulphonylurea dose-effect curve may be bell-shaped, perhaps due to down regulation of sulphonylurea receptors during chronic exposure. Alternatively, the finding could be a rebound phenomenon, secondary to preceding hypoglycaemia. The optimum dose for NANSY was found to be 1 mg glimepiride. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Constitution_MeSH M_Body_Mass_Index_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Glucose_Intolerance_MeSH S_blood_MeSH Glucose_Intolerance_blood_MeSH S_drug_therapy_MeSH Glucose_Intolerance_drug_therapy_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_epidemiology_MeSH Hyperlipidemia_epidemiology_MeSH M_Hypertension_MeSH S_epidemiology_MeSH Hypertension_epidemiology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Norway_MeSH M_Placebos_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Sweden_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 11919121 ----K E ----T Effects of dietary treatment alone or diet with voglibose or glyburide on abdominal adipose tissue and metabolic abnormalities in patients with newly diagnosed type 2 diabetes. ----A OBJECTIVE; To examine the effects of diet and diet with voglibose or glyburide on abdominal adiposity and metabolic abnormalities in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 36 Japanese patients with newly diagnosed type 2 diabetes (50.8 +/- 8.6 years of age, BMI 24.5 +/- 3.5 kg/m(2)) and 273 normal control subjects were studied. The patients were treated for 3 months with diet alone (30 kcal/kg per day) (n = 15), diet with voglibose (n = 12), or diet with glyburide (n = 9). They underwent 75-g oral glucose tolerance testing, assessment of insulin sensitivity (SI), and acute insulin response (AIR) with intravenous glucose tolerance testing based on the minimal model, and measurement of abdominal visceral adipose tissue area (VAT) and subcutaneous adipose tissue area (SAT) by computed tomography before and after treatment. RESULTS: The diabetic patients had comparable SAT but larger VAT than the control subjects. With a mean weight loss of 2-3 kg, VAT and SAT were decreased similarly in all treatment groups. The VAT-to-SAT ratio was decreased only in the voglibose group. Glycemic control and serum lipid profiles were improved in all groups. Changes in glycemic control after diet were closely correlated with changes in VAT but not with changes in SAT. SI and AIR were unchanged in the diet group but were improved in the voglibose and glyburide groups. CONCLUSIONS: In Japanese patients with newly diagnosed type 2 diabetes who were relatively lean but had excess VAT, diet with or without voglibose or glyburide effectively reduced VAT. Decrease in VAT was closely associated with improvement of glycemic control with diet. Additional use of voglibose or low-dose glyburide had no detrimental effects on abdominal adiposity and had beneficial effects on SI and AIR. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Abdomen_MeSH M_Adipose_Tissue_MeSH S_anatomy_&_histology_MeSH Adipose_Tissue_anatomy_&_histology_MeSH S_drug_effects_MeSH Adipose_Tissue_drug_effects_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH P_Diabetic_Diet_MeSH M_Energy_Intake_MeSH M_Fasting_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Glucose_Tolerance_Test_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH M_Inositol_MeSH S_analogs_&_derivatives_MeSH Inositol_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Inositol_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 11921502 ----K I ----T Patient compliance and persistence with anti-hyperglycemic therapy: evaluation of a population of type 2 diabetic patients. ----A The persistence and compliance of type 2 diabetic patients to different regimens of anti-hyperglycemic therapy were assessed retrospectively. The pharmacy claims from a pharmacy benefit management organization were analysed from the third quarter of 1996 to the fourth quarter of 1999. Of the 23,400 patients enrolled and initiating anti-diabetic therapy, 85% started treatment with monotherapy, 9.5% with insulin alone, 4.1% with polytherapy and 1.3% with insulin plus another therapy. Monotherapy patients were characterized as receiving metformin, sulfonylurea or another agent. For the 1-year follow-up period, 70.5% of the metformin patients, 75.3% of the sulfonylurea patients and 86.8% of the polytherapy patients underwent no regimen modification (except discontinuation). For the patients who had no modification of their medication regimen, persistence with sulfonylurea or metformin monotherapy was 65% greater than with polytherapy over a 1-year period. Compliance with sulfonylurea or metformin monotherapy was 45% greater than with polytherapy. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Cohort_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Patient_Compliance_MeSH M_Retrospective_Studies_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 11939753 ----K E ----T Evaluation of innovative skin-marking technique performed before thyroid ultrasound-guided fine-needle aspiration biopsies. ----A OBJECTIVE: To introduce an innovative skin-marking technique performed before ultrasound-guided fine-needle aspiration biopsy (US-FNAB) of the thyroid. METHODS: We studied 248 patients with thyroid nodules, who were classified on the basis of physical examination into two groups-those with palpable nodules (N = 127) and those with nonpalpable or difficult-to-palpate nodules (N = 121). Each group was further subdivided according to the size of the thyroid nodule (< or = 15 mm versus >15 mm). Before US-FNAB, we performed the skin-marking technique with the aid of a catheter, a permanent marker, and ultrasound guidance. An established point for needle entry was indicated on the skin. The chi-square test was used to compare results between the groups of patients. RESULTS: The proportions of adequate and insufficient biopsy material in the overall group of patients were 88.7% and 11.3%, respectively. When the patients were stratified by palpable and nonpalpable thyroid nodules, biopsy specimens were adequate in 89.8% and insufficient in 10.2% of those with palpable nodules, whereas the corresponding proportions for those with nonpalpable nodules were 87.6% and 12.4%, respectively. No statistically significant differences were noted between the two groups. Comparisons between patients with thyroid nodules >15 mm in their largest diameter versus those with nodules < or =15 mm also showed no statistically significant differences in terms of insufficient biopsy material. CONCLUSION: Our technique creates a marking on the skin that leads directly to the thyroid nodule and facilitates the acquisition of adequate cytologic material. This is particularly relevant when small transducers are not available or when the physician needs reassurance about the accuracy of the thyroid biopsy site. ----P Journal_Article ----M M_Adult_MeSH M_Biopsy__Needle_MeSH S_methods_MeSH Biopsy__Needle_methods_MeSH M_Carcinoma__Medullary_MeSH S_pathology_MeSH Carcinoma__Medullary_pathology_MeSH M_Carcinoma__Papillary_MeSH S_pathology_MeSH Carcinoma__Papillary_pathology_MeSH M_Cytodiagnosis_MeSH M_Female_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Palpation_MeSH P_Skin_MeSH M_Thyroid_Neoplasms_MeSH S_pathology_MeSH Thyroid_Neoplasms_pathology_MeSH M_Thyroid_Nodule_MeSH S_pathology_MeSH Thyroid_Nodule_pathology_MeSH P_Ultrasonography_MeSH ****** 11951812 ----K E ----T Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, controlled-release formulation of alpha-lipoic acid. ----A OBJECTIVE: To determine the pharmacokinetics, safety, and tolerability of a novel, controlled-release oral formulation of alpha-lipoic acid (LA) and to investigate whether sustaining the concentration of LA in plasma would have a beneficial effect on glycemic control in patients with type 2 diabetes. METHODS: For the pharmacokinetic study, a single, 600-mg dose of either controlled-release LA (CRLA) or quick-release LA (QRLA) was administered orally to 12 normal human subjects. The plasma profile of LA was determined for 24 hours after administration of the dose,and pharmacokinetic analyses were performed. For the safety and tolerability study, 21 patients with type 2 diabetes were given 900 mg of CRLA daily for 6 weeks, followed by 1,200 mg of CRLA daily for an additional 6 weeks. Active treatment was followed by a 3-week washout period. Throughout the study, patients continued to take their prestudy antidiabetic medications, which included metformin (Glucophage), sulfonylureas (Amaryl, glyburide, and Glucotrol), acarbose (Precose), troglitazone (Rezulin), and insulin (either as monotherapy or in combination). CRLA was evaluated for safety and tolerability as well as for effects on glycemic control. RESULTS: The Tmax (time to maximal plasma concentration) of LA administered as CRLA was 1.25 hours and was approximately 2.5-fold longer in comparison with the Tmax for QRLA (Tn,5X = 0.5 hour; P<0.02). No severe side effects or changes in either liver or kidney function or hematologic profiles were noted after the administration of CRLA. In 15 patients, the mean plasma fructosamine concentration was reduced from 313 to 283 micromol/L(P<0.05) after 12 weeks of treatment with CRLA. CONCLUSION: CRLA increased the plasma concentration of LA over time in healthy subjects, and CRLA was safe, well tolerated, and effective in reducing plasma fructosamine in patients with type 2 diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acarbose_MeSH S_therapeutic_use_MeSH Acarbose_therapeutic_use_MeSH M_Aged_MeSH M_Antioxidants_MeSH S_administration_&_dosage_MeSH Antioxidants_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Antioxidants_pharmacokinetics_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Delayed-Action_Preparations_MeSH S_administration_&_dosage_MeSH Delayed-Action_Preparations_administration_&_dosage_MeSH S_adverse_effects_MeSH Delayed-Action_Preparations_adverse_effects_MeSH S_pharmacokinetics_MeSH Delayed-Action_Preparations_pharmacokinetics_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Fructosamine_MeSH S_blood_MeSH Fructosamine_blood_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Thioctic_Acid_MeSH S_administration_&_dosage_MeSH Thioctic_Acid_administration_&_dosage_MeSH S_adverse_effects_MeSH Thioctic_Acid_adverse_effects_MeSH S_pharmacokinetics_MeSH Thioctic_Acid_pharmacokinetics_MeSH ****** 11952881 ----K E ----T A rapid increase in beta-cell function by multiple insulin injections in type 2 diabetic patients is not further enhanced by prolonging treatment. ----A OBJECTIVE: Intensive insulin treatment in type 2 diabetes can improve beta-cell function. It is not known which duration of treatment achieves maximal improvement. We addressed this question in type 2 diabetic patients who displayed features of 'secondary failure'. RESEARCH DESIGN AND METHOD: Ten patients were randomized to multiple insulin injection (MI) therapy for 9 weeks. Another 10 patients started with bedtime insulin (BTI) and continued their peroral medication. Following 9 weeks of treatment, patients on MI switched to BTI and glibenclamide. RESULTS: Three days of MI led to a decrease in fasting proinsulin/insulin ratio, 0.43 +/- 0.20 vs. 0.29 +/- 0.11, P=0.01 and an increase in glucagon-stimulated C-peptide over baseline, 0.77 +/- 0.43 vs. 1.28 +/- 0.44 nmol L-1, P 0.02. Nine weeks of MI treatment successively decreased fasting and nonfasting blood glucose in parallel with increasing insulin dosage. Initial improvements in secretion parameters were upheld but not further enhanced, the 9 week proinsulin/insulin ratio being 99 +/- 23% and that of glucagon-stimulated C-peptide being 95 +/- 24% of the values obtained after 3 days of treatment. Eight weeks after termination of MI there persisted a total weight gain that tended to be larger than after continuous peroral medication with BTI. CONCLUSION: Improvement of insulin secretion by intensive insulin treatment is rapidly gained with no further effect obtained after a longer treatment period. This finding, as well as undesirable effects of MI on body weight, argues against prolonged MI treatment as a prelude to other therapeutic regimens in type 2 diabetic patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Glucagon_MeSH S_metabolism_MeSH Glucagon_metabolism_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_secretion_MeSH Insulin_secretion_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_metabolism_MeSH Islets_of_Langerhans_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH ****** 11978249 ----K E ----T Which oral antihyperglycemics are most efficacious in reducing hemoglobin A1C in diabetic patients? ----A ----P Comment Journal_Article ----M ****** 12041635 ----K E ----T Thiazolidinediones and type 2 diabetes: new drugs for an old disease. ----A Thiazolidinediones are a new class of drugs for the treatment of type 2 diabetes, and act by improving insulin sensitivity in adipose tissue, liver and skeletal muscle. Rosiglitazone and pioglitazone are registered for use in monotherapy, and in combination with sulfonylureas and metformin. Pioglitazone is also licensed for use in combination with insulin. There is level II evidence that in patients with inadequate glycaemic control both drugs reduce the level of HbA1c and fasting plasma glucose (FPG) when used as monotherapy and in combination with sulfonylurea or metformin or insulin; and both drugs increase levels of HDL and LDL and lower free fatty acid levels, but only pioglitazone significantly lowers triglyceride levels. Both drugs lower fasting insulin and C-peptide levels. In monotherapy, they may be slightly less potent at reducing the level of HbA1c than sulfonylureas or metformin. The maximal effect of these agents may not be seen for 6-14 weeks after commencement. Both drugs are well tolerated but liver function must be checked at baseline every second month for the first year, and periodically thereafter. The drugs are currently contraindicated in patients with moderate to severe liver dysfunction and alanine aminotransferase levels more than 2.5 times normal, New York Heart Association III-IV cardiac status, pregnancy, lactation and in children. The main side effects include weight gain, oedema, and mild dilutional anaemia. ----P Journal_Article Review Review__Tutorial ----M M_Adult_MeSH M_Aged_MeSH M_Australia_MeSH S_epidemiology_MeSH Australia_epidemiology_MeSH M_Clinical_Trials_MeSH P_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Human_MeSH P_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_contraindications_MeSH Hypoglycemic_Agents_contraindications_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH P_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_contraindications_MeSH Thiazoles_contraindications_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 12041735 ----K E ----T Multiple drug targets in the management of type 2 diabetes. ----A Diabetes mellitus (DM) is being diagnosed at an alarming rate around the world. More than 90% of the estimated 200 million affected persons with diabetes worldwide have type 2 DM, an often clinically silent disorder. In the United States, nearly half of the estimated 16 million persons with diabetes remain undiagnosed. Type 2 diabetes is preceded by a long period of impaired glucose tolerance (IGT), a potentially reversible metabolic state associated with increased risk for macrovascular complications. At the time of diagnosis more than one-third of patients have already developed long-term complications of diabetes. Genetic and acquired factors contribute to the pathogenesis of type 2 diabetes. The pathophysiological hallmarks consist of progressive insulin resistance, pancreatic beta-cell dysfunction, and excessive hepatic glucose production. The ideal treatment for type 2 diabetes should correct insulin resistance, beta-cell dysfunction, and normalize hepatic glucose output, as well as prevent, delay, or reverse diabetic complications. Emerging targets for therapy of type 2 diabetes include inhibition of gluconeogenesis, lipolysis, and fatty acid oxidation, as well as stimulation of beta3-adrenergic receptors. Drug intervention for obesity is a legitimate adjunct to diabetes management. Additional drug targets include interventions to prevent or delay the progression of specific complications. Finally, primary prevention of type 2 diabetes is an important emerging strategy. The specific pharmacological agents acting at the various targets are discussed in this review. A targeted approach to the multiple underlying pathophysiologic processes offers the best chance of controlling diabetes and complications. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH S_etiology_MeSH Hyperglycemia_etiology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_Resistance_MeSH S_genetics_MeSH Insulin_Resistance_genetics_MeSH M_Islets_of_Langerhans_MeSH S_physiology_MeSH Islets_of_Langerhans_physiology_MeSH M_Obesity_in_Diabetes_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH S_etiology_MeSH Obesity_in_Diabetes_etiology_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 12040862 ----K E ----T Current oral agents for type 2 diabetes. Many options, but which to choose when? ----A Increasingly, type 2 diabetes takes a toll on public health and healthcare costs in the United States. Although the remedy for this growing problem is very complex, two critical components of its control are prevention and effective therapy. Progress in diabetes prevention is likely to take decades. But fortunately, growth in our understanding of what occurs in this chronic disease has led to advances in the pharmacologic options aimed at decreasing hyperglycemia, the main clinically measurable metabolic consequence of diabetes. In this article, Drs Ahmann and Riddle provide an overview of the oral agents now available for the treatment of diabetes and discuss the clinical factors that help determine when to use which medication and what outcome to expect. ----P Journal_Article Review Review__Tutorial ----M M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Cyclohexanes_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Monitoring_MeSH S_methods_MeSH Drug_Monitoring_methods_MeSH M_Drug_Therapy__Combination_MeSH M_Glycoside_Hydrolases_MeSH S_antagonists_&_inhibitors_MeSH Glycoside_Hydrolases_antagonists_&_inhibitors_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Receptors__Cytoplasmic_and_Nuclear_MeSH S_agonists_MeSH Receptors__Cytoplasmic_and_Nuclear_agonists_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Transcription_Factors_MeSH S_agonists_MeSH Transcription_Factors_agonists_MeSH ****** 12043953 ----K I ----T Pharmacokinetics and pharmacodynamics of extended-release glipizide GITS compared with immediate-release glipizide in patients with type II diabetes mellitus. ----A This study was designed to compare the pharmacokinetic and short-term pharmacodynamic profile of extended-release glipizide GITS (Glucotrol XL) given in a dosage of 20 mg once daily with that of immediate-release glipizide (Glucotrol) 10mg twice daily in patients with type II diabetes mellitus. In an open-label, randomized, two-way crossover study, each glipizide formulation was administered for 5 days. Serial blood samples were drawn at baseline and on the 5th day of each treatment phase for measurement of glipizide, glucose, insulin, and C-peptide concentrations. At steady state, the mean Cmax after immediate-release glipizide was significantly greater than after glipizide GITS, and the tmax was considerably shorter. Although the mean Cmin with glipizide GITS was about 80% higher than with immediate-release glipizide, the mean AUC0-24 was significantly lower. Despite the lower plasma concentrations with glipizide GITS in this short-term study, the two formulations had similar effects on serum concentrations of glucose, insulin, and C-peptide. The absence of a pronounced peak plasma concentration with the GITS formulation might confer advantages in terms of maintaining clinical effectiveness and reducing the potential to cause adverse effects. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH S_pharmacology_MeSH Glipizide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12047396 ----K I ----T Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients. ----A AIMS/HYPOTHESIS: This study evaluated the addition of nateglinide, a d-phenylalanine derivative that restores early phase insulin release, to metformin in type 2 diabetes patients stabilized on high-dose metformin. METHODS: This multicentre, double-blind, parallel group trial included 467 metformin-treated patients with glycosylated haemoglobin (HbA1c) between 6.8% and 11%. Patients were randomized to add nateglinide 60 mg, 120 mg or placebo before three meals to metformin 1000 mg b.i.d. for 24 weeks. RESULTS: HbA1c was significantly reduced with nateglinide 60 mg and 120 mg plus metformin compared with metformin control (-0.36%, p = 0.003; -0.59%, p < 0.001 respectively). Greater benefits occurred if patients had elevated HbA1c at baseline (-1.38% with nateglinide 120 mg in patients with HbA1c > 9.5%). A modest fasting plasma glucose reduction was observed. Most symptoms suggestive of hypoglycaemia occurred in patients with low HbA1c levels (<or= 8%) at baseline, although no confirmed cases of hypoglycaemia occurred with nateglinide 60 mg in this patient group. Events suggestive of hypoglycaemia were confirmed in 1.1% of cases (plasma glucose <or= 3.3 mmol/l). Weight gain over 24 weeks was 0.9 kg with nateglinide 120 mg vs. metformin alone, and plasma lipids remained unchanged. CONCLUSIONS/INTERPRETATION: In patients stabilized on high-dose metformin, the addition of nateglinide improved glycaemic control. The combination of these agents was well tolerated and both doses of nateglinide proved effective. The efficacy of nateglinide 60 mg and the low rate of hypoglycaemia observed at this dose make it suitable for patients close to their therapeutic target on metformin monotherapy. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Body_Weight_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Continental_Population_Groups_MeSH M_Cyclohexanes_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Placebos_MeSH M_Safety_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 12047399 ----K E ----T Simultaneous glyburide/metformin therapy is superior to component monotherapy as an initial pharmacological treatment for type 2 diabetes. ----A OBJECTIVE: To evaluate whether simultaneous initial treatment of both insulin resistance and impaired beta-cell insulin secretion with glyburide/metformin tablets is superior to monotherapy with each component agent. RESEARCH DESIGN AND METHODS: In this randomized, parallel-group, placebo-controlled, multicentre study, 806 patients with type 2 diabetes (mean duration, 3 years) who had failed diet and exercise were randomly assigned to 4 weeks of therapy with placebo, glyburide 2.5 mg, metformin 500 mg, glyburide/metformin 1.25/250 mg, or glyburide/metformin 2.5/500 mg once daily. Doses were then titrated over 8 weeks based on glycaemic response. The primary outcome measure was change from baseline in mean HbA1c after 20 weeks. Changes in fasting plasma glucose, lipids and body weight were also assessed along with 2-h postprandial glucose and insulin values after a standardized meal. RESULTS: At week 20, patients taking glyburide/metformin 1.25/250 mg or 2.5/500 mg tablets had greater reductions in HbA1c levels (-1.48% and -1.53% respectively) compared with placebo (-0.21%; both p < 0.001), glyburide (-1.24%; p = 0.016 and p = 0.004 respectively) or metformin (-1.03%; both p < 0.001). Fasting plasma glucose concentrations were reduced more in both glyburide/metformin groups compared with placebo and metformin (p < 0.001); patients in both combination therapy groups also had significantly lower postprandial glucose concentrations compared with placebo, glyburide and metformin. CONCLUSIONS: Initial combination treatment with glyburide/metformin tablets produces greater improvements in glycaemic control than either glyburide or metformin monotherapy. The superiority of initial therapy with glyburide/metformin tablets may arise from simultaneous treatment of both pathophysiological defects of type 2 diabetes. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Comparative_Study_MeSH M_Continental_Population_Groups_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH M_Female_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Postprandial_Period_MeSH M_Safety_MeSH M_Support__Non-U_S__Gov't_MeSH M_United_States_MeSH ****** 12071108 ----K E ----T Nateglinide, a new agent for postprandial glucose control in type 2 diabetes. ----A ----P Journal_Article Review Review__Tutorial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Clinical_Trials_MeSH M_Cyclohexanes_MeSH S_pharmacology_MeSH Cyclohexanes_pharmacology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_pharmacology_MeSH Phenylalanine_pharmacology_MeSH ****** 12074206 ----K E ----T Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy. ----A The glycaemic and lipid effects of treatment with pioglitazone in combination with a stable insulin regimen were evaluated in patients with type 2 diabetes. Patients (n=566) receiving stable insulin regimens for > or = 30 days yet who had HbA1c > or = 8.0% and C-peptide > 0.7 microg/l were randomised to receive once-daily 15 mg pioglitazone, 30 mg pioglitazone, or placebo in a 16-week multicentre, double-blind, placebo-controlled trial. Per study protocol, the insulin dose was to remain unchanged, but could be decreased in response to hypoglycaemia. At the end of double-blind treatment, patients receiving pioglitazone (15 mg or 30 mg) showed statistically significant mean decreases relative to baseline HbA1c (-1.0 and -1.3, respectively; p<0.0001) and fasting plasma glucose (FPG) (-34.5 mg/dl [-1.92 mmol/l] and -48.0 mg/dl [-2.67 mmol/l], respectively; p<0.0001); these differences compared with placebo were also significant (p<0.0001). Pioglitazone (15 or 30 mg) yielded significant increases in HDL-C levels (mean increases ranging from +7.1% to + 9.3%) compared with baseline or placebo (p<0.01). The 30 mg dose also significantly reduced mean triglyceride levels (-23.7%) compared with placebo (p=0.0218). No consistent changes in TC or LDL-C levels were observed. The incidence of adverse events was similar in all treatment groups, although the incidences of weight increase, hypoglycaemia and oedema were higher among patients receiving insulin plus pioglitazone. There was no evidence of hepatotoxicity or drug-induced elevations of serum ALT > or = 3 x ULN. Pioglitazone, when added to stable insulin regimens, significantly improved HbA1c and FPG in type 2 diabetes. Pioglitazone treatment also provided significant benefit with respect to plasma HDL-C and triglyceride levels. Whether these lipid changes have an impact on overall diabetic complications remains to be determined. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Analysis_of_Variance_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH P_Insulin_Resistance_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 12076188 ----K I ----T Gliclazide modified release. ----A Gliclazide modified release (MR) is a new formulation of the drug gliclazide and is given once daily. The hydrophilic matrix of hypromellose-based polymer in the new formulation effects a progressive release of the drug which parallels the 24-hour glycaemic profile in untreated patients with type 2 diabetes mellitus. The formulation shows high bioavailability and its absorption profile is unaffected by coadministration with food. Mean plasma glucose levels are significantly reduced over a 24-hour period in patients with type 2 diabetes mellitus treated with gliclazide MR once daily, in both fasting and postprandial states. No cardiovascular ATP-sensitive potassium channel interaction has been observed at therapeutic concentrations of gliclazide MR. Gliclazide MR has also demonstrated antioxidant properties that are independent of glycaemic control. In a randomised, double-blind, multicentre study, gliclazide MR 30 to 120 mg once daily showed similar efficacy to gliclazide immediate release (IR) 80 to 320 mg/day (in divided doses for doses >80 mg) in patients with type 2 diabetes mellitus over a 10-month period, reducing glycosylated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) to a similar extent. The drug appeared most efficacious in patients who had previously been treated by diet alone, where significant reductions in HbA(1c) from baseline of 0.9% and 0.95% were seen at 10 and 24 months. Similarly, a sustained effect of gliclazide MR was observed in a subgroup of elderly patients defined a priori; HbA(1c) was decreased to a similar degree to that observed in the general study population. Gliclazide MR showed similar tolerability to gliclazide IR after 10 months' treatment in the randomised trial. The most commonly observed adverse events were arthralgia, arthritis, back pain and bronchitis (each <5%). Bodyweight remained stable. In this study no episodes of nocturnal hypoglycaemia or hypoglycaemia requiring third party assistance were observed during treatment with gliclazide MR. Episodes of symptomatic hypoglycaemia were infrequent, occurring in approximately 5% of patients. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Biological_Availability_MeSH M_Delayed-Action_Preparations_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_adverse_effects_MeSH Gliclazide_adverse_effects_MeSH S_pharmacokinetics_MeSH Gliclazide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Randomized_Controlled_Trials_MeSH ****** 12083976 ----K E ----T Clinical pharmacokinetics and pharmacodynamics of repaglinide. ----A Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic beta-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia. ----P Journal_Article Review Review__Tutorial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Carbamates_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Interactions_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Kidney_Failure_MeSH S_etiology_MeSH Kidney_Failure_etiology_MeSH S_metabolism_MeSH Kidney_Failure_metabolism_MeSH M_Liver_Diseases_MeSH S_complications_MeSH Liver_Diseases_complications_MeSH S_metabolism_MeSH Liver_Diseases_metabolism_MeSH M_Male_MeSH M_Piperidines_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH M_Rifampin_MeSH S_therapeutic_use_MeSH Rifampin_therapeutic_use_MeSH ****** 12086556 ----K E ----T Orlistat use in type 2 diabetes. ----A OBJECTIVE: To review the use of orlistat in type 2 diabetes. DATA SOURCES: A MEDLINE search of the English-language literature (1990-August 2001) was performed using the key terms orlistat, obesity, glucose, and diabetes. DATA EXTRACTION: All articles pertaining to orlistat were considered for inclusion, with emphasis placed on randomized, placebo-controlled, double-blind clinical trials. DATA SYNTHESIS: In April 1999, orlistat was approved by the Food and Drug Administration for the treatment of obesity. Of 13 randomized, placebo-controlled studies, only 2 reported specific data in individuals with type 2 diabetes. Both reported significant weight reduction and improved glycemic control over placebo. CONCLUSIONS: Since weight loss is a difficult goal to achieve in patients with type 2 diabetes, orlistat can be a safe, effective addition to a multidisciplinary approach. ----P Journal_Article Review Review__Academic ----M M_Anti-Obesity_Agents_MeSH S_metabolism_MeSH Anti-Obesity_Agents_metabolism_MeSH S_pharmacokinetics_MeSH Anti-Obesity_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Anti-Obesity_Agents_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Half-Life_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Intestinal_Absorption_MeSH M_Lactones_MeSH S_metabolism_MeSH Lactones_metabolism_MeSH S_pharmacokinetics_MeSH Lactones_pharmacokinetics_MeSH S_therapeutic_use_MeSH Lactones_therapeutic_use_MeSH M_Obesity_in_Diabetes_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH M_Randomized_Controlled_Trials_MeSH M_Treatment_Outcome_MeSH ****** 12093468 ----K E ----T Desensitization of insulin secretion. ----A Desensitization of insulin secretion describes a reversible state of decreased secretory responsiveness of the pancreatic beta-cell, induced by a prolonged exposure to a multitude of stimuli. These include the main physiological stimulator, glucose, but also other nutrients like free fatty acids and practically all pharmacological stimulators acting by depolarization and Ca2+ influx into the beta-cell. Desensitization of insulin secretion appears to be an important step in the manifestation of type 2 diabetes and in the secondary failure of oral antidiabetic treatment. In this commentary, the basic concepts and the controversial issues in the field will be outlined. With regard to glucose-induced desensitization, two fundamentally opposing concepts have emerged. The first is that desensitization is the consequence of functional changes in the beta-cell that impair glucose-recognition. The second is that long-term increased secretory activity leads to a depletion of releasable insulin, often in spite of increased insulin synthesis. The latter concept is more appropriately termed beta-cell exhaustion. The same dichotomy applies to the desensitization evoked by pharmacological stimuli: again the relative contributions of a decreased insulin content versus alterations in signal transduction are in dispute. The action of tolbutamide on beta-cells may be an example of desensitization caused by a lack of releasable insulin since the signaling mechanisms are nearly unchanged, whereas the action of phentolamine, an imidazoline, induces a strong desensitization without reducing insulin content or secretory granules, apparently by abolishing Ca2+ influx. With pharmacological agents it seems that both, alterations in signal transduction and decreased availability of releasable insulin, can contribute to the desensitized state of the beta-cell, the relative contribution being variable depending upon the exact nature of the secretory stimulus. ----P Journal_Article Review Review__Academic ----M M_Animals_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Energy_Metabolism_MeSH M_Fatty_Acids__Nonesterified_MeSH S_metabolism_MeSH Fatty_Acids__Nonesterified_metabolism_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Human_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12116051 ----K E ----T Bioequivalence evaluation of two brands of gliclazide 80 mg tablets (Glyzide & Diamicron)--in healthy human volunteers. ----A A randomized, two-way, crossover, bioequivalence study in 24 fasting, healthy, male volunteers was conducted to compare two brands of gliclazide 80 mg tablets, Glyzide (Julphar, UAE) as test and Diamicron (Servier Industries, France) as reference product. The study was performed at the International Pharmaceutical Research Centre (IPRC), in joint venture with Speciality Hospital, Amman, Jordan. The drug was administered with 240 ml of 20% glucose solution after a 10 h overnight fasting. After dosing, serial blood samples were collected for a period of 48 h. Plasma harvested from blood was analyzed for gliclazide by validated HPLC method. Various pharmacokinetic parameters including AUC(0-t), AUC(0- proportional, variant), C(max), T(max), T(1/2), and elimination rate constant were determined from plasma concentrations of both formulations. Statistical modules (ANOVA and 90% confidence intervals) were applied to AUC(0-t), AUC(0- proportional, variant), and C(max) for bioequivalence evaluation of the two brands which revealed no significant difference between them, and 90% CI fell within US FDA accepted bioequivalence range of 80-125%. Based on these statistical inferences, Glyzide was judged bioequivalent to Diamicron. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adolescent_MeSH M_Adult_MeSH M_Area_Under_Curve_MeSH M_Chromatography__High_Pressure_Liquid_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_blood_MeSH Gliclazide_blood_MeSH S_pharmacokinetics_MeSH Gliclazide_pharmacokinetics_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Male_MeSH M_Tablets_MeSH M_Therapeutic_Equivalency_MeSH ****** 12143325 ----K E ----T Oral hypoglycaemics. When not to use what. ----A BACKGROUND: In the 1940s and '50s the first oral hypoglycaemic agents (the sulphonylureas and metformin) became available. These remained the only agents for the next 50 years. Over the last five years three new classes have been released. General practitioners now have a wider range of effective hypoglycaemic agents from which to choose. OBJECTIVES: This article focuses on those patients where particular agents should not be used: i.e. 'when not to use what'. DISCUSSION: In general however, it must be remembered that problems with oral hypoglycaemics are rare. The great majority of patients have no problems with their prescribed hypoglycaemic medication. ----P Case_Reports Journal_Article Review Review__Tutorial ----M M_Acarbose_MeSH S_adverse_effects_MeSH Acarbose_adverse_effects_MeSH S_contraindications_MeSH Acarbose_contraindications_MeSH M_Acidosis__Lactic_MeSH S_etiology_MeSH Acidosis__Lactic_etiology_MeSH M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_contraindications_MeSH Glyburide_contraindications_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_contraindications_MeSH Hypoglycemic_Agents_contraindications_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Kidney_Failure_MeSH M_Male_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_contraindications_MeSH Metformin_contraindications_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_contraindications_MeSH Thiazoles_contraindications_MeSH P_Thiazolidinediones_MeSH ****** 12149047 ----K E ----T Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. ----A Rosiglitazone, a thiazolidinedione with a different side chain from those of troglitazone and pioglitazone, reduces plasma glucose levels and glucose production and increases glucose clearance in patients with type 2 diabetes mellitus. Insulin sensitivity, pancreatic beta-cell function and surrogate markers of cardiovascular risk factors are significantly improved by rosiglitazone. Double-blind trials of 8 to 26 weeks of rosiglitazone 4 or 8 mg/day monotherapy indicate significant decreases in fasting plasma glucose (-2 to -3 mmol/L with 8 mg/day) and glycosylated haemoglobin levels [HbA(1c); -0.6 to -0.7% (-0.8 to -1.1% in drug-naive patients) with 8 mg/day]. Significant decreases in hyperglycaemic markers occurred when rosiglitazone was combined with metformin (HbA(1c) -0.8 to -1.0%), a sulphonylurea (-1.4%) or insulin (-1.2%) for 26 weeks versus little change with active comparator monotherapy. Efficacy was maintained in trials of < or = 2 years, and was also apparent in various ethnic subgroups, elderly patients, and both obese and nonobese patients. Rosiglitazone is currently not indicated in combination with injected insulin. It should be administered in conjunction with diet and exercise regimens. Rosiglitazone is generally well tolerated. Despite rare individual reports of liver function abnormalities in rosiglitazone recipients, the incidence of these in clinical trials (< or = 2 years' duration) was similar to that in placebo and active comparator groups. Fluid retention associated with rosiglitazone may be the cause of the increased incidence of anaemia in clinical trials, and also means that patients should be monitored for signs of heart failure during therapy. Although bodyweight is increased overall with rosiglitazone therapy, increases are in subcutaneous, not visceral, fat; hepatic fat is decreased. The pharmacokinetic profile of rosiglitazone is not substantially altered by age or renal impairment, nor are there important drug interactions. Rosiglitazone is not indicated in patients with active liver disease or increased liver enzymes. CONCLUSIONS: Oral rosiglitazone 4 or 8 mg/day provides significant antihyperglycaemic efficacy and is generally well tolerated, both as monotherapy and in combination with other antihyperglycaemic agents, in patients with type 2 diabetes mellitus who do not have active liver disease. Long-term data are required before conclusions can be drawn about the clinical significance of positive changes to surrogate markers of cardiovascular disease risk and improvements to pancreatic beta-cell function. Rosiglitazone significantly improves insulin sensitivity and, as such, is a welcome addition to the treatment options for patients with type 2 diabetes mellitus. ----P Journal_Article Review Review__Academic ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Area_Under_Curve_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Half-Life_MeSH M_Human_MeSH P_Hypoglycemic_Agents_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Intestinal_Absorption_MeSH M_Liver_MeSH S_drug_effects_MeSH Liver_drug_effects_MeSH S_metabolism_MeSH Liver_metabolism_MeSH M_Middle_Aged_MeSH M_Randomized_Controlled_Trials_MeSH M_Structure-Activity_Relationship_MeSH P_Thiazoles_MeSH S_metabolism_MeSH Thiazoles_metabolism_MeSH S_pharmacokinetics_MeSH Thiazoles_pharmacokinetics_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Treatment_Outcome_MeSH ****** 12212016 ----K I ----T Patient perceptions of prandial oral therapy for type 2 diabetes. ----A PURPOSE: This survey was conducted to assess patient perceptions of glycemic control, convenience, and flexibility of a prescribed prandial oral therapy for type 2 diabetes mellitus. METHODS: Questionnaires distributed by physicians yielded baseline responses from 3696 patients who were beginning repaglinide treatment. Data were analyzed from 1233 respondents who also completed follow-up questionnaires after 4 weeks of treatment. RESULTS: Among respondents, 60% were taking repaglinide with other antidiabetic agents in combination therapy; 59% were taking metformin, and 24% were taking troglitazone. Most respondents (84%) indicated that they were "satisfied" or "very satisfied" with repaglinide therapy, 92% wished to continue its use, and 60% believed that the treatment had improved their attitude toward taking antidiabetic medication. Patients perceived that fasting blood glucose levels were reduced during treatment, as was the incidence of hyperglycemia. Corresponding changes in perceived frequency of hypoglycemia during repaglinide treatment were minimal. CONCLUSIONS: Patient perceptions of prandial oral therapy with repaglinide were predominantly positive, due mostly to the perception that glucose control was achieved, with minimal perception of any increase in hypoglycemic episodes. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH P_Attitude_to_Health_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_psychology_MeSH Diabetes_Mellitus__Type_II_psychology_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Eating_MeSH S_physiology_MeSH Eating_physiology_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_epidemiology_MeSH Hypoglycemia_epidemiology_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Questionnaires_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12212341 ----K E ----T Tablet-breaking ability of older persons with type 2 diabetes mellitus. ----A PURPOSE: The purpose of this study was to assess the ability of older persons with type 2 diabetes to accurately break in half 2 different formulations of micronized glyburide tablets. METHODS: Thirty persons with type 2 diabetes, over age 70, were recruited from the St Louis University geriatric clinics. Participants were randomly assigned to 2 groups. Group A broke 30 Glynase Prestabs and 30 generic tablets using 2 different manual tablet-breaking methods. Group B broke 15 Glynase Prestabs and 15 generic tablets without instructions. Visual analog scales were used to assess pain and difficulty of tablet breaking. RESULTS: A higher percentage of successful tablet breaking was reported with Glynase Prestabs (80%) compared with the generic tablets (33%). Mean pain scores for breaking Glynase Prestabs were 0.1 (Group A) and 0.9 (Group B). Higher pain scores were obtained for the generic tablets (2.1 for Group A, 3.2 for Group B). Glynase Prestabs were easier to break in both groups, and the resultant half tablets showed less variance from the expected theoretical weight (50% of whole parent tablet weight). CONCLUSIONS: Older adults broke Glynase Prestabs more accurately and with less difficulty than generic micronized glyburide tablets. This variation in ease of tablet breaking and accuracy between different tablet formulations affect bioavailability and patient compliance. ----P Clinical_Trial Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drugs__Generic_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Psychomotor_Performance_MeSH M_Support__Non-U_S__Gov't_MeSH P_Tablets_MeSH ****** 12365465 ----K 5 ----T Metformin: evidence-based versus rational pharmacotherapy. ----A ----P Comment Editorial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH P_Evidence-Based_Medicine_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH ****** 12365467 ----K 5 ----T Factors associated with switching from oral hypoglycaemic agents to insulin therapy. ----A BACKGROUND: The aim of our study was to determine which factors are associated with switching from oral hypoglycaemic agents to insulin therapy in patients with type 2 diabetes mellitus in general practice. METHODS: Longitudinal, observational study in a Dutch general healthcare centre. All pharmacologically treated patients with type 2 diabetes mellitus were included (n = 152). Comorbidity, laboratory results and medication use were obtained from the general practitioners' files. RESULTS: A total of 31 (20.4%) patients switched from oral hypoglycaemic agents to insulin therapy; they were significantly younger at the onset of diabetes, 50.5 versus 57.7 years. Fasting blood glucose levels and HbA(1c) values were significantly higher after the switch compared with patients on oral treatment, 10.0 mmol/l versus 8.4 mmol/l and 8.8% versus 7.9%, respectively. Concerning comorbidity, they suffered more frequently from acute myocardial infarction, lipid disorders, depression, retinopathy and atrial fibrillation. Cardiovascular disease in general was more often present in patients who switched over to insulin, 77.4% versus 52.9% (OR 3.1; CI 1.2-7.6). CONCLUSIONS: Patients who switch over to insulin therapy are younger at diagnosis, suffer from more health problems besides diabetes, especially cardiovascular disease, and have worse metabolic control, compared with users of oral hypoglycaemic agents. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Age_of_Onset_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cardiovascular_Diseases_MeSH S_epidemiology_MeSH Cardiovascular_Diseases_epidemiology_MeSH M_Comorbidity_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Longitudinal_Studies_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12365468 ----K 6 ----T Discontinuation of metformin in type 2 diabetes patients treated with insulin. ----A BACKGROUND: Metformin added to insulin therapy in type 2 diabetic patients improves glycaemic control and decreases the required daily dose of insulin (DDI). Metformin should be discontinued if cardiac, hepatic or renal failure develops. We examined whether glycaemic control can be maintained after metformin cessation. METHODS: We included 45 type 2 diabetic patients treated with insulin plus metformin, and 45 matched controls treated with insulin only. After discontinuation of metformin in the first group, we aimed for tight fasting and postprandial blood glucose levels, 4-7 and 4-10 mmol/l, respectively, in both groups. During 12 weeks we assessed glycaemic control every two weeks and, if necessary, adjusted the insulin dosage. RESULTS: In the group in which metformin was discontinued, DDI increased from 67.9 +/- 22.9 to 92.2 +/- 29.4 IU (p < 0.001) leaving glycaemic control unchanged. In the controls, glycated haemoglobin (GHb) decreased by 0.93% (p < 0.001), while DDI increased slightly from 62.4 +/- 22.9 to 72.3 +/- 27.3 IU (p < 0.001). The increase in DDI was larger in patients in whom metformin was discontinued than in the controls (p < 0.001). CONCLUSIONS: In type 2 diabetic patients treated with insulin plus metformin, glycaemic control can be maintained after discontinuation of metformin by increasing the DDI substantially (20 to 36%) during application of an intensified treatment protocol. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Case-Control_Studies_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH ****** 12385492 ----K E ----T Quality of care in diabetes: understanding the guidelines. ----A We are in the midst of a global pandemic of diabetes. Despite the increasing burden of the disease, measurements of quality repeatedly show poor adherence to or implementation of current guidelines for diabetes care. This article will provide a brief review of the most significant randomized controlled clinical trials relevant to the current guidelines and then discuss essential treatment goals and the evidence that supports them. Several practical clinical questions related to the implementation of modern diabetes guidelines will be raised and answered. Finally, reasons for the poor quality performance observed will be examined. ----P Journal_Article Review Review__Tutorial ----M M_Anti-Inflammatory_Agents__Non-Steroidal_MeSH S_therapeutic_use_MeSH Anti-Inflammatory_Agents__Non-Steroidal_therapeutic_use_MeSH M_Aspirin_MeSH S_therapeutic_use_MeSH Aspirin_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus_MeSH S_epidemiology_MeSH Diabetes_Mellitus_epidemiology_MeSH S_therapy_MeSH Diabetes_Mellitus_therapy_MeSH M_Guidelines_MeSH M_Human_MeSH M_Kidney_MeSH S_pathology_MeSH Kidney_pathology_MeSH M_Lipids_MeSH S_metabolism_MeSH Lipids_metabolism_MeSH M_Quality_of_Health_Care_MeSH M_Randomized_Controlled_Trials_MeSH M_Retina_MeSH S_pathology_MeSH Retina_pathology_MeSH M_Risk_Factors_MeSH ****** 12423711 ----K I ----T Differential effect of glyburide (glibenclamide) and metformin on QT dispersion: a potential adenosine triphosphate sensitive K+ channel effect. ----A Glyburide (glibenclamide) is a specific blocker of the adenosine triphosphate (ATP) sensitive potassium (K+) channel. It has been reported to result in prolongation of the QT interval. QT interval dispersion (QTd) is a potentially sensitive marker for increased risk of arrhythmia and sudden cardiac death. The aim of the present study was to evaluate the effect of glyburide on QTd and compare it with that of metformin, a hypoglycemic agent that does not block the adenosine triphosphate sensitive K+ channel. Thirty patients with type 2 diabetes were randomized to glyburide and metformin groups. A 12-lead electrocardiogram was obtained before and at 2 months after being on glyburide or metformin. Therapy with QT and QTd were measured and QT corrected for rate (QTc). There was no significant difference between the glyburide and metformin groups in age (62 +/- 9 vs 59 +/- 10 years), baseline RR interval (819 +/- 86 vs 753 +/- 100 ms), QT (387 +/- 28 vs 383 +/- 27 ms), and QTc (433 +/- 25 vs 444 +/- 15 ms). Glyburide was associated with a significant increase in QTc (433 +/- 24 to 467 +/- 24 ms, p <0.001), QTd (24 +/- 16 to 60 +/- 22 ms, p <0.001), and QTc dispersion (QTcd) (35 +/- 18 to 68 +/- 21 ms, p <0.001). In contrast, metformin was associated with a decrease in QTc (444 +/- 15 to 432 +/- 15 ms, p <0.01) and did not affect QTd (14 +/- 5 to 12 +/- 6 ms, p = NS) and QTcd (23 +/- 9 to 22 +/- 10 ms, p = NS). Glyburide, unlike metformin, causes an increase in QT dispersion. Increased dispersion may be a factor underlying an increased risk of arrhythmias and sudden cardiac death. ----P Clinical_Trial Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Arrhythmia_MeSH S_physiopathology_MeSH Arrhythmia_physiopathology_MeSH S_prevention_&_control_MeSH Arrhythmia_prevention_&_control_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Electrocardiography_MeSH S_drug_effects_MeSH Electrocardiography_drug_effects_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Heart_Conduction_System_MeSH S_drug_effects_MeSH Heart_Conduction_System_drug_effects_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Treatment_Outcome_MeSH ****** 12442064 ----K E ----T Combination-therapy with bedtime nph insulin and sulphonylureas gives similar glycaemic control but lower weight gain than insulin twice daily in patients with type 2 diabetes. ----A BACKGROUND: To study the effect on body weight and glycaemic control of two insulin treatment regimens in patients with Type 2 diabetes and moderate failure to oral hypoglycaemic agents.METHODS: Sixteen patients treated with oral hypoglycaemic agents (6 men and 10 women) were included in this open-label, randomized, parallel group study. Their age was 62 +/- 2 (mean +/- SEM) years (range 44-79 years), body weight 71.3 +/- 2.9 kg, body mass index (BMI) 24.6 +/- 0.8 kg/m(2). The patients were switched to insulin treatment with bedtime NPH insulin combined with daytime sulphonylurea (combination group) or twice daily injections of a premixed combination of regular human and NPH insulin (insulin twice daily group) with measurements as given below before and after 12 and 24 weeks of treatment.RESULTS: HbA(1c) was lowered from 8.3 +/- 0.3% to 7.0 +/- 0.2% in the insulin twice daily group (p<0.05) and from 8.3 +/- 0.3% to 6.8 +/- 0.5% in the combination group (p<0.03; ns between treatment groups). Body weight increased from 71.7 +/- 4.0 kg to 77.6 +/- 4.4 kg in the insulin twice daily group (p<0.001) and from 70.8 +/- 4.6 kg to 72.7 +/- 5.1 kg in the combination group (ns; p<0.02 between groups). The dose of insulin at 24 weeks in the insulin twice daily group was 45.8 +/- 4.2 U and 29.4 +/- 5.4 U in the combination group (p=0.03). Combination treatment reduced fasting and stimulated C-peptide levels.CONCLUSIONS: Both treatments improved glycaemic control to the same extent but the combination of bedtime NPH insulin and daytime sulphonylurea gave a very small increase of body weight over a 6 months period. We conclude that combination therapy is an attractive alternative when starting insulin treatment in patients with Type 2 diabetes as this is a critical period for weight gain in such patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Body_Weight_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin__Isophane_MeSH S_therapeutic_use_MeSH Insulin__Isophane_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Weight_Gain_MeSH S_physiology_MeSH Weight_Gain_physiology_MeSH ****** 12469695 ----K E ----T Rosiglitazone and pioglitazone: new preparations. Two new oral antidiabetics both poorly assessed. ----A (1) Treatment of type 2 (non insulin-dependent) diabetes is based on lifestyle measures and management of cardiovascular risk. (2) The reference first-line drug therapy for type 2 diabetes, when drug therapy is needed, is single-agent treatment with metformin (a biguanide) for overweight patients, or with glibenclamide (a glucose-lowering sulphonylurea) for other patients. (3) If monotherapy fails to control blood glucose levels adequately, most clinical guidelines then recommend a combination of metformin with a glucose-lowering sulphonylurea, although the few available comparative clinical data raise the possibility of excess mortality with this treatment. (4) Rosiglitazone and pioglitazone (glitazones that reduce insulin resistance) have been authorized in the European Union for combination with a glucose-lowering sulphonylurea (for patients in whom metformin is ineffective or poorly tolerated) or with metformin (for obese patients). (5) None of the available trials of rosiglitazone and pioglitazone include data on mortality or morbidity. (6) There are fewer data on pioglitazone than on rosiglitazone. (7) According to short-term comparative trials, rosiglitazone and pioglitazone are more effective than placebo on blood glucose levels. Combinations of rosiglitazone or pioglitazone with metformin or with glucose-lowering sulphonylureas have not been compared with the metformin + glucose-lowering sulphonylurea combination or with insulin. (8) Rosiglitazone and pioglitazone frequently cause weight gain. (9) Pioglitazone has a slightly favourable effect on lipid profiles, unlike rosiglitazone, which increases LDL-cholesterol levels. (10) The main side effect of rosiglitazone and pioglitazone is sodium and water retention, which can provoke oedema, anaemia (by haemodilution), and even heart failure. Rosiglitazone and pioglitazone are also hepatotoxic. (11) Combining rosiglitazone with insulin is contraindicated, owing to the increased risk of heart failure. The same applies to pioglitazone. (12) In practice, neither rosiglitazone nor pioglitazone has a place in the management of type 2 diabetes, except in the context of strictly controlled long-term comparative clinical trials. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Clinical_Trials_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Approval_MeSH M_Drug_Evaluation_MeSH M_Europe_MeSH M_Evaluation_Studies_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH ****** 7833731 ----K I ----T United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. ----A OBJECTIVE--To assess the relative efficacy of treatments for non-insulin dependent diabetes over three years from diagnosis. DESIGN--Multicentre, randomised, controlled trial allocating patients to treatment with diet alone or additional chlorpropamide, glibenclamide, insulin, or metformin (if obese) to achieve fasting plasma glucose concentrations < or = 6 mmol/l. SETTING--Outpatient diabetic clinics in 15 British hospitals. SUBJECTS--2520 subjects who, after a three month dietary run in period, had fasting plasma glucose concentrations of 6.1-14.9 mmol/l but no hyperglycaemic symptoms. MAIN OUTCOME MEASURES--Fasting plasma glucose, glycated haemoglobin, and fasting plasma insulin concentrations; body weight; compliance; and hypoglycaemia. RESULTS--Median fasting plasma glucose concentrations were significantly lower at three years in patients allocated to chlorpropamide, glibenclamide, or insulin rather than diet alone (7.0, 7.6, 7.4, and 9.0 mmol/l respectively; P < 0.001) with lower mean glycated haemoglobin values (6.8%, 6.9%, 7.0%, and 7.6%, respectively; P < 0.001). Mean body weight increased significantly with chlorpropamide, glibenclamide, and insulin but not diet (by 3.5, 4.8, 4.8, and 1.7 kg; P < 0.001). A similar pattern was seen for mean fasting plasma insulin concentration (by 0.9, 1.2, 2.4, and -0.1 mU/l; P < 0.001). In obese subjects metformin was as effective as the other drugs with no change in mean body weight and significant reduction in mean fasting plasma insulin concentration (-2.5 mU/l; P < 0.001). More hypoglycaemic episodes occurred with sulphonylurea or insulin than with diet or metformin. CONCLUSION--The drugs had similar glucose lowering efficacy, although most patients remained hyperglycaemic. Long term follow up is required to determine the risk-benefit ratio of the glycaemic improvement, side effects, changes in body weight, and plasma insulin concentration. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH S_physiology_MeSH Body_Weight_physiology_MeSH M_Chlorpropamide_MeSH S_therapeutic_use_MeSH Chlorpropamide_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_blood_MeSH Obesity_in_Diabetes_blood_MeSH M_Patient_Compliance_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 7859936 ----K I ----T Bedtime insulin/daytime glipizide. Effective therapy for sulfonylurea failures in NIDDM. ----A Bedtime insulin (BI)/daytime sulfonylurea (DSU) therapy was studied double-blind in 30 non-insulin-dependent diabetes mellitus subjects in whom sulfonylurea (SU) therapy had failed. Subjects were switched to glipizide for 2 months (phase I) to confirm failure (fasting plasma glucose [FPG] 12.0 +/- 0.4 mmol/l) and then randomly assigned into three groups: BI-DSU; BI-no DSU; and DSU-no BI. During phase II (3 months), the BI dose was fixed (20 U/1.73 m2, low-dose). In phase III (3 months), BI was titrated up (high-dose) to achieve good control or until hypoglycemic symptoms prevented further dose increases. In phase IV (6 months), 25 of the 30 original subjects received open-labeled, high-dose BI-DSU. Low-dose BI-DSU markedly reduced FPG (13.6 +/- 0.8 to 8.0 +/- 0.6 mmol/l, P < 0.001), mean 24-h glucose (P < 0.001), HbA1c (8.9 +/- 0.7 to 7.6 +/- 0.3%, P = 0.07), and basal hepatic glucose production (HGP) (P < 0.005). A positive correlation (r = 0.69, P < 0.05) between the declines in FPG and HGP was observed. Neither low-dose BI alone nor DSU alone reduced FPG, mean 24-h glucose, HbA1c, or basal HGP. High-dose (40 +/- 5 U/day) BI plus DSU further reduced the FPG (6.3 +/- 0.6 mmol/l), HbA1c (7.1 +/- 0.3%), mean 24-h plasma glucose, and basal HGP (all P < 0.05 vs. phase II).(ABSTRACT TRUNCATED AT 250 WORDS) ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Glucose_Self-Monitoring_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glucose_MeSH S_biosynthesis_MeSH Glucose_biosynthesis_MeSH M_Glucose_Tolerance_Test_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Liver_MeSH S_metabolism_MeSH Liver_metabolism_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH ****** 7879817 ----K I ----T Low-dose oral glyburide reduces fasting blood glucose by decreasing hepatic glucose production in healthy volunteers without increasing carbohydrate oxidation. ----A Glyburide is an effective hypoglycemic agent in patients with type II diabetes even after the loss of its ability to increase insulin secretion. The exact mechanism is unknown. In an attempt to describe the direct effect of glyburide on glucose metabolism, a very low dose of glyburide (20 micrograms/kg body weight) was given orally to 12 healthy volunteers in an attempt to increase blood concentrations of the drug without causing a marked increase in insulin secretion. Fasting hepatic glucose production (HGP), carbohydrate oxidation (CO), leucine appearance, leucine oxidation, and fat oxidation were determined between hours 3 and 4 and hours 7 and 8. The changes seen in the glyburide-treated volunteers were compared with the changes seen in 5 non-treated, healthy volunteers during the same 8-hour period. Mean blood glucose decreased greater in the glyburide-treated volunteers (20 +/- 2% vs 5 +/- 2%, P < 0.01). Insulin and C-peptide concentrations after glyburide administration (hour 7 to 8) did not differ significantly from baseline (hour 3 to 4) values (insulin: 53 +/- 9 pmol/L vs 52 +/- 9 pmol/L; C-peptide: 0.34 +/- 0.06 ng/mL vs 0.39 +/- 0.07 ng/mL). This low dose of glyburide resulted in a significantly greater decrease in HGP (16 +/- 2%; P < 0.001) than seen with fasting alone (8 +/- 4%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) ----P Journal_Article ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Calorimetry__Indirect_MeSH M_Fasting_MeSH M_Female_MeSH M_Glucose_MeSH S_biosynthesis_MeSH Glucose_biosynthesis_MeSH M_Glucose_Tolerance_Test_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Kinetics_MeSH M_Leucine_MeSH S_blood_MeSH Leucine_blood_MeSH M_Liver_MeSH S_drug_effects_MeSH Liver_drug_effects_MeSH S_metabolism_MeSH Liver_metabolism_MeSH M_Male_MeSH M_Oxidation-Reduction_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 7698517 ----K I ----T Prolongation of near-normoglycemic remission in black NIDDM subjects with chronic low-dose sulfonylurea treatment. ----A Microvascular and neuropathic complications of diabetes mellitus can be significantly decreased by long-term, near-normoglycemic regulation in patients with insulin-dependent diabetes mellitus. Prevention or delay of onset of hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) patients should reduce morbidity and mortality from these complications. NIDDM can be nearly normoglycemic when diagnosed by screening before its symptomatic stage or when clinically hyperglycemic NIDDM goes into remission. One potential strategy to delay the onset of hyperglycemia in individuals at high risk is chronic low-dose sulfonylurea therapy. Thirty black NIDDM subjects who recently had developed near-normoglycemia were followed with no treatment or were randomly assigned to a 3-year, double-blind glipizide or placebo treatment. Baseline and follow-up parameters included fasting plasma glucose (FPG), HbA1c, plasma insulin, and glucose responses to an oral glucose tolerance test and insulin action, as determined by the euglycemic insulin clamp. Baseline FPG and HbA1c for all three groups were 107 mg/dl and 4.7%, respectively. Relapse to hyperglycemia was defined as an FPG level > or = 140 mg/dl on several consecutive visits or an FPG level > or = 140 mg/dl and symptoms of hyperglycemia. During the course of the treatment and follow-up, hyperglycemia occurred in 6 of 10 subjects in the no treatment group, 6 of 10 in the placebo group, and 2 of 10 in the glipizide treatment group. Prolongation of near-normoglycemia was significantly (P < 0.05) increased by low-dose (2.5 mg/day) glipizide compared with placebo treatment.(ABSTRACT TRUNCATED AT 250 WORDS) ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_African_Continental_Ancestry_Group_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH M_Human_MeSH M_Male_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Survival_Analysis_MeSH M_Time_Factors_MeSH ****** 7733122 ----K I ----T Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. ----A BACKGROUND: Acarbose delays release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, thereby attenuating postprandial increments in blood glucose and insulin. This multicenter, double-blind, placebo-controlled study compared the efficacy and safety of diet alone, acarbose, tolbutamide, and acarbose-plus-tolbutamide in non-insulin-dependent diabetes mellitus (NIDDM) patients. PATIENTS AND METHODS: A total of 290 patients with NIDDM and fasting plasma glucose levels of at least 140 mg/dL were randomized to receive treatment TID with acarbose 200 mg, tolbutamide 250 to 1,000 mg, a combination of both drugs, or placebo. A 6-week run-in period was followed by double-blind treatment for 24 weeks, then a 6-week follow-up period. RESULTS: All active treatments were superior (P < 0.05) to placebo in reducing postprandial hyperglycemia and HbA1c levels. The ranking in order of efficacy was: acarbose-plus-tolbutamide, tolbutamide, acarbose, and placebo. The postprandial reductions in glucose were approximately 85 mg/dL for acarbose-plus-tolbutamide, 71 mg/dL for tolbutamide, 56 mg/dL for acarbose, and 13 mg/dL for placebo. Tolbutamide was associated with increases in body weight and postprandial insulin levels when taken alone, but these were ameliorated when tolbutamide was taken in combination with acarbose. Acarbose alone or in combination with tolbutamide caused significantly more gastrointestinal adverse events (mainly flatulence and soft stools or diarrhea) than tolbutamide or placebo, but these were generally well tolerated. Clinically significant elevations in hepatic transaminase levels occurred in 3 patients in the acarbose group and 2 in the acarbose-plus-tolbutamide group. Transaminase levels returned to normal when therapy was discontinued. CONCLUSIONS: Acarbose was effective and well tolerated in the treatment of NIDDM. Control of glycemia was significantly better with acarbose compared with diet alone. Acarbose-plus-tolbutamide was superior to tolbutamide alone. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Acarbose_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Tolbutamide_MeSH S_adverse_effects_MeSH Tolbutamide_adverse_effects_MeSH S_therapeutic_use_MeSH Tolbutamide_therapeutic_use_MeSH M_Trisaccharides_MeSH S_adverse_effects_MeSH Trisaccharides_adverse_effects_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 7768272 ----K E ----T Acute effects of glyburide on the regulation of peripheral blood flow in normal humans. ----A Recent animal studies have demonstrated that selective blockade of ATP-sensitive K+ (KATP) channels of vascular smooth muscle results in a significant increase in peripheral vascular tone. The main aim of this study was to assess whether glyburide, a selective blocker of KATP channels and commonly used antidiabetic agent, influences resting blood flow and reactive hyperemic response of peripheral tissues of normal subjects. Baseline calf blood flow was measured non-invasively in six normal subjects with femoral venous occlusive plethysmography. Calf blood flow was also serially measured every 30-60 s after the release of calf arterial occlusion (10 min duration). Reactive hyperemia was expressed in terms of peak post-occlusive flow, duration of hyperemia and reactive hyperemic volume. In each subject, baseline flow and reactive hyperemia were measured before (control) and every hour for 5 h after the oral ingestion of either 7.5 mg glyburide or a placebo on two separate days. Baseline calf flow declined by 30 and 42% of control values after 1 and 2 h of glyburide intake (P < 0.05) with a return to control values by hours 3, 4 and 5. Peak post-occlusive flow after 1, 2 and 3 h of glyburide ingestion was lower than control values by 22, 30 and 28%, respectively (P < 0.05). The duration of reactive hyperemia after 2 and 3 h of glyburide ingestion was significantly longer than control values (P < 0.05), whereas reactive hyperemic volume remained unaffected by glyburide intake. Placebo elicited no significant changes in baseline flow or reactive hyperemia throughout the 5-h experimental period.(ABSTRACT TRUNCATED AT 250 WORDS) ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Femoral_Vein_MeSH S_drug_effects_MeSH Femoral_Vein_drug_effects_MeSH S_physiology_MeSH Femoral_Vein_physiology_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hyperemia_MeSH S_chemically_induced_MeSH Hyperemia_chemically_induced_MeSH M_Leg_MeSH S_blood_supply_MeSH Leg_blood_supply_MeSH M_Male_MeSH M_Plethysmography_MeSH M_Reference_Values_MeSH M_Regional_Blood_Flow_MeSH S_drug_effects_MeSH Regional_Blood_Flow_drug_effects_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7777712 ----K E ----T [Response of insulin and C-peptide to a mixed meal in non-insulin-dependent diabetics treated with insulin and chlorpropamide] ----A Glucose control in NIDDM is prone to progressive deterioration due to secondary failure to oral hypoglycemic therapy. Insulin may subsequently be required for optimal control in spite of peripheral hyperinsulinemia. In Mexico, diabetes associated with obesity is common. We therefore designed a prospective study combining insulin and chloropropamide in order to evaluate any improvement in insulin response to a standardized meal load and a consequent amelioration of glucose control. METHODS. Twenty diabetic patients with secondary failure to full doses of hypoglycemic drugs and moderate hyperglycemia were recruited. Therapy was initiated with human insulin 20 IU/day and 500 mg cholopropamide, titrating insulin dosage in order to achieve euglycemia. Before treatment and at the end of the study period, a glucose/insulin/C peptide response curve to a mixed standardized meal was performed. Blood glucose, serum lipids fructosamine and glycosylated hemoglobin levels were also determined. All patients were followed by capillary glucose measurements three times a week and glucose and fructosamine concentrations every two weeks during the study period. RESULTS. All patients required less insulin, and glucose control improved significantly. Glucose, fructosamine and glycosylated hemoglobin levels decreased from 262 mg/dL, 369 mmol/L and 14% to 111 mg/dL, 252 mmol/L, and 8% respectively; all differences were statistically significant. Insulin and C peptide levels increased significantly from 22.2 mU/mL and 1.65 ng/mL to 29.8 mU/mL and 1.97 ng/mL, respectively. When we measured the area under the curve, total values improved from 110 and 7.69 to 127 and 9.37, respectively; this was also statistically significant. Lipids levels decreased significantly, including triglicerides, total and LDL cholesterol whereas HDL cholesterol levels increased. CONCLUSIONS. Glucose control improved in our patient cohort the pancreatic insulin response probably due to a more adequate glycemic microenvironment and a possible enhanced exogenous and endogenous insulin function. ----P Journal_Article ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH S_secretion_MeSH C-Peptide_secretion_MeSH M_Chlorpropamide_MeSH S_pharmacology_MeSH Chlorpropamide_pharmacology_MeSH S_therapeutic_use_MeSH Chlorpropamide_therapeutic_use_MeSH M_Cohort_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Therapy__Combination_MeSH M_Eating_MeSH M_English_Abstract_MeSH M_Female_MeSH M_Fructosamine_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Hexosamines_MeSH S_blood_MeSH Hexosamines_blood_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH S_secretion_MeSH Insulin_secretion_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Secretory_Rate_MeSH S_drug_effects_MeSH Secretory_Rate_drug_effects_MeSH ****** 7781667 ----K E ----T Effect of insulin treatment on serum lipoprotein(a) in non-insulin-dependent diabetes. ----A In order to evaluate whether Lp(a), a lipoprotein that is potentially thrombogenic and atherogenic, is a potential risk factor for CAD in non-insulin-dependent diabetes (NIDDM), we compared the Lp(a) and its distribution in 145 NIDDM patients with that in 94 healthy control subjects. Furthermore, we studied the effect of insulin treatment on serum Lp(a) in 108 patients with NIDDM. Male and female NIDDM patients had similar Lp(a) concentrations to healthy controls (median value 167 mg L-1, range 15-1550 mg L-1 vs. 157 mg L-1, range 15-919 mg L-1, NS and 92, range 15-1190 mg L-1 vs. 103 mg L-1, range 15-842 mg L-1, NS). Also, the cumulative distribution of Lp(a) did not differ between the NIDDM patients and healthy subjects. Insulin treatment increased Lp(a) in diabetics with a Lp(a) concentration of less than 300 mg L-1, but this effect was not related to the concomitant improvement in metabolic control (mean change (+/- SEM) of HbA1c from 9.80 +/- 0.15 to 8.00 +/- 0.12; P < 0.001). In subjects with elevated Lp(a) concentrations (> 300 mg L-1) the Lp(a) concentration was unaffected by insulin, despite a similar improvement in glycaemic control. These results suggest that insulin may modulate the concentration of Lp(a). ----P Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Analysis_of_Variance_MeSH M_Apolipoproteins_B_MeSH S_blood_MeSH Apolipoproteins_B_blood_MeSH S_drug_effects_MeSH Apolipoproteins_B_drug_effects_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Cross-Sectional_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Human_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipoprotein(a)_MeSH S_blood_MeSH Lipoprotein(a)_blood_MeSH S_drug_effects_MeSH Lipoprotein(a)_drug_effects_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Lipoproteins__VLDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__VLDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Reference_Values_MeSH M_Sex_Characteristics_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 7601013 ----K E ----T Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. ----A The biguanide metformin (dimethylbiguanide) is an oral antihyperglycaemic agent used in the management of non-insulin-dependent diabetes mellitus (NIDDM). It reduces blood glucose levels, predominantly by improving hepatic and peripheral tissue sensitivity to insulin without affecting the secretion of this hormone. Metformin also appears to have potentially beneficial effects on serum lipid levels and fibrinolytic activity, although the long term clinical implications of these effects are unclear. Metformin possesses similar antihyperglycaemic efficacy to sulphonylureas in obese and nonobese patients with NIDDM. Additionally, interim data from the large multicentre United Kingdom Prospective Diabetes Study (UKPDS) indicated similar antihyperglycaemic efficacy for metformin and insulin in newly diagnosed patients with NIDDM. Unlike the sulphonylureas and insulin, however, metformin treatment is not associated with increased bodyweight. Addition of metformin to existing antidiabetic therapy confers enhanced antihyperglycaemic efficacy. This may be of particular use in improving glycaemic control in patients with NIDDM not adequately controlled with sulphonylurea monotherapy, and may serve to reduce or eliminate the need for daily insulin injections in patients with NIDDM who require this therapy. The acute, reversible gastrointestinal adverse effects seen with metformin may be minimised by administration with or after food, and by using lower dosages, increased slowly where necessary. Lactic acidosis due to metformin is rare, and the risk of this complication may be minimised by observance of prescribing precautions and contraindications intended to avoid accumulation of the drug or lactate in the body. Unlike the sulphonylureas, metformin does not cause hypoglycaemia. Thus, metformin is an effective antihyperglycaemic agent which appears to improve aberrant plasma lipid and fibrinolytic profiles associated with NIDDM. Possible long term clinical benefits of this drug with regard to cardiovascular mortality and morbidity are not yet established but are being assessed in a major ongoing study. Since metformin does not promote weight gain or hypoglycaemia it should be considered first-line pharmacotherapy in obese patients with NIDDM inadequately controlled by nonpharmacological measures. Metformin appears similarly effective for the pharmacological management of NIDDM in nonobese patients. ----P Journal_Article Review Review__Tutorial ----M M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_pharmacokinetics_MeSH Metformin_pharmacokinetics_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH ****** 7623902 ----K E ----T Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. ----A BACKGROUND: Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus (NIDDM) in the United States. Recently, however, metformin has been approved for the treatment of NIDDM. METHODS: We performed two large, randomized, parallel-group, double-blind, controlled studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes was inadequately controlled by diet (protocol 1: metformin vs. placebo; 289 patients), or diet plus glyburide (protocol 2: metformin and glyburide vs. metformin vs. glyburide; 632 patients). To determine efficacy we measured plasma glucose (while the patients were fasting and after the oral administration of glucose), lactate, lipids, insulin, and glycosylated hemoglobin before, during, and at the end of the study. RESULTS: In protocol 1, at the end of the study the 143 patients in the metformin group, as compared with the 146 patients in the placebo group, had lower mean (+/- SE) fasting plasma glucose concentrations (189 +/- 5 vs. 244 +/- 6 mg per deciliter [10.6 +/- 0.3 vs. 13.7 +/- 0.3 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.6 +/- 0.2 percent, P < 0.001). In protocol 2, the 213 patients given metformin and glyburide, as compared with the 210 patients treated with glyburide alone, had lower mean fasting plasma glucose concentrations (187 +/- 4 vs. 261 +/- 4 mg per deciliter [10.5 +/- 0.2 vs. 14.6 +/- 0.2 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.7 +/- 0.1 percent, P < 0.001). The effect of metformin alone was similar to that of glyburide alone. Eighteen percent of the patients given metformin and glyburide had symptoms compatible with hypoglycemia, as compared with 3 percent in the glyburide group and 2 percent in the metformin group. In both protocols the patients given metformin had statistically significant decreases in plasma total and low-density lipoprotein cholesterol and triglyceride concentrations, whereas the values in the respective control groups did not change. There were no significant changes in fasting plasma lactate concentrations in any of the groups. CONCLUSIONS: Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone. ----P Clinical_Trial Clinical_Trial__Phase_I Clinical_Trial__Phase_II Clinical_Trial__Phase_III Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH S_blood_MeSH Fasting_blood_MeSH M_Female_MeSH M_Folic_Acid_MeSH S_blood_MeSH Folic_Acid_blood_MeSH M_Glucose_Tolerance_Test_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lactates_MeSH S_blood_MeSH Lactates_blood_MeSH M_Lactic_Acid_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_blood_MeSH Obesity_in_Diabetes_blood_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Failure_MeSH M_Vitamin_B_12_MeSH S_blood_MeSH Vitamin_B_12_blood_MeSH ****** 7648802 ----K E ----T Energy expenditure in type 2 diabetic patients on metformin and sulphonylurea therapy. ----A Insulin and sulphonylurea therapies have both been reported to cause weight gain in Type 2 diabetic patients whereas metformin does not have this adverse effect. The mechanism for this difference is unclear. We have investigated in a cross-over study the effect of sulphonylurea and metformin therapy on energy expenditure and body composition in 10 Type 2 diabetic patients (7 females, 3 males) of various weights (mean body mass index 33.4 (SD 7.6 kg m-2)). Free living total energy expenditure was measured over 14 days by the doubly labelled water method adjusted for urinary glucose energy losses and resting energy expenditure by ventilated hood indirect calorimetry. Overall, total energy expenditure (12.88 +/- 4.17 vs 13.1 +/- 3.69 MJ 24 h-1) and resting metabolic rate (7.30 +/- 1.75 vs 7.23 +/- 1.74 MJ 24 h-1) were similar on metformin and sulphonylurea therapy, respectively. When adjusted for differences in fat free mass, resting metabolic rate on sulphonylurea therapy was slightly but significantly lower (mean difference -5.5 kJ 24 h-1 kg-1, 95% CI -1.2, -9.9 kJ 24 h-1 kg-1, p < 0.05). Fat free mass also increased significantly by 1.3 kg (95% CI 0.4, 2.4 kg, p < 0.05) when on sulphonylurea therapy, thus compensating for the lower resting metabolic rate per kg fat free mass to leave overall resting metabolic rate unchanged compared to metformin therapy. We also investigated the effect of adding metformin to six Type 2 diabetic patients already on insulin. This did not lead to any measurable changes in any of the components of energy expenditure.(ABSTRACT TRUNCATED AT 250 WORDS) ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Drug_Therapy__Combination_MeSH M_Energy_Metabolism_MeSH S_drug_effects_MeSH Energy_Metabolism_drug_effects_MeSH M_Female_MeSH M_Human_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 7657854 ----K E ----T The influence of orlistat on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers. ----A To assess the influence of orlistat on the pharmacokinetics and pharmacodynamics (the blood glucose-lowering effect) of glyburide, an open-label, placebo-controlled, randomized, two-way crossover study was done in 12 healthy male volunteers. Each subject received single 5-mg oral doses of glyburide (Micronase; The Upjohn Company, Kalamazoo, MI) on the fifth day of treatment with placebo (treatment A) and 80-mg orlistat (treatment B) three times a day for 4 1/3 days; the two treatments were separated by a five-day washout period. Serial blood samples were collected before and at appropriate intervals after each glyburide dose to determine plasma concentrations and blood glucose levels. Values of Cmax and AUC of glyburide showed an equality of the two treatments by the analysis of variance. There was an apparent correlation between blood glucose level and the logarithm of plasma glyburide concentration; this relationship appeared to not be altered when glyburide was administered with orlistat. In conclusion, orlistat administered at doses of 80-mg three times daily does not significantly alter the pharmacokinetics and blood glucose-lowering effect of a single 5-mg oral dose of glyburide in healthy volunteers. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diet__Atherogenic_MeSH M_Fasting_MeSH S_metabolism_MeSH Fasting_metabolism_MeSH M_Glyburide_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Intestinal_Absorption_MeSH M_Lactones_MeSH S_pharmacology_MeSH Lactones_pharmacology_MeSH M_Lipase_MeSH S_antagonists_&_inhibitors_MeSH Lipase_antagonists_&_inhibitors_MeSH S_pharmacology_MeSH Lipase_pharmacology_MeSH M_Male_MeSH ****** 7662219 ----K I ----T Insulin versus glipizide treatment in patients with non-insulin-dependent diabetes mellitus. Effects on blood pressure and glucose tolerance. ----A Insulin resistance that exists in patients with essential hypertension and in those with non-insulin-dependent diabetes mellitus (NIDDM) may be the common denominator for the impaired glucose homeostasis and elevated blood pressure (BP) levels in patients with NIDDM. Therefore, treatment that improves insulin action may also improve BP levels. Consequently, a four-phase (glipizide v insulin) cross-over design study was conducted to determine a better effect of glipizide treatment on insulin sensitivity and the effect this has on BP in 19 NIDDM patients. Patients were subjected to 1 month of diet only (phase I) followed by 3 months of glipizide treatment (phase II), then an additional 1 month of diet only (phase III), and finally 3 months of insulin treatment (phase IV). At the end of phases I, II, and IV oral glucose tolerance tests (OGTT) were performed and plasma glucose, insulin, and C-peptide levels were analyzed. Fasting plasma glucose, insulin, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides, glycated hemoglobin, fructosamine, and 2-h postprandial plasma glucose were also analyzed at each phase. Supine and sitting BP levels and body weights were determined biweekly during the study. With the exception of higher plasma insulin and C-peptide levels during the OGTT (area under the curve) in phase IV (insulin) v phase II (glipizide) (both P < .05), and higher fasting plasma insulin levels (P < .06), there were no consistently significant metabolic differences between phases IV and II.(ABSTRACT TRUNCATED AT 250 WORDS) ----P Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH S_drug_effects_MeSH C-Peptide_drug_effects_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Diet_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin_Resistance_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 7667166 ----K E ----T Dyslipidemias in patients with diabetes mellitus: classification and risks and benefits of therapy. ----A To characterize the lipid and lipoprotein abnormalities in patients with diabetes mellitus and evaluate the risks and benefits of marketed pharmacologic therapies, a MEDLINE search of the National Library of Medicine data base was performed of studies published from January 1966 to March 1994. Clinical trials assessing effects on lipids and lipoproteins, and adverse effects of marketed lipid-lowering agents were extracted. Reviews and other relevant articles were included if they provided information regarding lipid and lipoprotein metabolism or guidelines on the treatment of dyslipidemias in patients with diabetes mellitus. An extensive review of clofibrate was not included. The most common dyslipidemia in patients with poorly controlled insulin-dependent diabetes mellitus (IDDM) is combined elevated triglyceride and cholesterol levels, with reduced high-density lipoprotein (HDL) cholesterol (mixed hyperlipidemia). Hypertriglyceridemia combined with a reduced HDL cholesterol is the most common dyslipidemia in patients with noninsulin-dependent diabetes mellitus, but essentially any pattern of dyslipidemia may be present. Small and dense low-density lipoprotein (LDL), glycosylation of lipoproteins, and increased oxidized lipoproteins may be present in patients with diabetes mellitus; all contribute to accelerated atherosclerotic cardiovascular disease. Insulin therapy generally corrects quantitative lipid abnormalities in patients with IDDM, so drug treatment is seldom indicated. Diet, exercise, and insulin or oral sulfonylureas will improve hypertriglyceridemia and low HDL concentrations, but do not always return them to normal. Drug therapy is indicated when nonpharmacologic measures are inadequate. It is administered based on the effects of each agent on lipids and lipoproteins, patient age, adverse effect profile, patient tolerability, and drug-disease and drug-drug interactions. A fibric acid derivative is the drug of choice for marked hypertriglyceridemia in patients with diabetes mellitus. Niacin can worsen glycemic control, but it may be required in severe hypertriglyceridemia, hypercholesterolemia, or mixed hyperlipidemia. Bile-acid binding resins may accentuate hypertriglyceridemia but may be useful in selected patients with marked hypercholesterolemia and normal triglycerides. Hydroxymethylglutaryl coenzyme A reduced inhibitors are preferred in patients with elevated LDL cholesterol and mild hypertriglyceridemia. Patients with marked lipid abnormalities or mixed hyperlipidemias may require carefully dosed combinations of lipid-lowering drugs. ----P Journal_Article Review Review__Tutorial ----M M_Adult_MeSH M_Anticholesteremic_Agents_MeSH S_therapeutic_use_MeSH Anticholesteremic_Agents_therapeutic_use_MeSH M_Behavior_Therapy_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus_MeSH S_complications_MeSH Diabetes_Mellitus_complications_MeSH S_metabolism_MeSH Diabetes_Mellitus_metabolism_MeSH S_therapy_MeSH Diabetes_Mellitus_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_complications_MeSH Hyperlipidemia_complications_MeSH S_metabolism_MeSH Hyperlipidemia_metabolism_MeSH S_therapy_MeSH Hyperlipidemia_therapy_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Lipoproteins_MeSH S_blood_MeSH Lipoproteins_blood_MeSH M_Lipoproteins__LDL_MeSH S_blood_MeSH Lipoproteins__LDL_blood_MeSH M_Lipoproteins__VLDL_MeSH S_blood_MeSH Lipoproteins__VLDL_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Risk_Factors_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 7589771 ----K E ----T Effect of an alpha-glucosidase inhibitor combined with sulphonylurea treatment on glucose metabolism in patients with non-insulin-dependent diabetes mellitus. ----A Ten patients with non-insulin-dependent diabetes mellitus who were being treated with a sulphonylureal compound but whose glucose metabolism needed further improvement were given a combination of their usual sulphonylurea treatment and an alpha-glucosidase inhibitor. Treatment with the alpha-glucosidase inhibitor (0.6 mg/day), in addition to glibenclamide (7.5 mg/day in two patients; 5.0 mg/day in four; 2.5 mg/day in one) or tolbutamide (500 mg/day in three patients) for 4 weeks, improved hyperglycaemia after meals from 237-247 mg/dl to 192 mg/dl, and reduced glycosylated haemoglobin levels from 8.5-8.6% to 7.9% without causing hypoglycaemia. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Tolbutamide_MeSH S_administration_&_dosage_MeSH Tolbutamide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Tolbutamide_therapeutic_use_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 7555472 ----K E ----T Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. ----A OBJECTIVES--Optimal insulin regimens for non-insulin-dependent diabetes mellitus (NIDDM) patients with secondary failure are controversial. We evaluated the efficacy, side effects, and quality of life of patients receiving insulin either alone or in combination with their previous oral hypoglycemic agents (OHAs). RESEARCH DESIGN AND METHODS--Fifty-three Chinese patients with NIDDM (mean age 53.9 +/- 12.6 years, duration of diabetes 9.0 +/- 4.9 years, body wt 60.4 +/- 13.3 kg with corresponding body mass index 24.2 +/- 4.3 kg/m2, receiving the maximum dose of sulfonylurea and/or metformin) were confirmed to have OHA failure. Twenty-seven patients were randomized to continue OHAs and were given additional bedtime insulin (combination group); 26 patients were randomized to insulin therapy alone with twice-daily insulin (insulin group). Insulin doses were increased incrementally, aiming at fasting plasma glucose (FPG) < 7.8 mmol/l during a stabilization period of up to 8 weeks. Insulin dosage, body weight, glycemic control, and quality of life were assessed before and at 3 and 6 months after stabilization. RESULTS--Both groups showed similar improvement of glycemic control. For the combination group, FPG decreased from 13.5 +/- 2.7 to 8.9 +/- 3.0 mmol/l at 3 months (P < 0.0001) and to 8.6 +/- 2.5 mmol/l at 6 months (P < 0.0001). For the insulin group, FPG decreased from 13.5 +/- 3.6 to 7.5 +/-3.0 mmol/l at 3 months (P < 0.0001) and to 9.8 +/- 3.5 mmol/l at 6 months (P < 0.0001). No significant differences were observed between the groups. Similarly, both groups had significant improvement of fructosamine and glycosylated hemoglobin (HbA1c). Fructosamine fell from a mean of 458 to 365 mumol/l at 3 months (P < 0.0001) and to 371 mumol/l at 6 months (P < 0.0001) and from 484 to 325 mumol/l at 3 months (P < 0.0001) and to 350 mumol/l at 6 months (P < 0.0001) for the combination and insulin groups, respectively. HbA1c decreased from 10.2 to 8.4% at 3 months (P < 0.0001) and to 8.7% at 6 months (P < 0.0001) in the combination group and from 10.7 to 7.8% at 3 months (P < 0.0001) and to 8.4% at 6 months (P < 0.0001) in the insulin group. Despite similar improvement of glycemia, insulin requirements were very different. At 3 months, the combination group was receiving a mean of 14.4 U/day compared with 57.5 U/day in the insulin group (P < 0.0001). Similar findings were observed at 6 months (15.0 vs 57.2 U/day, P < 0>0001). Both groups gained weight. However, for the combination group, weight gain was 1.6 +/- 1.8 kg at 3 months and 2.1 +/- 2.5% kg at 6 months (both P < 0.0001 vs baseline), whereas for the insulin group, weight gain was 3.5 +/- 4.3 and 5.2 +/- 4.1 kg, respectively (both P < 0.0001 vs baseline). Weight gain was significantly greater in the insulin group (P < 0.05 at 3 months, and P < 0.005 at 6 months). Fasting plasma triglyceride decreased in the insulin group (1.8 +/- 1.0 to 1.4 +/- 0.8 mmol/l at 3 months [P < 0.005] and to 1.4 +/ 0.7 mmol/l at 6 months [P < 0.02] but not in the combination group. No changes were observed in total and high-density lipoprotein cholesterol. No severe hypoglycemic reactions were recorded in either group. Mild reactions occurred with similar frequency in both groups. Well-being and quality of life improved significantly in both groups. The majority of patients (82.7%) wanted to continue insulin beyond 6 months, irrespective of the treatment group. CONCLUSIONS--In NIDDM patients with secondary OHA failure, therapy with a combination of OHAs and insulin and with insulin alone was equally effective and well tolerated. However, combination therapy was associated with a lower insulin dose and less weight gain. Combination treatment may be considered when OHA failure occurs as a potential intermediate stage before full insulin replacement. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Analysis_of_Variance_MeSH M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Fructosamine_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Hexosamines_MeSH S_blood_MeSH Hexosamines_blood_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Failure_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 7555484 ----K E ----T Treatment of hypercholesterolemia in NIDDM with policosanol. ----A OBJECTIVE--To determine whether elevated levels of cholesterol and low-density lipoprotein (LDL) cholesterol in non-insulin-dependent diabetes mellitus (NIDDM) patients could be decreased by policosanol, a new cholesterol-lowering drug. NIDDM predisposes patients to coronary artery disease (CAD) through the direct action of hyperglycemia on the arteries as well as the dyslipidemia induced by NIDDM. RESEARCH DESIGN AND METHODS--This double-blind placebo-controlled trial was performed in 29 patients with NIDDM and hypercholesterolemia. After stable glycemic control was achieved by diet and/or oral hypoglycemic drugs, patients were instructed to follow a cholesterol-lowering diet for 6 weeks. Patients who met entry criteria received, under double-blind conditions, policosanol (5 mg) or placebo tablets twice a day for 12 weeks. RESULTS--Policosanol (10 mg/day) significantly reduced total cholesterol by 17.5% and LDL cholesterol by 21.8% compared with baseline and placebo. Furthermore, high-density lipoprotein (HDL) cholesterol was raised by 11.3% (not significant), and triglycerides showed a statistically nonsignificant decrease of 6.6%. These changes in lipid profile were similar to those induced by policosanol in nondiabetic patients with type II hyperlipoproteinemia. CONCLUSIONS--Glycemic control was unaffected by treatment. No clinically or biochemically adverse effects attributable to treatment were observed. Only one patient (placebo) withdrew from the trial because of an adverse experience (erythema). We concluded that policosanol is effective and safe in patients with NIDDM and hypercholesterolemia. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Anticholesteremic_Agents_MeSH S_therapeutic_use_MeSH Anticholesteremic_Agents_therapeutic_use_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Cholesterol__Dietary_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Diabetic_Diet_MeSH M_Double-Blind_Method_MeSH M_Fatty_Alcohols_MeSH S_therapeutic_use_MeSH Fatty_Alcohols_therapeutic_use_MeSH M_Female_MeSH M_Human_MeSH M_Hypercholesterolemia_MeSH S_blood_MeSH Hypercholesterolemia_blood_MeSH S_complications_MeSH Hypercholesterolemia_complications_MeSH S_drug_therapy_MeSH Hypercholesterolemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 7587846 ----K I ----T Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans Affairs Cooperative Study in Type II Diabetes. ----A OBJECTIVE--It is not clear whether intensive pharmacological therapy can be effectively sustained in non-insulin-dependent diabetes mellitus (NIDDM). The relative risks and benefits of intensive insulin therapy in NIDDM are not well defined. Accordingly, we designed a feasibility study that compared standard therapy and intensive therapy in a group of NIDDM men who required insulin due to sustained hyperglycemia. RESEARCH DESIGN AND METHODS--A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: 1) an evening insulin injection, 2) the same injection adding daytime glipizide, 3) two injections of insulin alone, and 4) multiple daily injections. Patient accrual and adherence, glycohemoglobin (HbA1c), side effects, and measurements of endpoints for a prospective long-term trial were assessed. RESULTS--Accrual goals were met, mean follow-up time was 27 months (range 18-35 months), and patients kept 98.6% of scheduled visits. After 6 months, the mean HbA1c in the intensive therapy group was at or below 7.3% and remained 2% lower than the standard group for the duration of the trial. Most of the decrease in the mean HbA1c in the intensive group was obtained by a single injection of evening intermediate insulin, alone or with daytime glipizide. By the end of the trial, 64% of the patients had advanced to two or more injections of insulin a day, aiming for normal HbA1c. However, only a small additional fall in HbA1c was attained. Severe hypoglycemia was rare (two events per 100 patients per year) and not significantly different between the groups, nor were changes in weight, blood pressure, or plasma lipids. There were 61 new cardiovascular events in 40 patients and 10 deaths (6 due to cardiovascular causes). CONCLUSIONS--Intense stepped insulin therapy in NIDDM patients who have failed glycemic control on pharmacological therapy is effective in maintaining near-normal glycemic control for > 2 years without excessive severe hypoglycemia, weight gain, hypertension, or dyslipidemia. Cardiovascular event rates are high at this stage of NIDDM. A long-term prospective trial is needed to assess the risk-benefit ratio of intensified treatment of hyperglycemia in NIDDM patients requiring insulin. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Aged_MeSH M_Albuminuria_MeSH S_epidemiology_MeSH Albuminuria_epidemiology_MeSH M_Animals_MeSH M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Glucose_Self-Monitoring_MeSH M_Blood_Pressure_MeSH M_Body_Mass_Index_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Angiopathies_MeSH S_epidemiology_MeSH Diabetic_Angiopathies_epidemiology_MeSH M_Diabetic_Retinopathy_MeSH S_epidemiology_MeSH Diabetic_Retinopathy_epidemiology_MeSH M_Feasibility_Studies_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Hospitals__Animal_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Patient_Selection_MeSH M_Quality_Control_MeSH M_Smoking_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH M_Time_Factors_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_United_States_MeSH ****** 7587856 ----K E ----T Comparison of bedtime NPH or preprandial regular insulin combined with glibenclamide in secondary sulfonylurea failure. ----A OBJECTIVE--To compare the effect of bedtime NPH insulin or preprandial regular insulin combined with glibenclamide on metabolic control in non-insulin-dependent diabetes mellitus (NIDDM) patients with secondary failure to sulfonylurea therapy. RESEARCH DESIGN AND METHODS--Eighty NIDDM patients were randomized to treatment with either three preprandial doses of regular insulin (daytime group D) or a bedtime dose of NPH insulin (nocturnal insulinization, group N), both regimens being combined with 10.5 mg of glibenclamide. Metabolic profiles were obtained at 0, 6, 16 weeks. RESULTS--Glycemic control had improved significantly in both groups after 4 months. Fasting blood glucose was significantly lower compared with baseline in both groups. The mean change +/- SD in group D was -2.8 +/- 3.5 mmol/l and in group N -6.4 +/- 3.0 mmol/L, the reduction being more pronounced in group N compared with group D (P < 0.0001). HbA1c was lowered similarly, from 9.2 +/- 1.4 to 7.1 +/- 1.2% in group D (P < 0.0001) and from 9.1 to 1.1 to 7.5 +/- 1.5% in group N (P < 0.0001). The total daily insulin doses were similar, 29 +/- 11 U in group D and 26 +/- 9 U in group N, and the circulating insulin levels during daytime were higher in group D than in group N. Total serum cholesterol and triglycerides were similarly and significantly lowered compared with baseline in both groups. Weight gain was more pronounced in group D (3.4 +/- 0.3 kg) than in group N (1.9 +/- 1.9 kg; D vs. N, P < 0.002), and the change was inversely correlated with initial eight but not with the improvement in HbA1c. CONCLUSIONS--The two insulin regimens exert similar effect on glucose metabolism and serum lipids in NIDDM patients on combination therapy. Weight gain is more pronounced in patients given insulin during the daytime when preprandial doses of short-acting insulin are used. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Eating_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin__Isophane_MeSH S_administration_&_dosage_MeSH Insulin__Isophane_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin__Isophane_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH M_Treatment_Failure_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8568117 ----K E ----T Metabolic benefits deriving from chronic vitamin C supplementation in aged non-insulin dependent diabetics. ----A OBJECTIVE: Our study investigated the metabolic benefits deriving from chronic pharmacological vitamin C administration in aged non-insulin dependent (Type II) diabetic patients. METHODS: Forty type II diabetic patients (age: 72 +/- 0.5 years) underwent placebo and vitamin C (0.5 g twice daily) administration in double-blind, randomized, cross-over fashion. All patients were treated by oral hypoglycaemic agents which continued throughout the study. After baseline observations, treatment periods lasted 4 months and were separated by a 30-day wash-out period. RESULTS: Patients' antropometric data were unchanged throughout the study. Chronic vitamin C administration vs placebo was associated with a significant decline in fasting plasma free radicals (0.26 +/- 0.06 vs 0.49 +/- 0.07 p < 0.03) and insulin (90 +/- 4 vs 73 +/- 6 pmol/L p < 0.04), total- (7.3 +/- 0.5 vs 5.8 +/- 0.4 mmol/L p < 0.03), LDL-cholesterol (5.6 +/- 0.6 vs 4.1 +/- 0.3 mmol/L p < 0.05) and triglycerides (2.58 +/- 0.07 vs 2.08 +/- 0.04 mmol/L p < 0.04) levels. In 20 patients, chronic vitamin C administration improved whole body glucose disposal and nonoxidative glucose metabolism. Percent increase in plasma vitamin C levels correlated with the percent decline in plasma LDL-cholesterol (r = 0.44; p < 0.007) and insulin levels (r = 0.42; p < 0.006). Finally percent increase in plasma vitamin C levels was correlated with the percent decline in plasma free radicals and increase in GSH levels. CONCLUSIONS: Chronic vitamin C administration has beneficial effects upon glucose and lipid metabolism in aged non-insulin dependent (type II) diabetic patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Ascorbic_Acid_MeSH S_pharmacology_MeSH Ascorbic_Acid_pharmacology_MeSH S_therapeutic_use_MeSH Ascorbic_Acid_therapeutic_use_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Food__Fortified_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Glucose_Clamp_Technique_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH ****** 7589820 ----K I ----T U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. ----A The objective of the U.K. Prospective Diabetes Study is to determine whether improved blood glucose control in type II diabetes will prevent the complications of diabetes and whether any specific therapy is advantageous or disadvantageous. The study will report in 1998, when the median duration from randomization will be 11 years. This report is on the efficacy of therapy over 6 years of follow-up and the overall incidence of diabetic complications. Subjects comprised 4,209 newly diagnosed type II diabetic patients who after 3 months' diet were asymptomatic and had fasting plasma glucose (FPG) 6.0-15.0 mmol/l. The study consists of a randomized controlled trial with two main comparisons: 1) 3,867 patients with 1,138 allocated to conventional therapy, primarily with diet, and 2,729 allocated to intensive therapy with additional sulfonylurea or insulin, which increase insulin supply, aiming for FPG < 6 mmol/l; and 2) 753 obese patients with 411 allocated to conventional therapy and 342 allocated to intensive therapy with metformin, which enhances insulin sensitivity. In the first comparison, in 2,287 subjects studied for 6 years, intensive therapy with sulfonylurea and insulin similarly improved glucose control compared with conventional therapy, with median FPG at 1 year of 6.8 and 8.2 mmol/l, respectively (P < 0.0001). and median HbA1c of 6.1 and 6.8%, respectively (P < 0.0001). During the next 5 years, the FPG increased progressively on all therapies (P < 0.0001) with medians at 6 years in the conventional and intensive groups, FPG 9.5 and 7.8 mmol/l, and HbA1c 8.0 and 7.1%, respectively. The glycemic deterioration was associated with progressive loss of beta-cell function. In the second comparison, in 548 obese subjects studied for 6 years, metformin improved glucose control similarly to intensive therapy with sulfonylurea or insulin. Metformin did not increase body weight or increase the incidence of hypoglycemia to the same extent as therapy with sulfonylurea or insulin. A high incidence of clinical complications occurred by 6-year follow-up. Of all subjects, 18.0% had suffered one or more diabetes-related clinical endpoints, with 12.1% having a macrovascular and 5.7% a microvascular endpoint. Sulfonylurea, metformin, and insulin therapies were similarly effective in improving glucose control compared with a policy of diet therapy. The study is examining whether the continued improved glucose control, obtained by intensive therapy compared with conventional therapy (median over 6 years HbA1c 6.6% compared with 7.4%), will be clinically advantageous in maintaining health. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cohort_Studies_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH P_Diabetic_Diet_MeSH M_Female_MeSH M_Great_Britain_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_epidemiology_MeSH Hyperglycemia_epidemiology_MeSH M_Hypertension_MeSH S_complications_MeSH Hypertension_complications_MeSH S_epidemiology_MeSH Hypertension_epidemiology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 7556806 ----K E ----T Comparison of miglitol and glibenclamide in diet-treated type 2 diabetic patients. ----A The efficacy of the new intestinal alpha-glucosidase inhibitor, miglitol, and glibenclamide were compared in a 6-month double-blind controlled protocol involving 100 non-insulin dependent diabetic patients under diet alone. HbA1c levels (initially between 7 and 11%) were reduced (p < 0.05): -0.78 +/- 0.21% after miglitol and -1.18 +/- 0.20% after glibenclamide. The difference between the two treatments was not significant, although glibenclamide appeared to be more active than miglitol at 8 (p = 0.002) and 16 weeks (p = 0.01) but not at 24 weeks. Fasting glycaemia decreased after miglitol (8.7 +/- 0.3 vs 9.6 +/- 0.3 mmol/l, p = 0.005) and after glibenclamide (8.0 +/- 0.3 vs 9.1 +/- 0.3, p = 0.007). After miglitol, a decrease was noted after breakfast (p < 0.001) and lunch (p < 0.001). The same was true for glibenclamide (p = 0.004 and p < 0.001 respectively). A significant reduction in glucose incremental area during a standard meal test was noted at the end of miglitol (p = 0.008) or glibenclamide treatment (p = 0.04). Subgroups of nonresponders to both treatments were identified (10/49 with miglitol, 9/47 with glibenclamide). Side effects were recorded in 10 patients treated with miglitol (flatulence and meteorism, diarrhoea, 1 discontinued therapy) and in 10 treated with glibenclamide (asthenia, sensation of hunger). This study indicates that miglitol is suitable for initial application in diet-resistant Type 2 diabetic patients, providing, a persistent effect and acceptable side effects. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article Multicenter_Study ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH P_Diabetic_Diet_MeSH M_Double-Blind_Method_MeSH M_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Enzyme_Inhibitors_therapeutic_use_MeSH M_Female_MeSH M_Glucosamine_MeSH S_analogs_&_derivatives_MeSH Glucosamine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Glucosamine_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Multivariate_Analysis_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH M_Treatment_Failure_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 8529760 ----K E ----T Comparison between acarbose, metformin, and insulin treatment in type 2 diabetic patients with secondary failure to sulfonylurea treatment. ----A The purpose of this study was to determine the most suitable treatment for Type 2 (non-insulin-dependent) diabetic patients with secondary failure to sulfonylureas (SFS). In a four-month comparative study, 36 Type 2 diabetic patients given SFS were allocated to three treatment groups: A (n = 12, M/F 6/6, HbAlc 9.1 +/- 1.6%) received 0.3 IU/Kg body weight (BW) of insulin-Zn between 10 and 11 p.m.; B (n = 12, M/F 6/6, HbAlc 9.2 +/- 1.6%) SFS plus 850 mg/day of metformin; and C (n = 12, M/F 6/6, HbAlc 9.5 +/- 2.4%) SFS plus acarbose 3 x 100 mg daily. Modifications in HbAlc, BW, blood pressure (BP), lipoprotein profile and insulin sensitivity were evaluated. HbAlc decreased in the three groups (A: 17.9 +/- 13.5%; B: 18.2 +/- 4.5%; C: 7.6 +/- 16.8%; all p < 0.05; A and B vs C = p < 0.05). BW increased in group A and decreased in the other groups. BP decreased statistically in group B. HDL-cholesterol increased (1.26 +/- 0.46 vs 1.49 +/- 0.36 mmol/L; p < 0.05) and triglyceride levels decreased (1.68 +/- 0.85 vs 1.16 +/- 0.43 mmol/L; p < 0.05) in group A. There were no significant changes in the other studied parameters. We conclude that, for Type 2 diabetic patients given SFS, both insulin and metformin plus SFS provided better glycaemic control than acarbose plus SFS. Metformin combined with SFS offered further advantages for the control of BW and BP. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Acarbose_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Body_Mass_Index_MeSH M_Body_Weight_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glucose_Tolerance_Test_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Failure_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_Trisaccharides_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 7486486 ----K E ----T Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: abnormalities in metabolism and function. ----A OBJECTIVE: To determine basal levels of cytosolic calcium ([Ca2+]i) and phagocytic activity in polymorphonuclear leukocytes (PMNLs) from patients with non-insulin-dependent diabetes (NIDDM). DESIGN: Prospective cohort study. SETTING: A university-county hospital. MEASUREMENTS: Cytosolic calcium levels, adenosine triphosphate (ATP) content, and phagocytosis of PMNLs from patients with NIDDM and from controls. INTERVENTION: In patients with NIDDM, we evaluated the effect of treatment with an oral hypoglycemic agent (glyburide) on [Ca2+]i levels, ATP content, and the phagocytosis of PMNLs. PATIENTS: 22 controls and 34 patients with NIDDM were examined. Fifteen patients were studied before and after 3 months of treatment with glyburide. RESULTS: Polymorphonuclear leukocytes from patients with NIDDM showed significantly elevated basal levels of [Ca2+]i (68 +/- 9.6 compared with 43 +/- 4.9 nmol/L; P < 0.01); reduced ATP content (1.30 +/- 0.58 compared with 2.35 +/- 0.45 nmol/10(6) PMNLs; P < 0.01); and impaired phagocytosis (117 +/- 21.0 compared with 145 +/- 17.4 micrograms oil/10(7) PMNLs per minute; P < 0.01) compared with controls. There was a direct and significant correlation (P < 0.01, r = 0.80) between [Ca2+]i levels in PMNLs and serum glucose levels and an inverse correlation between phagocytic ability and [Ca2+]i levels (P < 0.01; r = 0.62) as well as between phagocytic activity and fasting serum glucose levels (P < 0.01, r = 0.54) in patients with NIDDM. Glyburide therapy resulted in significant reduction in fasting serum glucose levels; in PMNLs, this treatment resulted in a significant reduction in [Ca2+]i levels, a significant increase in ATP content, and a significant improvement of phagocytosis. CONCLUSIONS: Patients with NIDDM have elevated [Ca2+]i levels in PMNLs. This abnormality is probably induced by hyperglycemia and is primarily responsible for the imparied phagocytosis seen in these patients. ----P Journal_Article ----M M_Adenosine_Triphosphate_MeSH S_blood_MeSH Adenosine_Triphosphate_blood_MeSH M_Adult_MeSH M_Aged_MeSH M_Calcium_MeSH S_blood_MeSH Calcium_blood_MeSH M_Cytosol_MeSH S_metabolism_MeSH Cytosol_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_blood_MeSH Hyperglycemia_blood_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Neutrophils_MeSH S_metabolism_MeSH Neutrophils_metabolism_MeSH S_physiology_MeSH Neutrophils_physiology_MeSH M_Phagocytosis_MeSH S_physiology_MeSH Phagocytosis_physiology_MeSH M_Prospective_Studies_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 7479199 ----K I ----T Pharmacokinetics and pharmacodynamics of glipizide after once-daily and divided doses. ----A STUDY OBJECTIVE. To determine the pharmacokinetics and pharmacodynamics of glipizide given as a single, oral, 20-mg dose, versus three different divided-dose regimens totaling 20 mg each. DESIGN. Randomized (in order of dosing regimens), open-label, crossover study. SETTING. University medical center clinical research center. PATIENTS. Six subjects with noninsulin-dependent diabetes mellitus. INTERVENTIONS. Patients were studied on four separate occasions separated by at least 3 days. The divided-dose regimens were designed to simulate delayed absorption of the drug over 2, 4, and 8 hours. Blood samples for measuring glipizide, glucose, and C-peptide were obtained over 24 hours. MEASUREMENTS AND MAIN RESULTS. Glipizide peak concentrations and time to peak differed significantly with the dosage schedule; when smaller doses were administered more often, peak concentrations were lower and more delayed. The mean values for area under the curve from time zero to infinity (range 7240.7-10,001.8 micrograms.L-1.hr-1; 16,226-22,414 nmol.L-1.hr-1), clearance (0.44-0.64 ml.min-1.kg-1; 0.07-0.11 ml.sec-1.kg-1), post-distribution phase volume (0.17-0.25 L.kg-1), and half-life (4.2-5.4 hrs) were not significantly different among regimens. Neither morning fasting glucose nor maximum and minimum times and concentrations of glucose and C-peptide over 24 hours were statistically different among regimens. Similarly, no significant differences were found in area under the concentration-time curve for glucose and C-peptide measured over 2.5 hours after each meal and from time zero to 24 hours. CONCLUSIONS. The timing of a glipizide dose in relation to a meal and simulated delayed or prolonged absorption appear to have little influence on the drug's pharmacodynamic effects. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Food_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH S_pharmacology_MeSH Glipizide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Intestinal_Absorption_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Time_Factors_MeSH ****** 8846678 ----K E ----T More uniform diurnal blood glucose control and a reduction in daily insulin dosage on addition of glibenclamide to insulin in type 1 diabetes mellitus: role of enhanced insulin sensitivity. ----A Combination therapy with insulin and sulphonylurea has gained acceptance in management of subjects with Type 2 (non-insulin-dependent) diabetes mellitus. However, its role in management of Type 1 (insulin-dependent) diabetes mellitus remains controversial. In this study, the effect of combination therapy with insulin and glibenclamide on metabolic control, daily insulin dosage, and insulin sensitivity was assessed in subjects with Type 1 diabetes mellitus. Ten men with Type 1 diabetes mellitus participated in a randomized, double-blind, crossover, clinical trial with three treatment regimens, namely (1) insulin alone, (2) insulin and placebo, (3) insulin and glibenclamide, each lasting 3 months. Combination therapy induced: (1) reduction in daily insulin dosage; (2) more uniform blood glucose control as reflected by a lower average 24 h blood glucose level, a smaller difference between mean preprandial and 2 h postprandial blood glucose concentrations, decreased 24 h urine glucose excretion, and a decline in number of hypoglycaemic events; (3) improved insulin sensitivity as expressed by more rapid plasma glucose disappearance rate, without a significant alteration in fasting plasma glucagon and 1h postprandial serum C-peptide levels; when compared with treatment with either insulin alone or with insulin and placebo. Therefore, it is apparent that the addition of glibenclamide to insulin reduces daily insulin dosage and renders a greater uniformity to diurnal blood glucose control, most probably secondary to enhancement of insulin sensitivity. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH P_Circadian_Rhythm_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH S_urine_MeSH Diabetes_Mellitus__Type_I_urine_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Glycosuria_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_prevention_&_control_MeSH Hypoglycemia_prevention_&_control_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8690177 ----K E ----T Unchanged gene expression of glycogen synthase in muscle from patients with NIDDM following sulphonylurea-induced improvement of glycaemic control. ----A We have previously shown that the mRNA expression of muscle glycogen synthase is decreased in non-insulin-dependent diabetic (NIDDM) patients; the objective of the present protocol was to examine whether the gene expression of muscle glycogen synthase in NIDDM is affected by chronic sulphonylurea treatment. Ten obese patients with NIDDM were studied before and after 8 weeks of treatment with a weight-maintaining diet in combination with the sulphonylurea gliclazide. Gliclazide treatment was associated with significant reductions in HbA1C (p=0.001) and fasting plasma glucose (p=0.005) as well as enhanced beta-cell responses to an oral glucose load. During euglycaemic, hyperinsulinaemic clamp (2 mU x kg-1 x min-1) in combination with indirect calorimetry, a 35% (p=0.005) increase in whole-body insulin-stimulated glucose disposal rate, predominantly due to an increased non-oxidative glucose metabolism (p=0.02) was demonstrated in teh gliclazide-treated patients when compared to pre-treatment values. In biopsies obtained from vastus lateralis muscle during insulin infusion, the half-maximal activation of glycogen synthase was achieved at a significantly lower concentration of the allosteric activator glucose 6-phosphate (p=0.01). However, despite significant increases in both insulin-stimulated non-oxidative glucose metabolism and muscle glycogen synthase activation in gliclazide-treated patients no changes were found in levels of glycogen synthase mRNA or immunoreactive protein in muscle. In conclusion, improved blood glucose control in gliclazide-treated obese NIDDM patients has no impact on the gene expression of muscle glycogen synthase. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Animals_MeSH M_Base_Sequence_MeSH M_Biopsy_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_DNA_Primers_MeSH M_DNA__Complementary_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_enzymology_MeSH Diabetes_Mellitus__Type_II_enzymology_MeSH M_Female_MeSH P_Gene_Expression_MeSH S_drug_effects_MeSH Gene_Expression_drug_effects_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Globins_MeSH S_biosynthesis_MeSH Globins_biosynthesis_MeSH M_Glucose_Clamp_Technique_MeSH M_Glucose_Tolerance_Test_MeSH M_Glycogen_Synthase_MeSH S_biosynthesis_MeSH Glycogen_Synthase_biosynthesis_MeSH M_Human_MeSH M_Hyperinsulinism_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Infusions__Intravenous_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_blood_MeSH Insulin_blood_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Molecular_Sequence_Data_MeSH M_Muscle__Skeletal_MeSH S_enzymology_MeSH Muscle__Skeletal_enzymology_MeSH S_pathology_MeSH Muscle__Skeletal_pathology_MeSH M_Polymerase_Chain_Reaction_MeSH M_RNA__Messenger_MeSH S_analysis_MeSH RNA__Messenger_analysis_MeSH S_biosynthesis_MeSH RNA__Messenger_biosynthesis_MeSH M_Rabbits_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8521759 ----K E ----T Prevention of complications in non-insulin-dependent diabetes mellitus (NIDDM). ----A It is expected that the number of patients with diabetes mellitus will increase in the near future. The high rate of microvascular and macrovascular complications developing in these patients will place an even higher burden on our healthcare systems. Several pathophysiological factors are involved in the development of complications, among which are hyperglycaemia per se, the consequent formation of advanced glycation end-products (AGEs) and the intracellular accumulation of sorbitol. In addition, hypertension and dyslipidaemia also play an important role, especially in the development of coronary heart disease and stroke. The major therapeutic goals in patients with non-insulin-dependent diabetes mellitus (NIDDM) are to reduce obesity and normalise lipid disturbances and increased blood pressure, in order to improve the well-being of the patient and reduce the risk of the development of late diabetic complications. Often, pharmacological treatment of the hyperglycaemia is necessary, in which case sulphonylureas, metformin, alpha-glucosidase inhibitors such as acarbose, or insulin may be employed. It is believed that medical interventions, by their effect on improving metabolic control, reduce the incidence and severity of diabetic complications, especially when considering the toxic effects of glucose and the accumulation of AGEs as a consequence of raised tissue glucose levels. This concept is also based on extrapolation of the finding of the Diabetes Control and Complications Trial that intensive glycaemic control in IDDM will prevent the progression of at least the microvascular complications like retinopathy and nephropathy. There are, however, no long term studies in NIDDM patients to show that treatment with oral antihyperglycaemic agents helps to postpone or prevent complications. It is expected that the UK Prospective Diabetes Study will show whether better metabolic control, either with oral antihyperglycaemics or with insulin, will indeed improve outcome. Several other studies aiming at specific risk factor intervention (hypertension, hyperlipidaemia, lipid oxidation) in NIDDM patients are currently ongoing. ----P Journal_Article Review Review__Academic ----M M_Acarbose_MeSH M_Aldehyde_Reductase_MeSH S_antagonists_&_inhibitors_MeSH Aldehyde_Reductase_antagonists_&_inhibitors_MeSH M_Biguanides_MeSH S_therapeutic_use_MeSH Biguanides_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Great_Britain_MeSH M_Guanidines_MeSH S_therapeutic_use_MeSH Guanidines_therapeutic_use_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH S_prevention_&_control_MeSH Hyperglycemia_prevention_&_control_MeSH M_Hypertension_MeSH S_drug_therapy_MeSH Hypertension_drug_therapy_MeSH S_prevention_&_control_MeSH Hypertension_prevention_&_control_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Prospective_Studies_MeSH M_Randomized_Controlled_Trials_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Trisaccharides_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 8590785 ----K E ----T Response of truncated glucagon-like peptide-1 and gastric inhibitory polypeptide to glucose ingestion in non-insulin dependent diabetes mellitus. Effect of sulfonylurea therapy. ----A Gastric inhibitory polypeptide (tGIP) and truncated glucagon like peptide-1 (GLP-1) are potent gastrointestinal insulinotropic factors (incretin), are most released after a meal or ingestion of glucose in man and animals. To investigate whether sulfonylurea (SU) affects the secretion of incretin, the modulation of plasma GIP and tGLP-1 levels following glucose ingestion in non-insulin-dependent diabetic type 2 patients with or without SU therapy was studied. A 75-G oral glucose tolerance test (OGTT) was carried out on 9 healthy subjects (controls) and 18 patients with non-obese type 2, 9 of whom were treated by diet alone (NIDDM-diet) and the other 9 with SU (glibenclamide 2.5 mg or gliclazide 40 mg) once a day (NIDDM-SU). Plasma GIP was measured by radioimmunoassay (RIA) with R65 antibody, and GLP-1 was measured by RIA with N-terminal-directed antiserum R1043 (GLP-1NT) and C-terminal-directed antiserum R2337 (GLP-1CT). Following OGTT, plasma glucose, GIP, GLP-1NT, and GLP-1CT in type 2 patients increased more markedly than in controls, despite the lower response of insulin. However, there were no significant differences in plasma levels of these peptides between the NIDDM-diet and NIDDM-SU groups. Therefore, it is unlikely that SU is involved in the high response of GIP and GLP-1s to OGTT in type 2 patients. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Gastric_Inhibitory_Polypeptide_MeSH S_blood_MeSH Gastric_Inhibitory_Polypeptide_blood_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH M_Glucose_MeSH S_administration_&_dosage_MeSH Glucose_administration_&_dosage_MeSH S_pharmacology_MeSH Glucose_pharmacology_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Peptide_Fragments_MeSH S_blood_MeSH Peptide_Fragments_blood_MeSH M_Protein_Precursors_MeSH S_blood_MeSH Protein_Precursors_blood_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 8554206 ----K I ----T United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. ----A PURPOSE: To report the progress (after 9-year follow-up) of a study designed to determine whether improved glucose control in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM) is effective in reducing the incidence of clinical complications. DATA SOURCE: A multicenter, randomized, controlled trial of different therapies for NIDDM. After initial diet therapy, 4209 asymptomatic patients who remained hyperglycemic (fasting plasma glucose levels, 6.0 to 15.0 mmol/L) were assigned to either a conventional therapy policy, primarily with diet alone, or to an intensive therapy policy, aiming for fasting plasma glucose levels of less than 6.0 mmol/L, with assignment to primary therapy with sulfonylurea or insulin (which increased insulin supply) or metformin (which enhanced insulin sensitivity). RESULTS: All three modes of pharmacologic therapy in the intensively treated group-sulfonylurea, insulin, and metformin-had similar efficacy in reducing the fasting plasma glucose and glycated hemoglobin levels. Over 9 years, patients assigned to intensive therapy with sulfonylurea or insulin had lower fasting plasma glucose levels (median, 7.3 and 9.0 mmol/L, respectively) than patients assigned to conventional therapy. Regardless of the assigned therapy, however, the fasting plasma glucose and hemoglobin A1c levels increased, and maintaining near-normal glycemia was, in general, not feasible. Even insulin therapy did not achieve the therapeutic goal of near-normal glycemia because of the difficulty in treating marked hyperglycemia and the risk for hypoglycemic episodes. Nine years after the diagnosis of diabetes, 29% of the patients had had a diabetes-related clinical end point, 20% had had a macrovascular complication, and 9% had had a microvascular complication. CONCLUSIONS: A report will be published in 1998 after a median duration from randomization of 11 years (range, 6 to 20 years) with an 81% power at a 1% level of significance of detecting whether the obtained improvement in glucose control causes a 15% decrease or increase in the incidence of major complications and whether any specific therapy is advantageous or disadvantageous. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH M_Combined_Modality_Therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Angiopathies_MeSH S_etiology_MeSH Diabetic_Angiopathies_etiology_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Fasting_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Great_Britain_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_physiopathology_MeSH Islets_of_Langerhans_physiopathology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 8593925 ----K E ----T Randomized study of glibenclamide versus traditional Chinese treatment in type 2 diabetic patients. Chinese-French Scientific Committee for the Study of Diabetes. ----A The purpose of this study was to evaluate the efficacy of a traditional Chinese treatment (TCT) based on three plants in association with a sulfonylurea, glibenclamide (2.5 mg X 3/d). A 2 X 2 factorial design was adopted for this multicentre randomized double-blind trial involving 4 groups [A = placebo (P) TCT + P glibenclamide; B = P TCT + verum glibenclamide; C = verum TCT + P glibenclamide; D = verum TCT + verum glibenclamide]. Patients included were type 2 diabetic outpatients, 40-70 years of age, treated by diet alone or oral anti-diabetic drugs. Endpoint criteria evaluated were HbA1, blood glucose and plasma insulin (at fasting, and 1 and 2 h after a test meal). At each visit, a clinical examination was performed, and a questionnaire on side effects and associated symptoms was completed. The dose was reduced by half in the case of hypoglycaemia. The 216 patients were recruited in 5 centres [Shanghai (1) = 48, Shanghai (2) = 40, Beijing = 40, Canton = 42, Chengdu = 46 and randomized into treatment groups A, B, C, D (56, 56, 50 and 54 respectively). Eleven patients were withdrawn for administrative reasons. In patients treated with glibenclamide, a significant increase in weight and insulinaemia was observed, together with a significant decrease in blood glucose values; in those receiving TCT, blood glucose values were significantly decreased only 2 h after the test meal. A synergistic effect on blood glucose was observed when both treatments were given. Hypoglycaemia occurred in 19 patients (all in the two verum glibenclamide groups). This first multicentre controlled trial showed that the 3 Chinese plants tested were well-tolerated and effective in Type 2 diabetes as indicated by a significant synergistic effect in association with a sulfonylurea. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Male_MeSH P_Medicine__Chinese_Traditional_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8556690 ----K E ----T Diet and diabetes in the elderly. ----A This article draws attention to some of the unique aspects of diabetes mellitus in the elderly and outlines the principles of management of diabetes in this age group with emphasis on diet therapy. The implications of the Diabetes Control and Complications Trial for the elderly person with diabetes is also briefly discussed. The new nutrition recommendations of the American Diabetes Association are summarized, and the evolving enhanced role of the dietitian in the management of diabetes is highlighted. ----P Journal_Article Review Review__Tutorial ----M M_Aged_MeSH M_Diabetes_Mellitus_MeSH S_diagnosis_MeSH Diabetes_Mellitus_diagnosis_MeSH S_diet_therapy_MeSH Diabetes_Mellitus_diet_therapy_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus_prevention_&_control_MeSH P_Diet__Reducing_MeSH M_Female_MeSH M_Human_MeSH M_Male_MeSH ****** 8596760 ----K E ----T [Activity of superoxide dismutase in erythrocytes and leukocytes and levels of zinc and copper in blood of patients with diabetes. Effect of diabetic treatment on examined parameters] ----A The purpose of the present work was to assess the relationship of leukocyte and erythrocyte superoxide dismutase activity to its cofactors concentrations i.e. zinc and copper in plasma and erythrocyte in diabetic patients and treatment variability. 104 patients were included in the study. 23 persons were in the control group. All patients were divided into 2 groups (NIDDM and IDDM). Patients with NIDDM were divided into 3 subgroups depending on treatment (insulin, gliclazide, dietary treated). In all groups, there were assessed following parameters: the leucocyte and erythrocyte SOD activity according to the method of Misra and Fridovich, and zinc and copper concentrations in plasma and erythrocyte, which were measured by flame absorption spectrophotometry. Statistical analysis was performed using the CRISP program. CONCLUSION: 1. The leukocyte and erythrocyte superoxide dismutase activity is significantly lowered in diabetes mellitus. 2. In diabetic patients both in type I and type II as in the healthy people, there is a close correlation between SOD activity and its cofactors i.e. zinc and copper erythrocyte concentrations. 3. Insulin and gliclazide treatment increases SOD activity and delays late diabetic complications. ----P Journal_Article ----M M_Adolescent_MeSH M_Adult_MeSH M_Child_MeSH M_Copper_MeSH S_blood_MeSH Copper_blood_MeSH M_Diabetes_Mellitus_MeSH S_blood_MeSH Diabetes_Mellitus_blood_MeSH S_therapy_MeSH Diabetes_Mellitus_therapy_MeSH M_Diabetic_Diet_MeSH M_English_Abstract_MeSH M_Erythrocytes_MeSH S_enzymology_MeSH Erythrocytes_enzymology_MeSH M_Female_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Leukocytes_MeSH S_enzymology_MeSH Leukocytes_enzymology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Superoxide_Dismutase_MeSH S_blood_MeSH Superoxide_Dismutase_blood_MeSH M_Zinc_MeSH S_blood_MeSH Zinc_blood_MeSH ****** 8684103 ----K E ----T Clinical usefulness of serum 1,5-anhydroglucitol in monitoring glycaemic control. ----A BACKGROUND: To evaluate prospectively the clinical value of measuring serum concentrations of 1,5-anhydroglucitol (1,5AG) in monitoring glycaemia in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM), we measured serum 1,5AG in 56 such patients. METHODS: 28 patients (group A) were started on, and continuously received, an oral hypoglycaemic agent for at least 6 weeks. The other 28 patients (group B) were given such agents for 4 weeks, and then stopped taking them for at least 2 weeks. All patients were then followed for an additional 10 weeks. Serum 1,5AG, fructosamine, glycated haemoglobin (HbA1c), and self-monitoring of blood glucose were monitored every 14 days for 16 weeks. FINDINGS: When sudden worsening of glycaemia occurred within 2 weeks, entailing withdrawal of oral treatment, 1,5AG accurately detected the slight change in glycaemia whereas HbA1c and fructosamine both failed to detect it. Although the change was detected by measurement of fasting plasma glucose (FPG) concentrations, FPG was less sensitive than 1,5AG. In patients with "near-normoglycaemia" (HbA1c about 6.5%) in the preceding 8 weeks, those who showed a lower concentration of 1,5AG (<10.0 micrograms/mL) manifested a higher mean daily plasma glucose concentration even though HbA1c measurement suggested good control of glycaemia. Results of 1,5AG were correlated more strongly with the FPG (r=0.790) and mean daily plasma glucose (r=-0.835) estimated on the same day than those estimaoffted in the preceding 2, 4 and 8 weeks, and with a fall in the Spearman correlation coefficient at any preceding time interval. INTERPRETATION: Because 1,5AG accurately detected a slight change in glycaemia without delay, it is suitable for use in monitoring for strict control of glycaemia, an important clinical goal. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Deoxyglucose_MeSH S_blood_MeSH Deoxyglucose_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diagnosis_MeSH Diabetes_Mellitus__Type_II_diagnosis_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Evaluation_Studies_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Isomerism_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Sensitivity_and_Specificity_MeSH M_Time_Factors_MeSH ****** 8684512 ----K E ----T [Drug-induced asterixis amplified by relative hypoglycemia] ----A A 58-year-old man with chronic paranoid-hallucinatoric psychosis had transient episodes with marked paranoid delusions, auditory hallucinations without confusion, shakiness of both upper extremities, tachycardia and sweating. EMG performed with surface electrodes revealed many silent periods in postural active muscles with maximum duration of 120 ms; blood glucose was 65-75 mg/dl. At other times, blood glucose was 135-140 mg/dl, EMG revealed few silent periods in postural active muscles with maximal duration of 50 ms and the patient noted some vibration in his outstretched hands only. Drug-induced asterixis (clozapine, benperidol) amplified by relative hypoglycemia was therefore assumed, and symptoms disappeared after oral antidiabetics were reduced. ----P Case_Reports Journal_Article ----M M_Antipsychotic_Agents_MeSH S_administration_&_dosage_MeSH Antipsychotic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Antipsychotic_Agents_adverse_effects_MeSH M_Clozapine_MeSH S_administration_&_dosage_MeSH Clozapine_administration_&_dosage_MeSH S_adverse_effects_MeSH Clozapine_adverse_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Therapy__Combination_MeSH M_Electromyography_MeSH S_drug_effects_MeSH Electromyography_drug_effects_MeSH M_English_Abstract_MeSH M_Fasciculation_MeSH S_chemically_induced_MeSH Fasciculation_chemically_induced_MeSH S_physiopathology_MeSH Fasciculation_physiopathology_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH M_Hallucinations_MeSH S_drug_therapy_MeSH Hallucinations_drug_therapy_MeSH S_physiopathology_MeSH Hallucinations_physiopathology_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_complications_MeSH Hypoglycemia_complications_MeSH S_physiopathology_MeSH Hypoglycemia_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Motor_Neurons_MeSH S_drug_effects_MeSH Motor_Neurons_drug_effects_MeSH S_physiology_MeSH Motor_Neurons_physiology_MeSH M_Muscle__Skeletal_MeSH S_innervation_MeSH Muscle__Skeletal_innervation_MeSH M_Myoclonus_MeSH S_chemically_induced_MeSH Myoclonus_chemically_induced_MeSH S_physiopathology_MeSH Myoclonus_physiopathology_MeSH M_Neurologic_Examination_MeSH S_drug_effects_MeSH Neurologic_Examination_drug_effects_MeSH M_Paranoid_Disorders_MeSH S_drug_therapy_MeSH Paranoid_Disorders_drug_therapy_MeSH S_physiopathology_MeSH Paranoid_Disorders_physiopathology_MeSH M_Tremor_MeSH S_chemically_induced_MeSH Tremor_chemically_induced_MeSH S_physiopathology_MeSH Tremor_physiopathology_MeSH ****** 8642720 ----K E ----T Endocrinology. ----A ----P Journal_Article ----M M_Bone_Resorption_MeSH M_Endocrinology_MeSH S_trends_MeSH Endocrinology_trends_MeSH M_Graves'_Disease_MeSH M_Human_MeSH M_Hyperparathyroidism_MeSH M_Hypoglycemic_Agents_MeSH M_Metformin_MeSH M_Osteoporosis_MeSH M_United_States_MeSH ****** 8656173 ----K E ----T Metformin: a new treatment option for non-insulin-dependent diabetes mellitus. ----A Metformin is a biguanide that can used alone or in combination with sulfonylureas or insulin in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). Since biguanides do not increase pancreatic insulin secretion, they are referred to as antihyperglycemic agents, as opposed to hypoglycemic agents. Biguanides reduce hyperglycemia by increasing, insulin sensitivity, decreasing glucose absorption, and inhibiting hepatic gluconeogenesis. Advantages of metformin include achieving glycemic control without exacerbating weight gain or hyperinsulinemia and beneficially affecting serum cholesterol concentrations. Although metformin has the potential to cause lactic acidosis, the incidence is significantly lower compared with phenformin. Risk factors for lactic acidosis include renal serum creatinine > 1.5 mg/dL and cardiovascular, pulmonary, and hepatic disease. Metformin should be temporarily discontinued prior to surgery and before administration of radiologic intravenous contrast, and in patients with sepsis, severe gastrointestinal disease, trauma, and acute cardiovascular events. ----P Journal_Article Review Review__Tutorial ----M M_Biguanides_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Glyburide_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_economics_MeSH Hypoglycemic_Agents_economics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_economics_MeSH Metformin_economics_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 8690621 ----K E ----T Efficacy of combination therapy with insulin and oral hypoglycemic agents in patients with type II diabetes during a 1-year period. ----A In this retrospective study, the authors assess the efficacy of combined insulin and oral hypoglycemic agents (OHAs) in controlling glycemic levels, as well as lipid levels and insulin requirements, in 48 patients with type II diabetes mellitus during a 1-year period. Thirty-two of these patients had secondary failure to an OHA (group 1). Sixteen patients (group 2) were taking high doses of insulin alone. Overall, 64.6% of all the patients responded to the combination therapy and insulin at 6 months. Response was defined as a decrease in hemoglobin A1c of more than 0.5%. At 12 months, 50% of these patients continued to respond to this regimen. No significant differences were seen in the patients' total cholesterol and triglyceride levels between responders and nonresponders in each group. After 1 year of combination OHA and insulin therapy, 50% of the patients showed a 21.4% reduction in their daily insulin dose. ----P Clinical_Trial Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Retrospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH ****** 8767351 ----K E ----T O[The effect of physical exercise on glycemia on healthy subjects following administration of glimepiride] ----A Sulfonylureas predispose to hypoglycaemia during and after exercise. The hypoglycaemic effect of the novel sulfonylurea glimepiride (G; CAS 93479-97-1) in male healthy volunteers under these conditions. Each subject was exposed to three experimental situations, administration of 3 mg G and rest, administration of 3 mg G and 60 min of bicycle ergometry (E) (work load adjusted to a heart rate of 120 bpm), or placebo (P) and bicycle ergometry as mentioned. Each of these was preceded and followed by 60 min of physical rest. Base line glycaemia was comparable (PE 83 +/- 8 mg/dl, GR 84 +/- 5 mg/dl, GE 86 +/- 7 mg/dl) and fell during GR to 63 +/- 6 mg/dl after 150 min. During GE glycaemia ceased to decline after 30 min exercise, and rose thereafter reaching values comparable to PE after 150 min (80 +/- 8 vs. 82 +/- 7 mg/dl). Serum insulin concentrations rose during exercise following administration of G to 6-7 microU/ml (AUC during the period 60-120 min after administration: GE 371 +/- 81 microU/ml.60 min, GR 414 +/- 77 microU/ml.60 min), and fell during PE to 4 microU/ml (265 +/- 49 microU/ml.60; p < 0.001 vs. GE and GR). During GE serum insulin concentrations fell to 6 microU/ml at the end of exercise and thereafter (AUC during the period 120-180 min after administration: 340 +/- 82 microU/ml.60 min), whereas they remained at 7 microU/ml during GR (399 +/- 109 microU/ml.60 min; p = 0.087 vs. GE). In conclusion, exercise blunts the hypoglycaemic effect of glimepiride in healthy individuals. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_English_Abstract_MeSH M_Exercise_MeSH S_physiology_MeSH Exercise_physiology_MeSH M_Exercise_Test_MeSH M_Female_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH M_Heart_Rate_MeSH S_drug_effects_MeSH Heart_Rate_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lactates_MeSH S_blood_MeSH Lactates_blood_MeSH M_Lactic_Acid_MeSH M_Male_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH ****** 8732716 ----K E ----T Does a high-carbohydrate diet have different effects in NIDDM patients treated with diet alone or hypoglycemic drugs? ----A OBJECTIVE--To compare the effects of a nigh-carbohydrate diet on blood glucose and plasma lipids in NIDDM patients with either mild or severe glucose intolerance. RESEARCH DESIGN AND METHODS--A crossover design with a 15-day intervention diet was used. Eighteen patients were separated into two groups on the basis of hypoglycemic treatment (diet, n = 9, or diet plus glibenclamide, n = 9) and were assigned to a 15-day treatment with a high-carbohydrate/low-fiber diet containing 60% energy from carbohydrate and 20% from fat or a low-carbohydrate/low-fiber diet with 40% energy from carbohydrate and 40% from fat and then crossed over to the other diet for 15 more days. RESULTS--The high-carbohydrate diet produced a significant increase in postprandial blood glucose in patients on glibenclamide (13.6 +/- 1.4 vs. 11.0 +/- 1.8 mmol/l, P < 0.002, while no difference was recorded in the group on diet alone (9.7 +/- vs. 8.9 +/- 0.6 mmol/l). Postprandial insulin levels were significantly higher after the high-carbohydrate diet in the group on diet along (248 +/- 32 vs. 192 +/- 28 pmol/l, P < 0.01), while no significant differences were observed in the other group (226 +/- 19 vs. 202 +/- 24 pmol/l) The high-carbohydrate diet also induced a significant increase in fasting plasma triglyceride concentrations in both groups (1.36 +/- 0.2 vs. 1.12 +/- 0.2 mmol/l, P < 0.05 and 1.4 +/- 0.3 vs. 1.1 +/- 0.1 mmol/l, P < 0.05). No differences were observed in fasting plasma cholesterol and HDL. CONCLUSIONS--The effects of the high-carbohydrate diet on blood glucose control in NIDDM patients differ according to severity of glucose intolerance. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Biological_Markers_MeSH S_blood_MeSH Biological_Markers_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH P_Dietary_Carbohydrates_MeSH M_Dietary_Fats_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8739909 ----K I ----T Sulphonylurea treatment of NIDDM patients with cardiovascular disease: a mixed blessing? ----A Non-insulin-dependent diabetic (NIDDM) patients show a high incidence of cardiovascular disease, with greater risk of recurrent myocardial infarction and a less favourable clinical outcome than non-diabetic patients. The majority of NIDDM patients are treated with sulphonylurea (SU) derivatives. In the 1970's the University Group Diabetes Program concluded that tolbutamide treatment caused increased cardiovascular mortality; the study, which led to curtailment of oral antidiabetic treatment in the USA, was received with scepticism in Europe. Later criticism of its methodology reduced the impact of the study; however, the question of the safety of SU in NIDDM patients with cardiovascular disease has been re-opened in the face of new experimental data. The heart and vascular tissues do have prerequisites for SU action, i.e. SU receptors and ATP-dependent K+ (K+ATP) channels. These channels play an important role in the protection of the myocardium against ischaemia-reperfusion damage, and their closure by SU could lead to amplified ischaemic damage. Here we review evidence from animal and human studies for deleterious SU effects on ischaemia-induced myocardial damage, either by direct action or through diminished cardioprotective preconditioning. Closure of K+ATP channels by SU can lead to reduction of post-infarct arrhythmias; the drug has also been claimed to improve various atherosclerosis risk factors. The evidence for these beneficial effects of SU is also reviewed. We look at the major difficulties that hamper transfer of information from experimental studies to clinical decision-making: a) The affinity of SU for heart K+ATP channels is orders of magnitude lower than for beta-cell channels; is it reasonable to expect in vivo cardiac effects with therapeutic 'pancreatic' SU doses? b) Most studies utilized high doses of acutely administered SU; are effects similar in the chronic steady-state of the SU-treated diabetic patient? c) Convincing SU effects have been demonstrated in acutely induced ischaemia by acutely administering the drug; do such effects persist in the clinical situation of gradually progressive ischaemia? d) Ischaemia and modification of K+ATP channel activity induce complex events, some with opposing effects; what is the net result of SU action, and do different SU derivatives lead to different outcomes? e) In the chronic (and hence clinically relevant) situation, how can direct (deleterious or beneficial) SU effects be separated from beneficial effects mediated by the metabolic action of the drug? Only large prospective clinical studies, making use of advanced technology for assessment of cardiovascular function, can answer these questions. Millions of NIDDM patients are treated with SU derivatives; many are in the age group where cardiovascular risks are extremely high. The question of whether SU derivatives are beneficial or deleterious for these patients must finally be settle unequivocally. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Cardiovascular_Diseases_MeSH S_complications_MeSH Cardiovascular_Diseases_complications_MeSH S_physiopathology_MeSH Cardiovascular_Diseases_physiopathology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Angiopathies_MeSH S_physiopathology_MeSH Diabetic_Angiopathies_physiopathology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Myocardial_Ischemia_MeSH S_physiopathology_MeSH Myocardial_Ischemia_physiopathology_MeSH M_Potassium_Channels_MeSH S_physiology_MeSH Potassium_Channels_physiology_MeSH M_Receptors__Drug_MeSH S_physiology_MeSH Receptors__Drug_physiology_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 8726592 ----K E ----T Metformin in noninsulin-dependent diabetes mellitus. ----A Metformin is an oral antihyperglycemic agent that is approved by the Food and Drug Administration for the treatment of noninsulin-dependent diabetes mellitus. It differs from the sulfonylureas in that it is does not enhance insulin secretion and normally does not produce hypoglycemia. Metformin acts to decrease preprandial and postprandial blood glucose concentrations by increasing skeletal muscle uptake of glucose, decreasing gluconeogenesis, and decreasing absorption of glucose. The addition of metformin to maximum dosages of a sulfonylurea may synergistically improve glucose control. The drug may offer other potential benefits, such as weight loss or minimal weight gain, improved blood flow in patients with peripheral vascular disease, reduction of tissue plasminogen activator inhibitor, and improved lipid profiles. It is relatively safe if taken appropriately. Its most common side effects are gastrointestinal (nausea, diarrhea, anorexia), metallic taste, and vitamin B12 malabsorption. Lactic acidosis may also occur, but it is rare if metformin is avoided in patients with contraindications to its use. With careful monitoring, the agent may be considered for the initial treatment of obese patients who fail dietary measures, and those whose disease is refractory to maximum dosages of sulfonylureas or who do not tolerate them. ----P Journal_Article Review Review__Tutorial ----M M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hypercholesterolemia_MeSH S_drug_therapy_MeSH Hypercholesterolemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_pharmacokinetics_MeSH Metformin_pharmacokinetics_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH ****** 8750768 ----K I ----T A novel mechanism of glipizide sulfonylurea action: decreased metabolic clearance rate of insulin. ----A To examine whether sulfonylureas inhibit the metabolic clearance rate (MCR) of insulin, 19 healthy young subjects participated in two experiments. In the first protocol (n = 10), a 3-h oral glucose load was performed with and without 2 mg of glipizide given 30 min before glucose ingestion. The total insulin response was 60% greater with than without glipizide (5.9 +/- 0.6 vs 3.7 +/- 0.5 microU/ml; P < 0.001). However, the total C-peptide responses were virtually identical (4.7 +/- 0.5 vs 4.8 +/- 0.4 nmol/l) in both studies. In the second protocol (n = 9), the MCR of insulin was measured during 4-h euglycemic insulin clamps performed with and without glipizide. In the study with glipizide, the subjects ingested 5 mg of glipizide at 120 min. The steady-state plasma insulin concentration during the 4th h, i.e., 1-2 h after glipizide ingestion, was significantly higher than during the 2nd h, i.e., before glipizide ingestion (99 +/- 22 vs 78 +/- 17 microU/ml; P < 0.01). In addition, glucose uptake during the 4th h was greater (8.0 +/- 1.6 vs 6.4 +/- 1.5 mg/kg.min) and the MCR of insulin was reduced (503 +/- 126 vs 621 +/- 176 ml/m2.min; P < 0.01). We conclude that glipizide augments plasma insulin levels both by enhancing its secretion and by decreasing the MCR of insulin. ----P Journal_Article ----M M_Adult_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Female_MeSH M_Glipizide_MeSH S_pharmacology_MeSH Glipizide_pharmacology_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Glucose_Clamp_Technique_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Infusions__Intravenous_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_blood_MeSH Insulin_blood_MeSH M_Kinetics_MeSH M_Male_MeSH M_Metabolic_Clearance_Rate_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 8742566 ----K E ----T Circulating catecholamines and metabolic effects of captopril in NIDDM patients. ----A OBJECTIVE: To evaluate the effects of captopril on circulating catecholamine levels in NIDDM patients and the possible relationship between captopril-related changes in circulating catecholamine levels and insulin sensitivity. RESEARCH DESIGN AND METHODS: Fourteen nonobese normotensive NIDDM men (aged 44.5 +/- 5.1 years) underwent a 2-h euglycemic-hyperinsulinemic clamp (40 mU.m-2.min-1). Baseline evaluation of insulin sensitivity was followed by the random assignment of each patient to either captopril or placebo treatment, according to a crossover double-blind design. Euglycemic-hyperinsulinemic clamp studies were then repeated for all patients after both placebo and captopril treatments. Plasma norepinephrine (NE) and epinephrine (E) levels were assessed before, during, and after each clamp. RESULTS: Resulting data showed that plasma catecholamine levels increased during baseline euglycemic-hyperinsulinemic clamp (NE: +23.6% time 0 vs. time 120 min, P < 0.05; E: +24.8% time 0 vs. time 120 min, P < 0.05). Captopril treatment significantly increased total glucose uptake (from 19.0 +/- 9.0 to 26.8 +/- 10.1 mmol.kg-1.min-1, P < 0.05) and reduced baseline plasma NE (P < 0.001) and E (P < 0.05) levels. However, the magnitude of the NE (+25.7% time 0 vs. time 120 min, P < 0.001) and E (+27.2% time 0 vs. time 120 min, P < 0.05) increments during euglycemic hyperinsulinemia were not affected by the drug. Percentage changes in the ratio of total body glucose uptake to circulating insulin levels and corresponding decrements of baseline plasma E levels after captopril therapy were negatively correlated (r = -0.57, P < 0.05). CONCLUSIONS: The reduction of circulating catecholamines could contribute, at least in part, to the captopril-related amelioration of insulin sensitivity. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Angiotensin-Converting_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Angiotensin-Converting_Enzyme_Inhibitors_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Captopril_MeSH S_therapeutic_use_MeSH Captopril_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Epinephrine_MeSH S_blood_MeSH Epinephrine_blood_MeSH M_Glucose_Clamp_Technique_MeSH M_Human_MeSH M_Infusions__Intravenous_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_blood_MeSH Insulin_blood_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH M_Male_MeSH M_Norepinephrine_MeSH S_blood_MeSH Norepinephrine_blood_MeSH ****** 8742572 ----K E ----T A comparison of acarbose versus metformin as an adjuvant therapy in sulfonylurea-treated NIDDM patients. ----A OBJECTIVE: To compare the effects of acarbose or metformin treatment used as an adjunct with a sulfonylurea agent in the treatment of NIDDM not adequately controlled with the use of a sulfonylurea agent alone. RESEARCH DESIGN AND METHODS: Of the poorly controlled female NIDDM patients on sulfonylurea treatment, 18 were randomly selected from the outpatient diabetic clinic for study. For 8 weeks, they received either acarbose (300 mg/daily) or metformin (1,500 mg/daily) in addition to sulfonylurea in a crossover design using a 3-week washout period between treatments. The efficacy of each drug regimen was assessed by measuring the levels of glycosylated hemoglobin, fasting and 2-h postprandial blood glucose (PPBG) levels, cholesterol, triglyceride, and fibrinogen levels before and after 8 weeks of therapy. RESULTS: The metabolic parameters measured before initiation of either treatment regimen were similar. Mean fasting and 2-h postprandial glucose levels were reduced moderately at the end of 8 weeks of both combination treatments (P < 0.05). Although the fasting and 2-h postprandial plasma insulin and C-peptide and fibrinogen levels at the end of the 8-week treatment periods were lower than those obtained at the beginning of the study, the differences between these values were not statistically significant. Cholesterol levels remained unchanged. Only the 2-h PPBG level in the group using acarbose plus a sulfonylurea was lower than the level achieved by the group using metformin plus a sulfonylurea (8.1 +/- 0.8 vs. 9.8 +/- 1.0 mmol/l, respectively, P < 0.05). The difference between pre- and posttreatment levels of the 2-h PPBG level in both arms of the study were statistically significant (delta-acarbose, 5.3 +/- 0.4 vs. delta-metformin, 2.9 +/- 0.3) (P < 0.05). Specific drug-associated side effects were observed in 12 patients on acarbose and 3 patients on metformin. CONCLUSIONS: Acarbose or metformin can be used as effective adjuvant therapies with a sulfonylurea agent in NIDDM patients who are poorly controlled with the sulfonylurea agent alone. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acarbose_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_Trisaccharides_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 8742586 ----K E ----T New and traditional treatment of glycemia in NIDDM. ----A ----P Congresses ----M M_Animals_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Gene_Therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Mice_MeSH M_Mice__Transgenic_MeSH M_Monosaccharide_Transport_Proteins_MeSH S_metabolism_MeSH Monosaccharide_Transport_Proteins_metabolism_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 8737030 ----K E ----T Daytime glibenclamide and bedtime NPH insulin compared to intensive insulin treatment in secondary sulphonylurea failure: a 1-year follow-up. ----A The aim of this study was to compare the metabolic effects of a combination of daytime glibenclamide and evening NPH insulin with intensive insulin treatment (rapid acting insulin before meals and NPH insulin at bedtime) in patients exhibiting secondary failure to sulphonylurea treatment. Thirty-nine mildly obese NIDDM patients (BMI 25.6 +/- 0.5) were randomized after 6 weeks of intensive insulin treatment to either a combination treatment (CT, n = 20) or continued intensive insulin treatment (IT, n = 19). There were no differences between the two groups in age, diabetes duration, BMI, HbA1c, or basal and glucagon stimulated C-peptide. The patients were followed for 1 year and the findings were analysed on an intent to treat basis. Two patients in the CT group were excluded after 2 and 6 months, respectively, due to unacceptably high postprandial glucose values. There was a significant difference in HbA1c between the CT and IT groups at 6 months (8.2 +/- 0.2, n = 19, vs 6.8 +/- 0.4%, n = 19, p < 0.001)), but not at 12 months (7.8 +/- 0.3, n = 18, vs 7.5 +/- 0.4%, n = 19). After the initial intensive insulin treatment, BMI was constant in the CT group but increased significantly at 6 and 12 months in the IT group. We conclude that both treatments are associated with a marked and long-term improvement of glycaemic control. The intensive insulin treatment leads to a more pronounced weight increase which in the long run might have negative effect on overall metabolic control. Therefore, the combination treatment together with intensified education and dietary advice should be regarded as the initial treatment of choice for oral agent failure in moderately obese NIDDM patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Albuminuria_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin__Isophane_MeSH S_administration_&_dosage_MeSH Insulin__Isophane_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin__Isophane_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Failure_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8718436 ----K E ----T Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. ----A OBJECTIVE: To investigate the clinical efficacy of troglitazone, a newly developed oral hypoglycemic agent, in patients with NIDDM. RESEARCH DESIGN AND METHODS: There were 284 NIDDM patients (20-82 years of age) whose glycemic control while on a diet was judged stable but was judged unsatisfactory (fasting plasma glucose [FPG] > or = 8.3 mmol/l) when entered into a multicenter and double-blind study with parallel groups study. They were randomly allocated into two groups, the troglitazone group (the T group: 400 mg/day p.o.) and the placebo group (the P group), and were treated with test drugs for 12 weeks. RESULTS: We evaluated efficacy in 136 patients of the T group and 126 patients of the P group. There was no significant difference in any of baseline characteristics between the T and P groups. In the T group, FPG and HbA1c decreased significantly after treatment (before versus after, FPG 10.1 +/- 1.6 vs. 8.8 +/- 1.9 mmol/l, P < 0.001; HbA1c: 8.6 +/- 1.5 vs 8.1 +/- 1.7%, P < 0.001). FPG and HbA1c did not change after treatment in the P group (before versus after, FPG 10.1 +/- 1.8 vs. 9.9 +/- 2.1 mmol/l; HbA1c 8.5 +/- 1.5 vs. 8.6 +/- 1.6%). Of 136 patients in the T group, 62 (45.6%) were classified as responders. Serum triglyceride level also decreased in the T group but not in the P group. Body weight increased slightly only in the T group. There were no differences in changes in blood pressure between the two groups. No serious adverse events occurred in either group. CONCLUSIONS: Troglitazone at 400 mg/day decreased FPG and HbA1c significantly in NIDDM patients who had failed to respond to diet therapy. Troglitazone, developed as a drug to enhance insulin action, can be a useful hypoglycemic agent for the treatment of NIDDM. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Pressure_MeSH M_Body_Weight_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Chromans_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH P_Diabetic_Diet_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8773160 ----K I ----T Effects of aspirin and ibuprofen on the pharmacokinetics and pharmacodynamics of glyburide in healthy subjects. ----A OBJECTIVE: To determine the effects of aspirin and ibuprofen on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers. DESIGN: Single-center, randomized, two-way, crossover design following an initial baseline evaluation phase. SETTING: Outpatient, university-based ambulatory care facility. PATIENTS: Sixteen healthy nonsmoking men aged 20-34 years. INTERVENTION: Three phases consisting of six treatments. Phase 1 began with treatment A, a baseline oral glucose tolerance test (GTT), followed by treatment B, glyburide 5 mg plus a GTT. The other two phases were administered in a crossover design. Phase 2 consisted of the administration of aspirin 975 mg qid for 4 days. On day 3 a GTT was administered (treatment C) and on day 4 glyburide 5 mg plus a GTT was administered (treatment E). Phase 3 consisted of the administration of ibuprofen 600 mg qid for 4 days with a GTT on day 3 (treatment D) and glyburide 5 mg plus a GTT on day 4 (treatment F). MAIN OUTCOME MEASURES: Serum glyburide concentrations after each treatment, as well as glucose and insulin, ibuprofen, and salicylate serum concentrations and glyburide free fractions. RESULTS: Aspirin administration resulted in an 85% increase in mean total glyburide oral clearance and a 29% increase in glyburide free fraction. Ibuprofen administration resulted in a slight increase in mean glyburide free fraction, but no significant changes in glyburide pharmacokinetic parameters were observed. Insulin concentrations were increased during the glyburide plus aspirin treatment. Conflicting results were observed in the glucose parameters. CONCLUSIONS: The potential for this glyburide-aspirin interaction resulting in a transient hypoglycemia should be considered in diabetic patients receiving glyburide therapy. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Anti-Inflammatory_Agents__Non-Steroidal_MeSH S_pharmacology_MeSH Anti-Inflammatory_Agents__Non-Steroidal_pharmacology_MeSH M_Aspirin_MeSH S_pharmacology_MeSH Aspirin_pharmacology_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cross-Over_Studies_MeSH M_Drug_Interactions_MeSH M_Glucose_Tolerance_Test_MeSH M_Glyburide_MeSH S_blood_MeSH Glyburide_blood_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Ibuprofen_MeSH S_pharmacology_MeSH Ibuprofen_pharmacology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8799649 ----K E ----T American Diabetes Association Postgraduate Course, 1996: treatment and prevention of diabetes. ----A ----P Congresses ----M P_Diabetes_Mellitus_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_II_prevention_&_control_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Disease_Management_MeSH M_Education__Medical__Continuing_MeSH M_Health_Education_MeSH M_Human_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Managed_Care_Programs_MeSH P_Societies__Medical_MeSH M_United_States_MeSH ****** 8848822 ----K I ----T The effects of obesity on the pharmacokinetics and pharmacodynamics of glipizide in patients with non-insulin-dependent diabetes mellitus. ----A The pharmacokinetics and pharmacodynamics of glipizide were evaluated in 20 patients with non-insulin-dependent diabetes mellitus (NIDDM). The group consisted of 12 obese subjects (seven women, five men; mean +/- SD age, 53.5 +/- 8.5 years; total body weight (TBW), 95.5 +/- 17.2 kg; percentage > IBW (ideal body weight), 57.8 +/- 31.7%); and eight nonobese subjects (two women, six men; age, 57.8 +/- 11.7 years; TBW, 80.8 +/- 9.9 kg; percentage > IBW, 15.6 +/- 10.3%). After a 2-week antidiabetic drug-free period, patients were started on glipizide therapy for 12 weeks. Glipizide dosages were titrated to achieve specified therapeutic goals or a maximum daily dose of 40 mg. Glipizide pharmacokinetics were assessed by serum concentrations obtained during a 24-h pharmacokinetic evaluation performed after the first 5-mg dose (SD) and after 12 weeks of chronic therapy (CD). Glipizide pharmacodynamics were evaluated with serum glucose, insulin, and C-peptide responses to Sustacal tolerance test done at baseline, after SD, and after CD. No statistically significant differences in the SD pharmacokinetic parameters (Tmax = 3.1 +/- 1.2 vs. 2.8 +/- 1.6 h; Cmax = 332.5 +/- 92.5 vs. 420.8 +/- 142 g/L; area under the curve extrapolated to infinity (AUCI) = 2,598.3 +/- 1,148 vs. 3,138.9 +/- 1,847 g/h/L; oral clearance/bioavailability (CL/F), 2.3 +/- 1.0 vs. 2.0 +/- 1.0 L/h; volume of distribution/bioavailability (V/F), 19.5 +/- 4.4 vs. 17.2 +/- 4.3 L; t1/2 = 5.0 +/- 2.3 vs. 5.2 +/- 2.0 h) were observed between the obese and nonobese groups, respectively. The pharmacokinetic parameters assessed under CD conditions were also closely matched in the two groups. No differences in glucose responses to Sustacal challenge at baseline, SD, and CD (AUC0-->4.glucose:baseline, 52.3 +/- 18.0 vs. 44.9 +/- 9.8; SD, 50.4 +/- 20.9 vs. 36.1 +/- 11.0; CD, 37.8 +/- 10.7 vs. 36.6 +/- 8.5 mM/h) were noted between the obese and nonobese groups, respectively. However, glucose concentrations increased more and decreased to a smaller extent after SD in the obese as compared to nonobese subjects. Mean fasting serum insulin and C-peptide concentrations were not statistically different between the two groups. However, obese subjects exhibited higher fasting insulin (114.0 +/- 69 vs. 68.8 +/- 52 pM) at week 12 evaluation and C-peptide concentrations (0.83 +/- 0.2 vs. 0.63 +/- 0.2 nM) after SD as compared to the nonobese group. A smaller percentage increase in C peptide in response to Sustacal challenge was observed in the obese compared to the nonobese subjects (baseline, 60 +/- 25 vs. 117 +/- 117; SD, 119 +/- 39 vs. 193 +/- 149; and CD, 97 +/- 56 vs. 163 +/- 67%). In summary, the influence of obesity on glipizide pharmacokinetics appeared to be of little clinical significance. The observed differences in pharmacodynamics require further evaluation. ----P Clinical_Trial Journal_Article ----M M_Biological_Availability_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Obesity_MeSH S_metabolism_MeSH Obesity_metabolism_MeSH M_Retrospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8842603 ----K I ----T A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. The Glimepiride Protocol #201 Study Group. ----A OBJECTIVE: To assess the efficacy, safety, and dose-response relationship of glimepiride in patients with NIDDM. RESEARCH DESIGN AND METHODS: After a 21-day placebo washout period, 304 patients were randomized to receive either placebo or glimepiride, 1, 4, or 8 mg once daily. Fasting plasma glucose (FPG), 2-h postprandial glucose (PPG), and HbA1c were measured at predetermined intervals during the washout period and the 14-week study. Adverse events were tabulated. RESULTS: At each patient visit, reduction from baseline FPG was greater in each glimepiride group than in the placebo group (P < 0.001). Changes from baseline to endpoint after 1, 4, and 8 mg glimepiride exceeded those after placebo (P < 0.001) by 2.4, 3.9, and 4.1 mmol/l, respectively, for FPG; by 1.2, 1.8, and 1.9 percentage points, respectively, for HbA1c; and by 3.5, 5.1, and 5.2 mmol/l, respectively, for 2-h PPG. Greater reductions in these parameters were observed with 8 and 4 mg than with 1 mg (P < 0.05), indicating a dose-response relationship. When patients with baseline HbA1c levels > or = 8% were assessed, more patients who received 8 mg glimepiride had HbA1c values < 8% at endpoint compared with patients receiving 4 mg. Glimepiride had a favorable safety profile. CONCLUSIONS: Glimepiride in 1-, 4-, or 8-mg doses was effective and well tolerated. Although the 4- and 8-mg once-daily doses were significantly more potent than the 1-mg dose, all three doses yielded clinical improvement. Because the 8-mg dose controlled HbA1c values in a greater number of patients with high baseline HbA1c levels than did the 4-mg dose, this higher dose might be beneficial for patients who are difficult to treat. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Postprandial_Period_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Refusal_MeSH ****** 8842604 ----K E ----T Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas. ----A OBJECTIVE: To investigate the acute effects of glibenclamide and glucagon-like peptide I (GLP-I) and their combination in perfused isolated rat pancreas and in patients with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: Rat islets were perfused with 10 nmol/l GLP-I in combination with 2 mumol/l glibenclamide. In human experiments, GLP-I (0.75 pmol. kg-1.min-1) was given as a continuous infusion during 240 min, while glibenclamide (3.5 mg) was administered orally. Eight patients participated in the study (age 57.6 +/- 2.7 years, BMI 28.7 +/- 1.5 kg/m2, mean +/- SE). In all subjects, blood glucose was first normalized by insulin infusion administered by an artificial pancreas (Biostator). RESULTS: GLP-I increased the insulinotropic effect of glibenclamide fourfold in the perfused rat pancreas. In human experiments, treatment with GLP-I alone and in combination with glibenclamide significantly decreased basal glucose levels (5.1 +/- 0.4 and 4.5 +/- 0.1 vs. 6.0 +/- 0.3 mmol/l, P < 0.01), while with only glibenclamide, glucose concentrations remained unchanged. GLP-I markedly decreased total integrated glucose response to the meal (353 +/- 60 vs. 724 +/- 91 mmol.l-1. min-1, area under the curve [AUC] [-30-180 min], P < 0.02), whereas glibenclamide had no effect (598 +/- 101 mmol.l-1. min-1, AUC [-30-180 min], NS). The combined treatment further enhanced the glucose lowering effect of GLP-I (138 +/- 24 mmol. l-1.min, AUC [-30-180 min], P < 0.001). GLP-I, glibenclamide, and combined treat-stimulated meal-induced insulin release as reflected by insulinogenic indexes (control 1.44 +/- 0.4; GLP-I 6.3 +/- 1.6, P < 0.01; glibenclamide 6.8 +/- 2.1, P < 0.01; combination 20.7 +/- 5.0, P < 0.001). GLP-I inhibited basal but not postprandial glucagon responses. Using paracetamol as a marker for gastric emptying rate of the test meal, treatment with GLP-I decreased gastric emptying at 180 min by approximately 50% compared with the control subjects (P < 0.01). CONCLUSIONS: In acute experiments on overweight patients with NIDDM, GLP-I exerted a marked antidiabetogenic action on the basal and postprandial state. The peptide stimulated insulin, suppressed basal glucagon release, and prolonged gastric emptying. The glucose-lowering effect of GLP-I was further enhanced by glibenclamide. This action may be at least partially accounted for by a synergistic effect of these two compounds on insulin release. Glibenclamide per se enhanced postprandial but not basal insulin release and exerted a less pronounced antidiabetogenic effect compared with GLP-I. ----P Clinical_Trial Journal_Article ----M M_Analysis_of_Variance_MeSH M_Animals_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Synergism_MeSH M_Drug_Therapy__Combination_MeSH M_Gastric_Emptying_MeSH S_drug_effects_MeSH Gastric_Emptying_drug_effects_MeSH M_Glucagon_MeSH S_pharmacokinetics_MeSH Glucagon_pharmacokinetics_MeSH S_pharmacology_MeSH Glucagon_pharmacology_MeSH S_therapeutic_use_MeSH Glucagon_therapeutic_use_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_In_Vitro_MeSH M_Infusions__Intravenous_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Middle_Aged_MeSH M_Peptide_Fragments_MeSH S_blood_MeSH Peptide_Fragments_blood_MeSH S_pharmacokinetics_MeSH Peptide_Fragments_pharmacokinetics_MeSH S_pharmacology_MeSH Peptide_Fragments_pharmacology_MeSH S_therapeutic_use_MeSH Peptide_Fragments_therapeutic_use_MeSH M_Perfusion_MeSH M_Protein_Precursors_MeSH S_pharmacokinetics_MeSH Protein_Precursors_pharmacokinetics_MeSH S_pharmacology_MeSH Protein_Precursors_pharmacology_MeSH S_therapeutic_use_MeSH Protein_Precursors_therapeutic_use_MeSH M_Rats_MeSH M_Rats__Sprague-Dawley_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Failure_MeSH ****** 8842609 ----K E ----T The effect of glipizide gastrointestinal therapeutic system on islet cell hormonal responses to a test meal in NIDDM. ----A OBJECTIVE: To determine whether the abnormal glucagon and amylin secretions in NIDDM are secondary to hyperglycemia and relative hypoinsulinemia. RESEARCH DESIGN AND METHODS: A total of 13 patients with NIDDM were studied before and after treatment with glipizide gastrointestinal therapeutic system (GITS) in a randomized double-blind placebo-controlled fashion. Of the 13 subjects, 9 were randomized to the glipizide GITS arm and 4 were randomized to the placebo arm of the study. Serum glucose, insulin, C-peptide, plasma glucagon, and plasma amylin concentrations were measured under fasting and postprandial (post-Sustacal ingestion) conditions. The Sustacal challenge was performed at baseline and after 12 weeks of treatment with either glipizide GITS or placebo. RESULTS: Glipizide GITS treatment resulted in a significant reduction in hyperglycemia and increases in insulin and C-peptide secretion. Hyperglucagonemia was not ameliorated, and amylin secretion was not altered after glipizide GITS treatment. Placebo-treated patients did not show significant changes in any of the parameters measured. CONCLUSIONS: Glipizide GITS treatment failed to ameliorate the hyperglucagonemia of NIDDM and did not alter amylin secretion even though it increased insulin secretion and significantly ameliorated the hyperglycemia. These observations suggest that NIDDM related abnormalities in some of the islet cell hormonal responses are the result of changes inherent in the islet cells and may be independent of hyperglycemia and relative hypoinsulinemia. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Amyloid_MeSH S_blood_MeSH Amyloid_blood_MeSH S_secretion_MeSH Amyloid_secretion_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH S_secretion_MeSH C-Peptide_secretion_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH P_Eating_MeSH M_Fasting_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH S_secretion_MeSH Glucagon_secretion_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Postprandial_Period_MeSH M_Single-Blind_Method_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8853933 ----K I ----T Pharmacokinetics of oral antihyperglycaemic agents in patients with renal insufficiency. ----A This paper reviews the effects of renal insufficiency on the pharmacokinetics of oral antidiabetic drugs. Of the 3 groups of drugs currently available for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), the sulphonylureas and metformin are, in general, well-tolerated and generally safe. In patients with chronic renal insufficiency, however, care must be exercised in the use of many of these drugs, as accumulation, either of the active drug or of active metabolites, can lead to serious adverse effects such as hypoglycaemia or, with metformin, lactic acidosis. The sulphonylurea drugs, to a greater or lesser degree, are metabolised in the liver to a variety of active or inactive compounds which, in general, are excreted by the kidneys. In addition, varying amounts of parent compound may depend on renal elimination. As a result, sulphonylurea drugs such as tolazamide, acetohexamide, chlorpropamide and glibenclamide (glyburide) are more likely to cause significant hypoglycaemia, as the metabolism of these drugs, compared with other commonly prescribed sulphonylureas, can lead to the accumulation of either the parent drug or the active metabolite in the presence of renal insufficiency. Tolbutamide, glipizide, gliclazide and gliquidone are much less likely to cause hypoglycaemia as their metabolites are either inactive or have minimal hypoglycaemic potency. Metformin is dependent on renal excretion and is not significantly metabolised. As a result, caution is required when treating patients with renal insufficiency where metformin accumulation can occur, with the danger of lactic acidosis. Although the correlation between creatinine clearance (CLCR) and total oral clearance of drug is weaker than the correlation between CLCR and renal clearance (CLR) of metformin, it is clear that renal insufficiency is associated with most cases of metformin-induced lactic acidosis. For this reason, clinicians in general would regard a raised plasma creatinine as a contraindication to metformin treatment. Acarbose, an alpha-glucosidase inhibitor, and a relatively new agent for treating NIDDM, is likely to be safe in patients with impaired renal function, as the drug is not significantly absorbed from the gut, but data on this subject are lacking. ----P Journal_Article Review Review__Tutorial ----M M_Acarbose_MeSH M_Administration__Oral_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Kidney_Failure_MeSH S_metabolism_MeSH Kidney_Failure_metabolism_MeSH M_Metformin_MeSH S_pharmacokinetics_MeSH Metformin_pharmacokinetics_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Trisaccharides_MeSH S_pharmacokinetics_MeSH Trisaccharides_pharmacokinetics_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 9162613 ----K E ----T Effect of combination therapy of troglitazone and sulphonylureas in patients with Type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. ----A The clinical efficacy of troglitazone, a new oral hypoglycaemic agent was investigated in Type 2 diabetes in combination with sulphonylureas. Two hundred and ninety-one patients with Type 2 diabetes (age 21-81 years) whose previous glycaemic control by sulphonylureas was judged stable but unsatisfactory (fasting plasma glucose (FPG) > 8.3 mmol I-1) were randomly allocated into the troglitazone treatment group (troglitazone group, n = 145) or the placebo treatment group (placebo group, n = 146). They were treated by test drugs for 12 weeks in combination with the same dose of sulphonylureas before the trial. One hundred and twenty-two patients who received troglitazone and 126 patients who received placebo were evaluated for efficacy. The baseline characteristics did not differ significantly between the two groups. In the troglitazone group, FPG and HbA(1c) decreased significantly after the treatment (before vs after, FPG: 10.8 +/- 2.0 mmol I(-1) vs 9.2 +/- 2.5 mmol I(-1), p< 0.001; HbA(1c): 9.2 +/- 1.4% vs 8.5 +/- 1.5%, p< 0.001). FPG and HbA(1c) did not change after the treatment in the placebo group (before vs after, FPG: 10.5 +/- 1.7 mmol I(-1) vs 10.7 +/- 2.2 mmol I(-1); HbA(1c): 9.0 +/- 1.5% vs 9.2 +/- 1.6 %). Serum total cholesterol and HDL-cholesterol did not change in either group, however, serum triglyceride significantly decreased in the troglitazone group. No serious adverse events occurred in either group. In conclusion, troglitazone 400 mg day(-1) had a significant hypoglycaemic effect in combination with sulphonylureas without any serious adverse events. Troglitazone, developed as an insulin action enhancer, can be a useful hypoglycaemic agent in the treatment of patients with Type 2 diabetes who are not well controlled by sulphonylureas alone. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Chromans_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Demography_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Treatment_Outcome_MeSH ****** 8866563 ----K E ----T Effect of troglitazone on insulin sensitivity and pancreatic beta-cell function in women at high risk for NIDDM. ----A We conducted a randomized placebo-controlled study to determine the effects of the thiazolidinedione compound troglitazone on whole-body insulin sensitivity (SI), pancreatic beta-cell function, and glucose tolerance in 42 Latino women with impaired glucose tolerance (IGT) and a history of gestational diabetes mellitus (GDM), characteristics that carry an 80% risk of developing NIDDM within 5 years. After baseline oral (OGTT) and intravenous (IVGTT) glucose tolerance testing, subjects were assigned to take placebo or 200 or 400 mg troglitazone daily for 12 weeks (14 subjects per treatment group). An OGTT and IVGTT were repeated during the 12th week of treatment. Five subjects failed to complete the trial for personal reasons, and medication compliance averaged 90% in the remaining subjects, none of whom experienced a serious adverse event. SI, calculated by minimal model analysis of IVGTT results, changed by only 4 +/- 14% during 12 weeks of placebo administration, but increased 40 +/- 22 and 88 +/- 22% above basal during treatment with 200 and 400 mg troglitazone, respectively (P = 0.01 among groups). Troglitazone administration was also associated with a dose-dependent reduction in the total insulin area during IVGTTs, which was highly significant (P < 0.001), and with a reduction during OGTTs, which approached statistical significance (P = 0.09). Glucose tolerance improved slightly in all groups, but the magnitude of change did not differ significantly among groups, whether it was assessed as the number of subjects who continued to manifest IGT at 12 weeks (P = 0.64 among groups), the change in total glucose area during OGTTs (P = 0.58), or the change in fractional glucose disappearance rates during IVGTTs (P = 0.28). Among the women who received troglitazone, the greatest improvement in SI occurred in the women who had the highest diastolic blood pressures and the best IVGTT insulin responses during baseline testing. Our findings indicate that troglitazone improved whole-body insulin sensitivity and lowered circulating insulin concentrations in women with prior GDM who are at very high risk for NIDDM. The lack of improvement in glucose tolerance despite improved insulin sensitivity may be a manifestation of the beta-cell defect that predisposes the women to NIDDM. The overall pattern of response to troglitazone in our high-risk patients indicates that the drug is an ideal agent with which to test whether the amelioration of insulin resistance can delay or prevent diabetes in women with limited beta-cell reserve. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Blood_Pressure_MeSH M_Body_Mass_Index_MeSH M_California_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH P_Diabetes__Gestational_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Glucose_Intolerance_MeSH S_blood_MeSH Glucose_Intolerance_blood_MeSH S_drug_therapy_MeSH Glucose_Intolerance_drug_therapy_MeSH S_physiopathology_MeSH Glucose_Intolerance_physiopathology_MeSH M_Glucose_Tolerance_Test_MeSH M_Hispanic_Americans_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Placebos_MeSH M_Pregnancy_MeSH M_Risk_Assessment_MeSH M_Risk_Factors_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Tolbutamide_MeSH S_diagnostic_use_MeSH Tolbutamide_diagnostic_use_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8874372 ----K 2 ----T The effect on metabolic control of second-generation sulfonylurea drugs in patients with NIDDM after secondary failure to first-generation agents. ----A BACKGROUND: The literature contains few data examining the results of therapy with second-generation sulfonylurea drugs in subjects with non-insulin-dependent diabetes mellitus (NIDDM) after the onset of secondary failure to first-generation agents. The present study was undertaken to assess the efficacy of therapy with second-generation sulfonylurea in subjects with NIDDM following secondary failure to first-generation agents. METHODS: The study included 55 subjects with NIDDM who manifested secondary failure to first-generation sulfonylurea therapy. Of these, 29 subjects underwent therapy with the second-generation sulfonylurea glipizide, and 26 subjects were treated with glyburide, both drugs administered in the maximum daily dosage. Before initiation of the second-generation sulfonylurea agents and again at the end of 6 months, metabolic control was assessed by determination of fasting plasma glucose, glycosylated hemoglobin (HbA1c), and the lipid profile. RESULTS: Fasting plasma glucose and HbA1c levels were 209 +/- 31 mg/dL and 12.3 +/- 2.1%, respectively, before initiation of glipizide, and did not significantly change following therapy (fasting plasma glucose, 211 +/- 34 mg/dL; HbA1c, 11.7 +/- 1.8%). Similarly, no significant alteration was noted in these metabolic values in the glyburide group (before glyburide therapy, fasting plasma glucose, 180 +/- 16 mg/dL; HbA1c, 11.2 +/- 1.6%; after glyburide therapy, fasting plasma glucose, 184 +/- 20 mg/dL; HbA1c, 11.0 +/- 1.5%). Lipids also were not significantly altered following therapy with either glipizide or glyburide. Finally, for all subjects, fasting plasma glucose and HbA1c were 200 +/- 27 mg/dL and 11.9 +/- 2.0%, respectively, during treatment with first-generation drugs and did not change significantly following therapy with the second-generation agents (fasting plasma glucose, 205 +/- 20 mg/dL; HbA1c, 11.2 +/- 1.2%). P values were > .60 for all comparisons. CONCLUSIONS: Treatment with second-generation sulfonylurea agents for patients with NIDDM following onset of secondary failure to first-generation sulfonylurea drugs achieves no better metabolic control than treatment with first-generation agents. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Treatment_Failure_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8875112 ----K E ----T Conference report: renal disease, metformin, and the adipocyte. ----A ----P Congresses ----M M_Adipocytes_MeSH S_cytology_MeSH Adipocytes_cytology_MeSH S_physiology_MeSH Adipocytes_physiology_MeSH M_Animals_MeSH P_Diabetes_Mellitus_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_I_physiopathology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diabetic_Nephropathies_MeSH S_physiopathology_MeSH Diabetic_Nephropathies_physiopathology_MeSH M_Glycosylation_MeSH M_Glycosylation_End_Products__Advanced_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Kidney_Failure__Chronic_MeSH S_physiopathology_MeSH Kidney_Failure__Chronic_physiopathology_MeSH M_Leptin_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Mice_MeSH M_Mice__Mutant_Strains_MeSH M_Mice__Obese_MeSH M_Obesity_MeSH S_physiopathology_MeSH Obesity_physiopathology_MeSH M_Proteins_MeSH S_biosynthesis_MeSH Proteins_biosynthesis_MeSH S_pharmacology_MeSH Proteins_pharmacology_MeSH ****** 8888072 ----K I ----T The influence of multiple dosing and age on the pharmacokinetics and pharmacodynamics of glipizide in patients with type II diabetes mellitus. ----A STUDY OBJECTIVES: To determine the pharmacokinetics and pharmacodynamics of glipizide after a single dose and 12 weeks of dosing in patients with type II diabetes mellitus, and evaluate the influence of aging. DESIGN: Comparison of single and multiple doses of glipizide. SETTING: University-affiliated outpatient internal medicine clinic and diabetes care unit. PATIENTS: Twenty patients (11 men, 9 women, mean age 55.2 +/- 9.9 yrs) with type II diabetes mellitus who were currently receiving oral hypoglycemic agents or were hyperglycemic with diet. INTERVENTIONS: A 24-hour pharmacokinetic evaluation of glipizide was assessed after a 5-mg dose at the start of therapy and after 12 weeks of therapy. Pharmacokinetic parameters were assessed using compartmental population analysis techniques. Glipizide pharmacodynamic evaluation was assessed by serum glucose, insulin, and C-peptide responses during a 4-hour Sustacal tolerance test performed at baseline before instituting glipizide therapy, with the first 5-mg dose, and at week 12 of therapy. Glipizide dosages were titrated to a targeted goal of fasting plasma glucose of 7.8 mmol/L or less or to reach maximum daily doses of 40 mg. MEASUREMENTS AND MAIN RESULTS: No significant differences in time to peak concentration, apparent volumes of distribution for the central and peripheral compartments, apparent oral clearance from the central compartment, distributional clearance between the central and peripheral compartments, or terminal elimination half-life were observed with a single dose and long-term dosing. The mean +/- SD terminal elimination half-lives were 9.67 +/- 5.6 and 9.35 +/- 4.6 hours after a single dose and 12 weeks, respectively. Fasting plasma glucose concentrations decreased from 12.3 +/- 3.6 mmol/L before the first dose of glipizide to 9.2 +/- 1.7 mmol/L after 12 weeks of treatment. The values for area under the serum concentration-time curve from zero to 4 hours for glucose (AUC0-4.glucose) were significantly reduced at week 12 (baseline 49.8 +/- 15.6, week 12 37.8 +/- 9.8 mmol/L/hr). Glipizide provoked an increase in serum insulin and C-peptide concentrations (AUC0-4.insulin: baseline 698 +/- 327, single dose 954 +/- 461, long-term dosing 945 +/- 600 pmol/L/hr). No significant change in insulin response was observed between single and multiple doses. No age-related differences in the pharmacokinetic parameters or the pharmacodynamic responses of glipizide were observed. CONCLUSIONS: Long-term dosing and aging have little effect on the pharmacokinetic profile of glipizide. In addition, glipizide stimulates insulin secretion to a similar extent following glucose challenge after a single dose and long-term administration. ----P Journal_Article ----M M_Adult_MeSH M_Age_Factors_MeSH M_Aged_MeSH M_Area_Under_Curve_MeSH M_Biological_Availability_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Metabolic_Clearance_Rate_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 8888075 ----K E ----T A review of the safety and efficacy of acarbose in diabetes mellitus. ----A Acarbose is a novel oral anti-hyperglycemic agent approved for the treatment of noninsulin-dependent diabetes mellitus. It inhibits alpha-glucosidases in the small intestine, an action that delays the digestion and absorption of complex carbohydrates. Subsequently, there is a smaller rise in the postprandial plasma glucose levels and an overall decrease in the glycosylated hemoglobin by 0.5-1.0%. Potential advantages of acarbose include a greater effectiveness in controlling postprandial hyperglycemia, a low risk of hypoglycemia, and a possible delay in initiating insulin therapy. Acarbose can potentiate the hypoglycemic effects of sulfonylureas or insulin. It has not been associated with weight gain and hyperinsulinemia, both of which can occur with sulfonylureas or insulin. Gastrointestinal adverse effects are common with acarbose, and may decrease with continued treatment. Although rare, elevated serum transaminase levels have been reported. ----P Journal_Article Review Review__Tutorial ----M M_Acarbose_MeSH M_Adult_MeSH M_Carbohydrate_Sequence_MeSH M_Child_MeSH M_Clinical_Trials_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus_MeSH S_drug_therapy_MeSH Diabetes_Mellitus_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Drug_Therapy__Combination_MeSH M_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Enzyme_Inhibitors_therapeutic_use_MeSH M_Gastrointestinal_Diseases_MeSH S_chemically_induced_MeSH Gastrointestinal_Diseases_chemically_induced_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Molecular_Sequence_Data_MeSH M_Trisaccharides_MeSH S_administration_&_dosage_MeSH Trisaccharides_administration_&_dosage_MeSH S_contraindications_MeSH Trisaccharides_contraindications_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 8895047 ----K E ----T The effect of a very low dose of tolbutamide combined with an alpha-glucosidase inhibitor in non-insulin-dependent diabetes mellitus. ----A The effect of adding a very low dose of a sulphonylurea (tolbutamide) to the treatment of 10 patients with noninsulin-dependent diabetes mellitus (NIDDM) was investigated. Patients took 0.1 mg tds of an alpha-glucosidase inhibitor orally for 8 weeks, and 50 mg tds of the sulphonylurea, tolbutamide, for the last 4 weeks of this period. The glycosylated haemoglobin level was significantly reduced during the combined treatment period compared with the level after treatment with alpha-glucosidase inhibitor alone (P = 0.035), although not compared with the pretreatment level. There were no significant changes in post-prandial blood glucose, serum lipid levels or connective peptide immunoreactivities. These preliminary results indicate that the addition of a very low dose of tolbutamide to a recommended diet and treatment with an alpha-glucosidase inhibitor, may improve glucose metabolism without raising insulin secretion or influencing lipid metabolism. ----P Clinical_Trial Journal_Article ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Connective_Tissue_MeSH S_metabolism_MeSH Connective_Tissue_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Enzyme_Inhibitors_MeSH S_administration_&_dosage_MeSH Enzyme_Inhibitors_administration_&_dosage_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Immunohistochemistry_MeSH M_Inositol_MeSH S_administration_&_dosage_MeSH Inositol_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Inositol_analogs_&_derivatives_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Middle_Aged_MeSH M_Peptides_MeSH S_metabolism_MeSH Peptides_metabolism_MeSH M_Tolbutamide_MeSH S_administration_&_dosage_MeSH Tolbutamide_administration_&_dosage_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 8908377 ----K 3 ----T Metformin's effects on glucose and lipid metabolism in patients with secondary failure to sulfonylureas. ----A OBJECTIVE: To compare results obtained with metformin versus those obtained with DNA-recombinant insulin in obese patients with NIDDM suffering from secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: We conducted an open, prospective, randomized, and comparative study comprising a total of 60 patients selected and placed in two parallel groups. We had previously confirmed that the subjects had secondary failure to high doses of sulfonylureas. The initial metformin dosage was a single 850 mg tablet, and the dosage was increased to two or three tablets depending on the patient's metabolic changes. The initial dosage of DNA-recombinant insulin was 24 U, subcutaneously administered and divided into two portions: two-thirds at around 8:00 A.M., before breakfast, and the remaining third at 8:00 P.M., before dinner. The dosage was adjusted based on the patient's clinical and metabolic response. RESULTS: The initial average glucose value for the metformin group was 269.1 +/- 32.2 mg/dl, decreasing by the end of the study to 159.7 +/- 30.5 mg/dl. For the insulin group, these figures went from 270.7 +/- 24.0 mg/dl at the beginning of the study to 134.8 +/- 26.7 mg/dl. This decrease correlates with the reduction in glycosylated hemoglobin from 12.8 to 8.9% for the first group and from 12.3 to 8.2% for the second, as well as with the reduction in triglyceride values from 230.3 to 183.1 mg/dl and from 218.4 to 186.3 mg/dl, respectively. The BMI (27.5-26.4), blood pressure (systolic from 145.7-132.1 mmHg, diastolic from 90.3-84.8 mmHg), and total cholesterol levels (235-202 mg/dl) decreased in only the metformin group. CONCLUSIONS: Metformin is an effective, safe, and well-tolerated treatment that improves metabolic control and favorably modifies secondary clinical alterations due to insulin resistance, such as arterial hypertension, overweight, and hyperlipidemia, in obese patients with NIDDM suffering from secondary failure to sulfonylureas. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_blood_MeSH Obesity_in_Diabetes_blood_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH M_Recombinant_Proteins_MeSH S_adverse_effects_MeSH Recombinant_Proteins_adverse_effects_MeSH S_therapeutic_use_MeSH Recombinant_Proteins_therapeutic_use_MeSH M_Regression_Analysis_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Treatment_Failure_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8908379 ----K I ----T Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Glimepiride Study Group. ----A OBJECTIVE: To compare the efficacy and safety of two daily doses of the new sulfonylurea, glimepiride (Amaryl), each as a once-daily dose or in two divided doses, in patients with NIDDM. RESEARCH DESIGN AND METHODS: Of the previously treated NIDDM patients, 416 entered this multicenter randomized double-blind placebo-controlled fixed-dose study. After a 3-week placebo washout, patients received a 14-week course of placebo or glimepiride 8 mg q.d., 4 mg b.i.d., 16 mg q.d., or 8 mg b.i.d. RESULTS: Fasting plasma glucose (FPG) and HbA1c values were similar at baseline in all treatment groups. The placebo group's FPG value increased from 13.0 mmol/l at baseline to 14.5 mmol/l at the last evaluation endpoint (P < or = 0.001). In contrast, FPG values in the four glimepiride groups decreased from a range of 12.4-12.9 mmol/l at baseline to a range of 8.6-9.8 mmol/l at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change [vs. placebo] from baseline). Two-hour postprandial plasma glucose (PPG) findings were consistent with FPG findings. In the placebo group, the HbA1c value increased from 7.7% at baseline to 9.7% at endpoint (P < or = 0.001), whereas HbA1c values for the glimepiride groups were 7.9-8.1% at baseline and 7.4-7.6% at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change from baseline). There were no meaningful differences in glycemic variables between daily doses of 8 and 16 mg or between once- and twice-daily dosing. Adverse events and laboratory data demonstrate that glimepiride has a favorable safety profile. CONCLUSIONS: Glimepiride is an effective and well-tolerated oral glucose-lowering agent. The results of this study demonstrate maximum effectiveness can be achieved with 8 mg q.d. of glimepiride in NIDDM subjects. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 8908409 ----K E ----T American Diabetes Association annual meeting 1996: the etiology of type II diabetes, obesity, and the treatment of type II diabetes. ----A ----P Congresses ----M M_Animals_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hypercholesterolemia_MeSH S_epidemiology_MeSH Hypercholesterolemia_epidemiology_MeSH M_Hypertension_MeSH S_epidemiology_MeSH Hypertension_epidemiology_MeSH M_Obesity_MeSH S_epidemiology_MeSH Obesity_epidemiology_MeSH S_etiology_MeSH Obesity_etiology_MeSH S_therapy_MeSH Obesity_therapy_MeSH M_Pregnancy_MeSH M_Pregnancy_in_Diabetics_MeSH M_Risk_Factors_MeSH M_Weight_Loss_MeSH ****** 8913408 ----K E ----T Acarbose: its role in the treatment of diabetes mellitus. ----A OBJECTIVES: To review the clinical pharmacology of acarbose, an alpha-glucosidase inhibitor, and to summarize its role in the pharmacotherapy of diabetes mellitus. DATA SOURCES: A MEDLINE search identified all relevant articles, including reviews; Bayer Pharmaceuticals. STUDY SELECTION: Due to the large number of clinical trials available, specific criteria were used to narrow the focus of this review: (1) randomized, double-blind, placebo-controlled, parallel-group study design; (2) a minimum of 25 patients enrolled per treatment arm; (3) a treatment duration of 90 days or more; and (4) adherence to Food and Drug Administration Good Clinical Practice guidelines. DATA EXTRACTION: All clinical trials that were available up to December 1995 were reviewed. Preliminary trials and unpublished reports were not reviewed. DATA SYNTHESIS: Acarbose is effective in reducing postprandial hyperglycemia. It does not stimulate endogenous insulin secretion and, therefore, will not cause hypoglycemia when used as monotherapy. The enhanced glycemic control achieved with acarbose is additive to that of sulfonylureas. It lowers postprandial serum glucose and insulin concentrations and does not promote weight gain. Acarbose can be used as first-line therapy with diet and exercise, or it can be used in combination with sulfonylureas to lower hemoglobin A1c concentrations an additional 0.5-0.9%. Acarbose is not a cure for diabetes, nor is it a substitute for diet, exercise, oral hypoglycemic agents, or insulin. Adverse effects are gastrointestinal and can be diminished by starting with an initial dosage of 25 mg tid. Depending on patient response, the dosage can be increased up to a maximum of 100 mg tid over time. CONCLUSIONS: Acarbose, through its unique mechanism of action, appears to be a safe and effective adjunctive agent to diet/exercise therapy or sulfonylurea therapy for treatment of non-insulin-dependent diabetes mellitus. ----P Journal_Article Review Review_Literature ----M M_Acarbose_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Randomized_Controlled_Trials_MeSH M_Trisaccharides_MeSH S_adverse_effects_MeSH Trisaccharides_adverse_effects_MeSH S_pharmacology_MeSH Trisaccharides_pharmacology_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 8941458 ----K E ----T Comparison of different insulin regimens in elderly patients with NIDDM. ----A OBJECTIVE: To compare the metabolic effects of three different frequently used regimens of insulin administration on blood glucose control and serum lipids, and the costs associated with this treatment, in subjects with NIDDM, who were poorly controlled with oral antihyperglycemic agents. RESEARCH DESIGN AND METHODS: We studied 95 elderly patients with NIDDM (age 68 +/- 9 years, BMI 26.0 +/- 4.6 kg/m2, and median time since diagnosis of diabetes 9 years [range 1-37]; 37 men, 58 women), who were poorly controlled, despite diet and maximal doses of oral antihyperglycemic agents. Three insulin administration regimens were compared during a 6-month period: patients were randomized for treatment with a two-injection scheme (regimen A) or a combination of glibenclamide with one injection of NPH insulin, administered either at bedtime (regimen B) or before breakfast (regimen C), and insulin treatment was mainly instituted in an outpatient setting. RESULTS: After 6 months of insulin treatment, fasting blood glucose of the total patient population had decreased from an average of 14.1 +/- 2.2 to 8.3 +/- 2.0 mmol/L (P < 0.001), and HbA1c fell from 11.0 +/- 1.3 to 8.3 +/- 1.2% (P < 0.001); 34 patients reached HbA1c levels below 8.0%, 25 of them even below 7.5%. With two insulin injections daily, HbA1c decreased from 11.2 +/- 1.3 to 8.2 +/- 1.2%, while during combined treatment, HbA1c fell from 10.5 +/- 1.2 to 8.1 +/- 1.1% (regimen B) and from 11.1 +/- 1.3 to 8.5 +/- 1.1% (regimen C). Comparable improvement of the other measures of glycemic control, lipids and lipoproteins, was observed in the different treatment regimens. Body weight increase was moderate (mean +/- 4.0 kg) and similar in all patient groups. One-third of patients starting with one insulin injection daily needed a second injection to control glycemia. One episode of severe hypoglycemia was observed. Combined insulin-sulfonylurea treatment was almost 20% more expensive than twice-daily administration of insulin alone. CONCLUSIONS: Insulin treatment can safely be instituted in elderly patients with NIDDM. However, it is difficult to obtain optimal glycemic control. Insulin has moderate beneficial effects on serum lipoproteins. Although on the basis of glycemic control and weight gain, no preference for any treatment regimen can be discerned, twice-daily insulin administration is the most simple and cost-effective regimen. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Apolipoprotein_A-I_MeSH S_blood_MeSH Apolipoprotein_A-I_blood_MeSH M_Apolipoproteins_B_MeSH S_blood_MeSH Apolipoproteins_B_blood_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Costs_and_Cost_Analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH M_Drug_Administration_Schedule_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Fructosamine_MeSH S_blood_MeSH Fructosamine_blood_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_economics_MeSH Insulin_economics_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Lipoprotein(a)_MeSH S_blood_MeSH Lipoprotein(a)_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Male_MeSH M_Netherlands_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 8944206 ----K E ----T New treatments for patients with type 2 diabetes mellitus. ----A In subjects with type 2 diabetes, both defects of insulin secretion and insulin resistance contribute to the development of hyperglycaemia. The major goals of treatment are to optimise blood glucose control, and normalise the associated lipid disturbances and elevated blood pressure. Pharmacologic treatment is often necessary. This paper discusses new forms of oral treatment for subjects with type 2 diabetes. These include a new sulphonylurea compound glimepiride (Amaryl), which binds to a different protein of the putative sulphonylurea receptor than glibenclamide, and seems to have a lower risk of hypoglycaemia. A new class of drugs with insulin secretory capacity, of which repaglinide (NovoNorm) is the leading compound, is now in phase III clinical trials. Alpha-glucosidase inhibitors reversibly inhibit alpha-glucosidase enzymes in the small intestine, which delays cleavage of oligo- and disaccharides to monosaccharides. This leads to a delayed and reduced blood glucose rise after a meal. Two compounds are in development or have been marketed, ie, miglitol and acarbose (Glucobay). Another new class of drugs is the thiazolidine-diones, which seem to work by enhancing insulin action. The 'insulin sensitising' effects of the leading compounds, troglitazone and BRL 49653C, do not involve any effect on insulin secretion. These drugs also seem to beneficially influence serum cholesterol and triglyceride levels. Oral antihyperglycaemic agents can be used only during a limited period of time in most patients, after which the diabetic state 'worsens' and insulin therapy has to be started. In this light, two new forms of treatment which require subcutaneous injections are also discussed: the synthetic human amylin analogue AC137 (pramlintide) and glucagon-like peptide-1 (7-36)-amide, a strong glucose-dependent stimulator of insulin secretion. It remains to be seen whether these compounds can be developed further for clinical use in patients with diabetes. ----P Journal_Article Review Review__Tutorial ----M M_Amyloid_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Glucagon_MeSH S_therapeutic_use_MeSH Glucagon_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Insulin_Resistance_MeSH M_Peptide_Fragments_MeSH S_therapeutic_use_MeSH Peptide_Fragments_therapeutic_use_MeSH M_Protein_Precursors_MeSH S_therapeutic_use_MeSH Protein_Precursors_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 8949976 ----K I ----T The UK Prospective Diabetes Study. UK Prospective Diabetes Study Group. ----A The Diabetes Control and Complications Study has shown that improved blood glucose control would delay the progress of microvascular complications of diabetes. However, in patients with non-insulin-dependent diabetes mellitus, the major morbidity and mortality arises from premature cardiovascular disease. It is uncertain whether therapy aimed to improve diabetes control will prevent cardiovascular complications, and whether the available therapies, sulphonylurea, biguanides or insulin, may even have long-term deleterious side-effects. The UK Prospective Diabetes Study started in 1977 and is evaluating whether long-term therapy to improve glucose control would be advantageous in clinical practice. The study has demonstrated that it is difficult to maintain improved glucose control because of the progressive beta-cell dysfunction. The study is also evaluating whether improved control of hypertension would be advantageous. The progress of the study is summarized. The results are expected to be published in 1998. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Cardiovascular_Diseases_MeSH S_epidemiology_MeSH Cardiovascular_Diseases_epidemiology_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_epidemiology_MeSH Diabetic_Angiopathies_epidemiology_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Great_Britain_MeSH S_epidemiology_MeSH Great_Britain_epidemiology_MeSH M_Human_MeSH M_Hypertension_MeSH S_complications_MeSH Hypertension_complications_MeSH M_Hypoglycemia_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_metabolism_MeSH Islets_of_Langerhans_metabolism_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_MeSH S_complications_MeSH Obesity_complications_MeSH M_Prospective_Studies_MeSH M_Quality_of_Life_MeSH M_Risk_Factors_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Weight_Gain_MeSH ****** 8960852 ----K I ----T Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment. ----A The pharmacokinetics, efficacy and safety of glimepiride were investigated in a single- and a multiple-dose open study in patients with non-insulin-dependent diabetes mellitus and renal impairment and an initial creatinine clearance above 10 ml/ min. Patients were divided into three groups with creatinine clearance above 50 ml/min, 20-50 ml/min and under 20 ml/min. Fifteen fasting patients received a single dose of 3 mg glimepiride and serial blood and urine samples were taken over 24 h for pharmacokinetic and efficacy analyses. A further 16 patients received glimepiride over a 3-month period, an initial dose of 1 mg glimepiride being adjusted within the range 1 to 8 mg to achieve good glucose control. Pharmacokinetic evaluation was done on day 1 and after 3 months. Mean relative total clearance and mean volume of distribution of both single (41.6 ml/ min and 8.47 litres, respectively, when creatinine clearance was above 50 ml/min) and multiple doses of glimepiride increased in proportion to the degree of renal impairment (to 91.1 ml/min and 14.98 litres, respectively, when creatinine clearance was below 20 ml/min, single dose), whereas the terminal halflife and mean time remained unchanged. Lower relative total clearance and renal clearance of both glimepiride metabolites correlated significantly with lower creatinine clearance values. Of the 16 patients 12 required between 1 and 4 mg glimepiride to stabilize their fasting blood glucose. Glimepiride was well-tolerated and there were no drug-related adverse events. In conclusion glimepiride is safe, effective and has clearly-definable pharmacokinetics in diabetic patients with renal impairment. The increased plasma elimination of glimepiride with decreasing kidney function is explainable on the basis of altered protein binding with an increase in unbound drug. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Cohort_Studies_MeSH M_Comparative_Study_MeSH M_Creatinine_MeSH S_metabolism_MeSH Creatinine_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Diabetic_Nephropathies_MeSH S_blood_MeSH Diabetic_Nephropathies_blood_MeSH S_metabolism_MeSH Diabetic_Nephropathies_metabolism_MeSH M_Female_MeSH M_Half-Life_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Kidney_MeSH S_drug_effects_MeSH Kidney_drug_effects_MeSH S_metabolism_MeSH Kidney_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Regression_Analysis_MeSH M_Safety_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 8960854 ----K I ----T NIDDM: a rapid progressive disease. Results from a long-term, randomised, comparative study of insulin or sulphonylurea treatment. ----A The objective of the present study was to assess the relative efficacy of insulin or glibenclamide treatment for non-insulin-dependent diabetes mellitus (NIDDM) over 42 months. We performed a randomised, controlled trial allocating patients treated with diet and oral antihyperglycaemic agents to treatment with glibenclamide or insulin to achieve HbAlc levels under 7.5%. We included 36 subjects with established NIDDM of more than 2 years' duration. Mean HbAlc levels were significantly reduced in patients allocated to insulin treatment from 9.1 +/- 1.4% before the start to 7.8 +/- 1.3% (p < 0.05) after 1 year, and did not change significantly thereafter throughout the study period. Mean HbAlc levels increased during the study in the patients allocated to glibenclamide treatment, and 11 of 18 patients had to be switched to insulin treatment due to increasing hyperglycaemia (HbAlc > 10%). Mean body weight increased in the subjects allocated to insulin by 7.2 +/- 4.1 kg during the study period. In conclusion, insulin was more effective than glibenclamide treatment in obtaining control over hyperglycaemia in these patients, and once improved, glycaemic control did not deteriorate over 42 months in the insulin-treated group. Two thirds of the patients allocated to glibenclamide treatment had to be given insulin due to inadequate glycaemic control. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 9026680 ----K 2 ----T [Comparative study of the efficiency of ultralente insulin and NPH insulin combined with sulfonylurea in type 2 diabetes patients with secondary tolerance to sulfonylurea. Possible selection criteria] ----A The treatment of NIDDM patients with secondary failure to sulfonylureas is still a debated problem. In this study we compared in NIDDM patients with secondary failure to glyburide, the effect of adding a single, low-dose bed time either NPH or ultralent insulin injection (0.15-0.2 U/kg) to the previously ineffective sulfonylurea treatment. Both NPH and ultralent insulin therapy have been demonstrated to be effective in ameliorating metabolic control in NIDDM patients with secondary failure to sulfonylureas. However, the addition of bed-time ultralent insulin caused a greater and significant decrease in post prandial plasma glucose. In contrast, the average fasting plasma glucose decrease was significantly greater after NPH insulin administration. These results indicate that in NIDDM patients with secondary failure to glyburide bed-time ultralent insulin administration is a better tool to improve the post prandial plasma glucose. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_C-Peptide_MeSH S_analysis_MeSH C-Peptide_analysis_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Drug_Tolerance_MeSH M_Eating_MeSH M_English_Abstract_MeSH M_Fasting_MeSH S_blood_MeSH Fasting_blood_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin__Isophane_MeSH S_administration_&_dosage_MeSH Insulin__Isophane_administration_&_dosage_MeSH S_pharmacology_MeSH Insulin__Isophane_pharmacology_MeSH M_Insulin__Lente_MeSH S_administration_&_dosage_MeSH Insulin__Lente_administration_&_dosage_MeSH S_pharmacology_MeSH Insulin__Lente_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Treatment_Outcome_MeSH ****** 9024742 ----K E ----T Blockade of K(ATP) channels with glibenclamide does not abolish preconditioning during demand ischemia. ----A The role of adenosine triphosphate-sensitive potassium channels in the adaptive response to demand ischemia was tested in 22 patients treated with placebo or glibenclamide before sequential exercise testing or atrial pacing. Glibenclamide did not affect the improvement in signs of ischemia in both protocols, indicating that opening of these channels is not a mechanism of this adaptive response in humans. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adaptation__Physiological_MeSH M_Adenosine_Triphosphate_MeSH S_pharmacology_MeSH Adenosine_Triphosphate_pharmacology_MeSH M_Aged_MeSH M_Cardiac_Pacing__Artificial_MeSH M_Double-Blind_Method_MeSH M_Electrocardiography_MeSH M_Exercise_Test_MeSH M_Female_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Myocardial_Ischemia_MeSH S_physiopathology_MeSH Myocardial_Ischemia_physiopathology_MeSH M_Potassium_Channels_MeSH S_drug_effects_MeSH Potassium_Channels_drug_effects_MeSH S_physiology_MeSH Potassium_Channels_physiology_MeSH ****** 9055142 ----K E ----T Eprosartan, an angiotensin II receptor antagonist, does not affect the pharmacodynamics of glyburide in patients with type II diabetes mellitus. ----A The potential for eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, to affect the 24-hour plasma glucose profiles in type II diabetic patients treated with glyburide was investigated in this randomized, placebo-controlled, double-blind (eprosartan-placebo phase only), two-period, period-balanced, crossover study. All patients received a stable oral dose (3.75-10 mg/day) of glyburide for at least 30 days before the first dose of double-blind study medication was administered. Patients were randomized to receive either 200-mg oral doses of eprosartan twice daily or matching oral placebo doses concomitantly with glyburide for 7 days during each treatment period. After a minimum washout period of 14 days, patients were crossed over to the alternate treatment. Serial samples to measure glucose concentrations in plasma were collected over a 24-hour period on the day before administration of eprosartan or placebo and again on day 7. Mean glucose concentrations were comparable between treatment groups before administration of eprosartan or placebo. The point estimate (90% confidence interval) for the ratio of the average mean 24-hour plasma glucose concentrations of eprosartan + glyburide to placebo + glyburide after 7 days of administration was 0.96 (0.90, 1.01). Eprosartan did not significantly alter the 24-hour plasma glucose profile in patients with type II diabetes mellitus who were previously stabilized on glyburide. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acrylates_MeSH S_adverse_effects_MeSH Acrylates_adverse_effects_MeSH S_pharmacology_MeSH Acrylates_pharmacology_MeSH M_Antihypertensive_Agents_MeSH S_adverse_effects_MeSH Antihypertensive_Agents_adverse_effects_MeSH S_pharmacology_MeSH Antihypertensive_Agents_pharmacology_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Double-Blind_Method_MeSH M_Drug_Interactions_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Imidazoles_MeSH S_adverse_effects_MeSH Imidazoles_adverse_effects_MeSH S_pharmacology_MeSH Imidazoles_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Receptors__Angiotensin_MeSH S_antagonists_&_inhibitors_MeSH Receptors__Angiotensin_antagonists_&_inhibitors_MeSH M_Support__Non-U_S__Gov't_MeSH M_Sweating_MeSH ****** 9059766 ----K E ----T Short-term effects of continuous subcutaneous insulin infusion treatment on insulin secretion in non-insulin-dependent overweight patients with poor glycaemic control despite maximal oral anti-diabetic treatment. ----A It is difficult to treat obese non-insulin-dependent diabetic patients (NIDDs) whose glycaemic control remains poor despite maximal oral antidiabetic therapy. We studied the effect of a continuous subcutaneous insulin infusion (CSII) associated with a low-calorie diet and metformin 1,700 mg/day on glycaemic control and basal and stimulated insulin secretion in a series of 82 overweight NIDD before (T1), during CSII (T2), and after CSII withdrawal (T3). Patients were treated for 8 to 23 days with a mean amount of 0.50 +/- 0.02 IU/kg/day. Glycaemic control was very good after 3-5 days of CSII and remained good at T3. At T2, fasting and postprandial plasma C peptide levels decreased significantly. At T3, fasting C peptide was very similar to T1, and postprandial C peptide was significantly higher than at T1. The molar fasting and postprandial plasma C peptide/glycaemia ratios increased significantly at T3. After glucagon injection, the molar delta C peptide/glycaemia ratio was significantly increased at T2 and even higher at T3. At T2, as at T1 and T3, there were significant correlations between fasting and postprandial C peptide levels and between the glucagon-induced C peptide peak and fasting and postprandial C peptide levels. Between T1 and T3 weight changes correlated significantly with the molar fasting C peptide/glycaemia ratio at T1. Twenty-nine of the 30 patients for whom this ratio was > 6.6 x 10(-8) lost weight. The length of CSII treatment did not correlate with weight changes or other biological parameters. This study shows that CSII with moderate amounts of insulin associated with a low-calorie diet and metformin provided rapid glycaemic control, led to weight loss, maintained regulation of insulin secretion and seemed to improve insulin secretion and sensitivity. These results were obtained in only 8 to 10 days. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Administration__Cutaneous_MeSH M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Human_MeSH M_Infusions__Parenteral_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_physiopathology_MeSH Obesity_in_Diabetes_physiopathology_MeSH M_Secretory_Rate_MeSH S_drug_effects_MeSH Secretory_Rate_drug_effects_MeSH M_Time_Factors_MeSH ****** 9068933 ----K E ----T A study of the potential effect of sertraline on the pharmacokinetics and protein binding of tolbutamide. ----A The effect of the selective serotonin reuptake inhibitor (SSRI) sertraline 200 mg/day on the metabolism of intravenously administered tolbutamide was examined in a randomised nonblinded parallel-group study in 25 healthy male volunteers. There was a small but statistically significant decrease (16%) in the clearance of tolbutamide in patients receiving the maximum recommended dosage of sertraline. The terminal elimination rate constant was also significantly reduced, corresponding to the increase in the terminal elimination half-life (from 6.9 to 8.6 hours). The decrease in clearance was not associated with any significant changes in plasma protein binding or in the apparent volume of distribution of tolbutamide. This suggests that the change in tolbutamide clearance may be due to a slight inhibition of the cytochrome P450 (CYP) isoenzyme CYP2C9/10 when sertraline was administered in its maximum recommended dosage. However, the small changes in the volume of distribution and plasma binding of tolbutamide after sertraline treatment indicate that there is a minimal interaction between sertraline and tolbutamide. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_1-Naphthylamine_MeSH S_analogs_&_derivatives_MeSH 1-Naphthylamine_analogs_&_derivatives_MeSH S_pharmacology_MeSH 1-Naphthylamine_pharmacology_MeSH M_Adolescent_MeSH M_Adult_MeSH M_Antidepressive_Agents_MeSH S_pharmacology_MeSH Antidepressive_Agents_pharmacology_MeSH P_Aryl_Hydrocarbon_Hydroxylases_MeSH M_Blood_Proteins_MeSH S_metabolism_MeSH Blood_Proteins_metabolism_MeSH M_Cytochrome_P-450_Enzyme_System_MeSH S_antagonists_&_inhibitors_MeSH Cytochrome_P-450_Enzyme_System_antagonists_&_inhibitors_MeSH M_Drug_Synergism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Male_MeSH M_Mixed_Function_Oxygenases_MeSH S_antagonists_&_inhibitors_MeSH Mixed_Function_Oxygenases_antagonists_&_inhibitors_MeSH M_Protein_Binding_MeSH M_Serotonin_Uptake_Inhibitors_MeSH S_pharmacology_MeSH Serotonin_Uptake_Inhibitors_pharmacology_MeSH M_Sertraline_MeSH P_Steroid_16-alpha-Hydroxylase_MeSH M_Steroid_Hydroxylases_MeSH S_antagonists_&_inhibitors_MeSH Steroid_Hydroxylases_antagonists_&_inhibitors_MeSH M_Tolbutamide_MeSH S_blood_MeSH Tolbutamide_blood_MeSH S_metabolism_MeSH Tolbutamide_metabolism_MeSH S_pharmacokinetics_MeSH Tolbutamide_pharmacokinetics_MeSH ****** 9069587 ----K 5 ----T Increased complications in noninsulin-dependent diabetic patients treated with insulin versus oral hypoglycemic agents: a population study. ----A A cross-sectional population study was performed in a cohort of 890 non-insulin-dependent diabetes mellitus (NIDDM) patients residing in the greater Denver metropolitan region. Its purpose was to evaluate the relationship between insulin and oral hypoglycemic agents (OHAs) with regard to metabolic control and diabetic complications. The mean glycosylated hemoglobin for patients treated with insulin was 12.0 +/- 0.15% versus 11.4 +/- 0.14% (p < .03) for OHA. The difference in fasting blood sugar for the insulin-treated group (195.0 +/- 3.5 mg/dl) versus the OHA-treated group (194.0 +/- 2.9 mg/dl) was not statistically significant. Categorical increases in urinary albumin excretion were associated positively within insulin versus OHA therapy (p < .0001). Patients treated with insulin therapy had a higher frequency of peripheral vascular disease (insulin therapy, 14%; OHA therapy, 10%; p < .05); neuropathy (insulin therapy, 55%; OHA therapy, 37%; p < .0001); and retinopathy (insulin therapy, 71%; OHA therapy, 45%; p < .0001). The frequency of cardiovascular disease was equivalent in the two groups (17% versus 13%). In protocols correcting for diabetes duration, glycosylated hemoglobin, and gender in a multivariate model, the use of insulin still was related significantly to increases in urinary albumin excretion (p < .01), retinopathy (p < .0001), and neuropathy (p < .0008). In a subgroup of individuals with diabetes duration > 10 years (n = 211 for insulin treatment, n = 118 for OHA treatment), the frequency of neuropathy still was significantly higher in the insulin group (63% vs 49%; p < .016) as was retinopathy (85% vs 58%; p < .0001). Overt albuminuria also was more significant in the insulin-treated patients (p < .04). In summary, the NIDDM patients treated with insulin had more nephropathy, retinopathy, and neuropathy than did NIDDM patients treated with OHA, independent of duration of diabetes, fasting blood glucose, glycosylated hemoglobin, age, and blood pressure level. These results in NIDDM patients may be due to contributions from worse blood glucose control at an earlier stage in the patients' diabetes and/or the mitogenic, atherogenic, thrombogenic, and vascular permeability effects of insulin. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Albuminuria_MeSH S_etiology_MeSH Albuminuria_etiology_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cohort_Studies_MeSH M_Comparative_Study_MeSH M_Cross-Sectional_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_etiology_MeSH Diabetic_Angiopathies_etiology_MeSH M_Diabetic_Nephropathies_MeSH S_etiology_MeSH Diabetic_Nephropathies_etiology_MeSH M_Diabetic_Neuropathies_MeSH S_etiology_MeSH Diabetic_Neuropathies_etiology_MeSH M_Diabetic_Retinopathy_MeSH S_etiology_MeSH Diabetic_Retinopathy_etiology_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 9069698 ----K E ----T Drug interaction: rifampicin and glibenclamide. ----A BACKGROUND: Rifampicin is a potent inducer of the hepatic microsomal enzyme system. However, the drug has been shown to cause clinically important interactions with many drugs. This study was designed to test the interaction of rifampicin with the oral hypoglycaemic agent glibenclamide. METHODS: Twenty-nine well-controlled diabetic patients on a combination therapy of diet and glibenclamide, and willing to participate in the trial, received a daily dose of 450 mg (body weight < 50 kg) or 600 mg (body-weight > 50kg) of rifampicin for 10 days. RESULTS: There was a significant (p < 0.001) worsening of fasting and post-prandial blood sugar after administration of rifampicin. Dose modification of glibenclamide was required in 15 of the 17 patients in whom the diabetes became uncontrolled. Blood sugar normalized by day 6 after stopping rifampicin in all patients. CONCLUSION: Rifampicin and glibenclamide interact. Therefore, necessary dose modifications should be made in order to achieve euglycaemia if these two drugs are given together. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Antibiotics__Antitubercular_MeSH S_administration_&_dosage_MeSH Antibiotics__Antitubercular_administration_&_dosage_MeSH S_pharmacology_MeSH Antibiotics__Antitubercular_pharmacology_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Rifampin_MeSH S_administration_&_dosage_MeSH Rifampin_administration_&_dosage_MeSH S_pharmacology_MeSH Rifampin_pharmacology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9075819 ----K E ----T Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation. ----A One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT), a tolbutamide modified frequently sampled intravenous glucose tolerance test, and a glucagon test to examine for a possible early beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues. ----P Journal_Article ----M M_Adolescent_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Mutation_MeSH S_genetics_MeSH Mutation_genetics_MeSH M_Pedigree_MeSH M_Support__Non-U_S__Gov't_MeSH M_Tolbutamide_MeSH S_pharmacology_MeSH Tolbutamide_pharmacology_MeSH M_Transcription_Factors_MeSH S_genetics_MeSH Transcription_Factors_genetics_MeSH ****** 9096964 ----K 2 ----T Sulfonylurea treatment prevents recurrence of hyperglycemia in obese African-American patients with a history of hyperglycemic crises. ----A OBJECTIVE: Many newly diagnosed obese African-American patients with history of severe hyperglycemia or diabetic ketoacidosis (DKA) are able to discontinue pharmacological treatment with continued good metabolic control. However, many of these individuals relapse into hyperglycemia within 1 year. In such patients, we compared the effect of low-dose sulfonylurea and dietary therapy in the prevention of recurrence of hyperglycemia. RESEARCH DESIGN AND METHODS: We conducted an intention-to-treat study in 35 obese newly diagnosed diabetic patients (17 with DKA and 18 with severe hyperglycemia). After discontinuation of insulin, seven of 17 patients with DKA and seven of 18 patients with hyperglycemia were managed with diet and glyburide (1.25-2.5 mg/day), whereas other patients were followed with diet alone. In all patients, pancreatic insulin reserve was documented 1 day after resolution of hyperglycemic crises and within 1 week of discontinuation of insulin. Recurrence of hyperglycemia was defined as fasting blood glucose > 7.8 mmol/l (140 mg/dl) or random blood glucose > 10 mmol/l (180 mg/dl) on two or more consecutive determinations, or HbA1c > 7.5%. RESULTS: Both treatment groups were comparable in age, sex, duration of diabetes, months of insulin therapy, BMI, glucose, and HbA1c. At presentation, the acute C-peptide response to glucagon in obese DKA patients was lower than in patients with hyperglycemia (P < 0.01), but responses were comparable after discontinuation of insulin. Sulfonylurea treatment significantly reduced recurrence of hyperglycemia in both obese DKA and obese hyperglycemic patients (P = 0.03). With a median follow-up of 16 months, hyperglycemia recurred in six of 10 DKA patients and in five of 11 hyperglycemia patients treated with diet alone, compared with one of seven DKA and one of seven hyperglycemia patients treated with glyburide. Readmission with metabolic decompensation occurred in four patients treated with diet but in none of the patients treated with diet and glyburide. CONCLUSIONS: Low-dose sulfonylurea therapy prevents recurrence of hyperglycemia in newly diagnosed obese African-American patients with a history of hyperglycemic crises. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH P_African_Americans_MeSH M_African_Continental_Ancestry_Group_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Combined_Modality_Therapy_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH P_Diabetic_Diet_MeSH M_Diabetic_Ketoacidosis_MeSH S_drug_therapy_MeSH Diabetic_Ketoacidosis_drug_therapy_MeSH S_prevention_&_control_MeSH Diabetic_Ketoacidosis_prevention_&_control_MeSH M_Female_MeSH M_Georgia_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_prevention_&_control_MeSH Hyperglycemia_prevention_&_control_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_diet_therapy_MeSH Obesity_in_Diabetes_diet_therapy_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH M_Recurrence_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9096986 ----K I ----T Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Results of two multicenter, randomized, placebo-controlled clinical trials. The Glipizide Gastrointestinal Therapeutic System Study Group. ----A OBJECTIVE: To investigate the efficacy, safety, and dose-response characteristics of an extended-release preparation of glipizide using the gastrointestinal therapeutic system (GITS) on plasma glucose, glycosylated hemoglobin (HbA1c), and insulin secretion to a liquid-mixed meal in NIDDM patients. RESEARCH DESIGN AND METHODS: Two prospective, randomized, double-blind, placebo-controlled, multicenter clinical trials were performed in 22 sites and 347 patients with NIDDM (aged 59 +/- 0.6 years; BMI, 29 +/- 0.3 kg/m2; known diabetes duration, 8 +/- 0.4 years) were studied. Each clinical trial had a duration of 16 weeks with a 1-week washout, 3-week single-blind placebo phase, 4-week titration to a fixed dose, and 8-week maintenance phase at the assigned dose. In the first trial, once-daily doses of 5, 20, 40, or 60 mg glipizide GITS were compared with placebo in 143 patients. In the second trial, doses of 5, 10, 15, or 20 mg of glipizide GITS were compared with placebo in 204 patients. HbA1c, fasting plasma glucose (FPG), insulin, C-peptide, and glipizide levels were determined at regular intervals throughout the study. Postprandial plasma glucose (PPG), insulin, and C-peptide also were determined at 1 and 2 h after a mixed meal (Sustacal). RESULTS: All doses of glipizide GITS in both trials produced significant reductions from placebo in FPG (range -57 to -74 mg/dl) and HbA1c (range -1.50 to -1.82%). Pharmacodynamic analysis indicated a significant relationship between plasma glipizide concentration and reduction in FPG and HbA1c over a dose range of 5-60 mg, with maximal efficacy achieved at a dose of 20 mg for FPG and at 5 mg for HbA1c. PPG levels were significantly lower, and both postprandial insulin and C-peptide levels significantly higher in patients treated with glipizide GITS compared with placebo. The percent reduction in FPG was comparable across patients with diverse demographic and clinical characteristics, including those with entry FPG > or = 250 mg/dl, resulting in greater absolute decreases in FPG and HbA1c in patients with the most severe hyperglycemia. Despite the forced titration to a randomly assigned dose, only 11 patients in both studies discontinued therapy because of hypoglycemia. Glipizide GITS did not alter lipids levels or produce weight gain. CONCLUSIONS: The once-daily glipizide GITS 1) lowered HbA1c, FPG, and PPG over a dose range of 5-60 mg, 2) was maximally effective at 5 mg (using HbA1c) or 20 mg (using FPG) based on pharmacokinetic and pharmacodynamic relationships, 3) maintained its effectiveness in poorly controlled patients (those with entry FPG > or = 250 mg/dl), 4) was safe and well tolerated in a wide variety of patients with NIDDM, and 5) did not produce weight gain or adversely affect lipids. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Delayed-Action_Preparations_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Digestive_System_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Fasting_MeSH M_Female_MeSH M_Glipizide_MeSH S_adverse_effects_MeSH Glipizide_adverse_effects_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Single-Blind_Method_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 9105542 ----K 2 ----T Duration of action and pharmacokinetics of the oral antidiabetic drug gliquidone in patients with non-insulin-dependent (type 2) diabetes mellitus. ----A The duration of action and the pharmacokinetics of gliquidone (1-cyclohexyl-3-[[4-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2(1H)-isochinolyl)ethyl]phenyl]-sulfonyl]-urea, AR-DF 26 SE, CAS 33342-05-1, Glurenorm, Beglynor) were investigated in 32 patients with non-insulin-dependent (type 2) diabetes mellitus over 16 h. In a single-blinded cross-over design vs. placebo, one 30 mg tablet gliquidone was administered 15 min before breakfast. Concomitant to the measurement of glucose and insulin, the gliquidone plasma levels of 20 subjects were determined by a new specific liquid chromatographic (HPLC) assay method with fluorescence detection, and the pharmacokinetic parameters calculated. Following the gliquidone administration, the mean plasma glucose profiles of the responders were up to 15% lower than with placebo (p < 0.005) between 8 a.m. and 6 p.m., representing a duration of the blood sugar-lowering effect of 8 to 10 h. Insulin values were raised, with peaks over 40% higher, during or shortly after meals. Subsequently, the insulin levels returned to approximately the same levels obtained with placebo during the postprandial phase. Plasma concentrations of gliquidone showed pronounced interindividual variability. The mean maximum concentration in plasma Cmax was 0.65 microgram/ml, (range: 0.12-2.14 micrograms/ml, coefficient of variation (CV): 82%). The median time to reach maximum plasma concentrations tmax was 2.25 h (range: 1.25-4.75 h). The areas under the plasma concentration-time curve from zero time to infinity (AUC0-infinity) and the mean terminal elimination half-lives (t1/2 beta) were computed from those patients (N = 8) who exhibited at least five plasma levels above the limit of quantitation in the terminal log-linear phase using a two-compartment model: the mean AUC0-infinity was 5.1 micrograms.h/ml (range: 1.5-10.1 micrograms.h/ml, CV 56%). The dominant half-life t1/2 alpha derived from therapeutically relevant plasma levels of gliquidone (> 80 ng/ml) was approximately 1.2 h (range: 0.4-3.0 h. CV: 71%) and the mean terminal half-life t1/2 beta was approximately 8 h (range: 5.7-9.4 h, CV: 17%). From the pharmacodynamic behavior as well as from the pharmacokinetic parameters it can be deduced that gliquidone belongs to the class of short-acting sulfonylureas used in antidiabetic therapy. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Calibration_MeSH M_Chromatography__High_Pressure_Liquid_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Half-Life_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Quality_Control_MeSH M_Single-Blind_Method_MeSH M_Spectrometry__Fluorescence_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH ****** 9114921 ----K E ----T Metformin hydrochloride: an antihyperglycemic agent. ----A The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of metformin hydrochloride are reviewed. Metformin is an antihyperglycemic agent; it lowers the blood glucose concentration without causing hypoglycemia. Proposed mechanisms of action include decreased intestinal absorption of glucose, increased glucose uptake from the blood into the tissues, decreased glucose production in the liver, and decreased insulin requirements for glucose disposal. Metformin is slowly absorbed from the small intestine and does not undergo hepatic metabolism. The half-life is about five hours. The major route of elimination is renal; the drug is contraindicated in patients with impaired renal function. In double-blind, placebo-controlled trials, metformin has shown efficacy in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). The drug is as effective as sulfonylureas in patients with diabetes who are nonobese or obese and whose diabetes is uncontrolled by diet alone. Metformin may be useful as addon therapy in obese patients with diabetes uncontrolled by sulfonylureas and diet. Lipid profiles may be favorably influenced. The most common adverse effects are gastrointestinal. A rare but potentially fatal adverse effect is lactic acidosis. Metformin has the potential to interact with cationic drugs eliminated by the renal tubular pathway. The usual effective dosage is 1.5-2.5 g/day orally in two or three divided doses. Metformin hydrochloride is an effective alternative to sulfonylureas in obese and non-obese patients with NIDDM in whom diet alone has not achieved glycemic control, and it may be useful as addon therapy in patients whose diabetes has not responded adequately to sulfonylureas plus dietary measures. ----P Journal_Article Review Review_Literature ----M M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Female_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_pharmacokinetics_MeSH Metformin_pharmacokinetics_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH ****** 9135927 ----K I ----T The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone. ----A OBJECTIVE: To compare the therapeutic effects of the alpha-glucosidase inhibitor miglitol (BAY m 1099), the sulfonylurea glibenclamide, and placebo on parameters of metabolic control and safety in patients with NIDDM that is inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS: After a 4-week placebo run-in period, 201 patients in 18 centers in 4 countries were randomized in a double-blind manner to miglitol (50 mg t.i.d., followed by 100 mg t.i.d.), glibenclamide (3.5 mg q.d/b.i.d.), or placebo for 24 weeks. Efficacy criteria were changes from baseline of HbA1c, fasting and postprandial blood glucose and insulin levels, body weight, and serum triglycerides. RESULTS: Efficacy was assessed in 119 patients who completed the full protocol, and the results were similar to those obtained in 186 patients who fulfilled the validity criteria for analysis. Compared with placebo, mean baseline-adjusted HbA1c decreased by 0.75% (P = 0.0021) and 1.01% (P = 0.0001) in the miglitol and glibenclamide treatment groups, respectively. Blood glucose decreased slightly in the fasting state and considerably in the postprandial state in both treatment groups but not in the placebo group. Fasting insulin levels increased slightly (NS) in all treatment groups; however, postprandial insulin levels decreased with miglitol, while increasing markedly with glibenclamide (P = 0.0001 between all treatment groups). Gastrointestinal side effects (flatulence and diarrhea) occurred mostly in the miglitol-treated patients, while some glibenclamide-treated patients had symptoms suggestive of hypoglycemia. CONCLUSIONS: Miglitol monotherapy is effective and safe in NIDDM patients. Compared with glibenclamide, it reduced HbA1c less effectively and caused more gastrointestinal side effects. On the other hand, glibenclamide, unlike miglitol, tended to cause hypoglycemia, hyperinsulinemia, and weight gain, which are not desirable in patients with NIDDM. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH P_Diabetic_Diet_MeSH M_Diarrhea_MeSH S_chemically_induced_MeSH Diarrhea_chemically_induced_MeSH M_Double-Blind_Method_MeSH M_Enzyme_Inhibitors_MeSH S_adverse_effects_MeSH Enzyme_Inhibitors_adverse_effects_MeSH S_therapeutic_use_MeSH Enzyme_Inhibitors_therapeutic_use_MeSH M_Fasting_MeSH M_Female_MeSH M_Flatulence_MeSH S_chemically_induced_MeSH Flatulence_chemically_induced_MeSH M_Glucosamine_MeSH S_adverse_effects_MeSH Glucosamine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Glucosamine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Glucosamine_therapeutic_use_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Postprandial_Period_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 9135928 ----K E ----T Comparative effects of glibenclamide and metformin on ambulatory blood pressure and cardiovascular reactivity in NIDDM. ----A OBJECTIVE: To compare the effects of chronic glibenclamide and metformin therapy on blood pressure (BP) and cardiovascular responsiveness in patients with NIDDM. RESEARCH DESIGN AND METHODS: Fourteen patients with NIDDM received metformin or glibenclamide for 1 month in a double-blind, randomized crossover study. At the end of each treatment period, patients were tested for forearm vascular responsiveness to intrabrachial arterial infusion of diazoxide (an ATP-sensitive potassium channel opener), acetylcholine, sodium nitroprusside, and norepinephrine, BP responses to intravenous infusions of NE and angiotensin II, BP responses to cold pressor testing and isometric exercise, and 24-h ambulatory BP monitoring. RESULTS: Metformin and glibenclamide produced similar glycemic control. Mean 24-h BPs did not differ between the two groups, but mean 24-h heart rates were significantly lower (75 +/- 6 bpm vs. 80 +/- 6 bpm) on glibenclamide therapy than on metformin. Plasma norepinephrine levels were significantly higher on glibenclamide (6.41 +/- 1.77 vs. 4.26 +/- 1.54 mmol/l, P < 0.01), and systolic BP responses to intravenous norepinephrine and angiotensin II were significantly higher on glibenclamide than on metformin (P < 0.02 and P < 0.05, respectively). Systolic BP responses to cold pressor testing appeared higher on glibenclamide than on metformin, but the difference did not quite achieve statistical significance (P = 0.052). Baseline forearm vascular resistance did not differ between the two drugs, nor did forearm vascular resistance responses to diazoxide, acetylcholine, sodium nitroprusside, and norepinephrine differ. CONCLUSIONS: Glibenclamide therapy is accompanied by greater systolic BP responses to norepinephrine and angiotensin II and higher plasma norepinephrine levels than those that occur on metformin therapy. Lower heart rates on glibenclamide therapy despite evidence of greater sympathetic activity suggests that glibenclamide may have negative chronotropic effects. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acetylcholine_MeSH S_diagnostic_use_MeSH Acetylcholine_diagnostic_use_MeSH M_Adult_MeSH M_Aged_MeSH M_Angiotensin_II_MeSH S_diagnostic_use_MeSH Angiotensin_II_diagnostic_use_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Diazoxide_MeSH S_administration_&_dosage_MeSH Diazoxide_administration_&_dosage_MeSH S_diagnostic_use_MeSH Diazoxide_diagnostic_use_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Forearm_MeSH S_blood_supply_MeSH Forearm_blood_supply_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Heart_Rate_MeSH S_drug_effects_MeSH Heart_Rate_drug_effects_MeSH M_Hemodynamic_Processes_MeSH S_drug_effects_MeSH Hemodynamic_Processes_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Infusions__Intra-Arterial_MeSH M_Lipoproteins_MeSH S_blood_MeSH Lipoproteins_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Nitroprusside_MeSH S_diagnostic_use_MeSH Nitroprusside_diagnostic_use_MeSH M_Norepinephrine_MeSH S_blood_MeSH Norepinephrine_blood_MeSH S_diagnostic_use_MeSH Norepinephrine_diagnostic_use_MeSH M_Regional_Blood_Flow_MeSH S_drug_effects_MeSH Regional_Blood_Flow_drug_effects_MeSH M_Vascular_Resistance_MeSH S_drug_effects_MeSH Vascular_Resistance_drug_effects_MeSH ****** 9143853 ----K E ----T Oral antihyperglycaemics. Considerations in older patients with non-insulin-dependent diabetes mellitus. ----A Non-insulin-dependent diabetes mellitus (NIDDM) is increasing in incidence as the population in most countries ages. Multiple pathology is common in the elderly, and cardiovascular disease is usually present at diagnosis. Patients who develop NIDDM at age 65 years may live long enough to develop microvascular complications. Others who are frail and have multiple pathologies may require treatment to prevent both symptomatic hyperglycaemia and dehydration, whilst avoiding hypoglycaemia. The goals in the management of NIDDM in elderly people are the prevention of complications and the relief of symptoms. Treatment must be tailored to the individual's expectations and should be reviewed regularly with the changing circumstances of aging. If dietary measures fail to control glucose levels, antihyperglycaemic sulphonylureas are the most frequently prescribed form of treatment. However, concern over the potential of these drugs to cause hypoglycaemia limits the choice to second generation sulphonylureas, agents that preserve the first phase of insulin release and have non-biologically active metabolites that are promptly eliminated. The biguanide agent metformin is also appropriate in elderly obese patients with NIDDM who do not have renal, liver or cardiac failure. The combination of a sulphonylurea and metformin can be effective in patients in whom insulin would otherwise be required. Novel compounds such as acarbose and the thiazolinediones may also be useful in the treatment of older diabetic patients. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Aging_MeSH S_metabolism_MeSH Aging_metabolism_MeSH S_pathology_MeSH Aging_pathology_MeSH M_Biguanides_MeSH S_administration_&_dosage_MeSH Biguanides_administration_&_dosage_MeSH S_adverse_effects_MeSH Biguanides_adverse_effects_MeSH S_pharmacokinetics_MeSH Biguanides_pharmacokinetics_MeSH S_therapeutic_use_MeSH Biguanides_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Drugs__Investigational_MeSH M_Enzyme_Inhibitors_MeSH S_administration_&_dosage_MeSH Enzyme_Inhibitors_administration_&_dosage_MeSH S_adverse_effects_MeSH Enzyme_Inhibitors_adverse_effects_MeSH S_pharmacokinetics_MeSH Enzyme_Inhibitors_pharmacokinetics_MeSH S_therapeutic_use_MeSH Enzyme_Inhibitors_therapeutic_use_MeSH M_Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH Glucosidases_antagonists_&_inhibitors_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Life_Expectancy_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 9146849 ----K E ----T Concentration-effect relations of glibenclamide and its active metabolites in man: modelling of pharmacokinetics and pharmacodynamics. ----A AIMS: The main purpose of this paper is to describe the relationship between serum concentrations of glibenclamide and its main metabolites and the effects on blood glucose levels, the clinically most relevant parameter to assess in diabetes. METHODS: Serum concentrations and blood glucose lowering effects (expressed as percent blood glucose reduction vs placebo) of glibenclamide (Gb) and its active metabolites, 4-trans-hydroxy-(M1) and 3-cis-hydroxy-glibenclamide (M2), were analysed in eight healthy subjects participating in a placebo-controlled, randomized, single-blind crossover study, using intravenous administration of each compound as well as oral administration of Gb. RESULTS: Plots of % blood glucose reduction vs log serum concentration demonstrated counter-clockwise hysteresis for parent drug and its metabolites. An effect compartment was linked to appropriate pharmacokinetic models and pharmacokinetic and pharmacodynamic modelling was used to fit the pharmacokinetics of Gb by both routes and the metabolites for each individual. Based on the individual concentration-time profiles a PK/PD-model was applied to all effect data simultaneously. An increase in the steady-state serum concentration when the effect is 50% of maximal, CEss50, was found in the sequence M1 (23 ng ml-1), M2 (37 ng ml-1) and Gb (108 ng ml-1). Corresponding interindividual variabilities expressed as CV% were 25%, 47% and 26%. The elimination rate constants from the effect site (kEO) were estimated and increased in the order M1 (0.178 h-1, CV 13%), M2 (0.479 h-1, CV 8.5%) and Gb (1.59 h-1, CV 36%). Corresponding equilibration half-lives for the effect site (kEO-HL) were 3.9 h, 1.4 h and 0.44 h. Estimated Emax-values obtained for M1, M2 and Gb were 40% (CV 30%), 27% (CV 56%) and 56% (CV 14%), respectively. CONCLUSIONS: It is concluded that the two major metabolites of Gb are hypoglycaemic in man, that they may have higher activity at low concentrations and that they may have a longer effect duration than the parent drug. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Computer_Simulation_MeSH M_Cross-Over_Studies_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Glyburide_analogs_&_derivatives_MeSH S_blood_MeSH Glyburide_blood_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Half-Life_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Injections__Intravenous_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Models__Chemical_MeSH M_Single-Blind_Method_MeSH M_Stereoisomerism_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9159660 ----K E ----T Treatment of non-insulin-dependent diabetes mellitus with metformin. ----A BACKGROUND: Metformin alleviates hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM) by inhibiting hepatic glucose production and improving peripheral insulin sensitivity. In contrast to sulfonylureas, metformin does not stimulate insulin-secretion, promote weight gain, exacerbate hyperinsulinemia, or cause hypoglycemia. It also favorably affects serum lipids. METHODS: A comprehensive review of the medical literature from 1968 to the present was conducted using the key words "metformin" and "non-insulin-dependent diabetes mellitus." RESULTS: Metformin monotherapy was superior to placebo and comparable to sulfonylureas in reducing fasting plasma glucose and glycosylated hemoglobin levels in patients with NIDDM uncontrolled by diet. Metformin and sulfonylureas, however, had diverse effects on body weight and fasting plasma insulin levels; both weight and insulin levels remained unchanged or decreased with metformin and increased with sulfonylureas. In patients with secondary sulfonylurea failure, the combination of metformin and a sulfonylurea synergistically improved glycemic control better than either drug alone and was comparable to insulin plus sulfonylurea. When hyperglycemia is uncontrolled by insulin after secondary sulfonylurea failure, limited data suggest the efficacy of metformin plus insulin. The mild, transient, self-limited gastrointestinal side effects that sometimes occur can be minimized by gradually increasing the doses and by taking metformin with food. Risk of metformin-associated lactic acidosis is low if prescribing guidelines are adhered to. Potential adverse drug interactions include hypoglycemia during concurrent sulfonylurea therapy and elevated metformin plasma concentrations when metformin is taken concomitantly with cimetidine. CONCLUSIONS: Metformin can be used safely and effectively as first-line monotherapy in NIDDM or in combination with a sulfonylurea when monotherapy with either agent fails. It can be particularly suitable when weight gain, hyperlipidemia, and hypoglycemia are clinically important issues. ----P Journal_Article Review Review__Tutorial ----M M_Acidosis__Lactic_MeSH S_chemically_induced_MeSH Acidosis__Lactic_chemically_induced_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Interactions_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH ****** 9167112 ----K I ----T Glipizide-GITS does not increase the hypoglycemic effect of mild exercise during fasting in NIDDM. ----A OBJECTIVE: This study compared the effect of mild exercise while fasting on plasma glucose concentrations in subjects with NIDDM treated with extended-release glipizide and subjects not taking an oral hypoglycemic agent. RESEARCH DESIGN AND METHODS: Twenty-five moderately obese subjects with NIDDM were randomized to treatment with extended-release glipizide or placebo. After 9 weeks of treatment, they fasted overnight, took their study drug, omitted breakfast, and exercised on a treadmill for 90 min. Glucose, insulin, and C-peptide concentrations were measured before, during, and after exercise. RESULTS: On the fasting-exercise day, fasting glucose concentrations were lower (153 vs. 241 mg/dl, P < 0.01) and insulin and C-peptide concentrations higher in the extended-release glipizide group. The decrement of glucose from the fasting baseline was modest and equivalent in the two groups: 17 vs. 21 mg/dl at the end of exercise and 28 vs. 27 mg/dl after 2 h of recovery. No subject had hypoglycemic symptoms. CONCLUSIONS: Chronic use of extended-release glipizide does not enhance the hypoglycemic effect of fasting plus mild exercise for people with NIDDM. Routine lifestyle treatments for NIDDM may be continued during ongoing use of this agent. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH P_Exercise_MeSH M_Exercise_Test_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_etiology_MeSH Hypoglycemia_etiology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_blood_MeSH Obesity_in_Diabetes_blood_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH S_physiopathology_MeSH Obesity_in_Diabetes_physiopathology_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 9184703 ----K I ----T Short-term comparison of once- versus twice-daily administration of glimepiride in patients with non-insulin-dependent diabetes mellitus. ----A OBJECTIVE: To investigate the metabolic effects and frequency of adverse events with 6 mg of glimepiride, a new oral sulfonylurea, given both in once- and twice-daily dosages to patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: This 15-week study involved 161 subjects with NIDDM. Subjects were randomized into two groups. For 4 weeks, group 1 received glimepiride 3 mg twice daily, and group 2 received glimepiride 6 mg once daily. After a 3-week placebo-washout period, twice- and once-daily regimens were crossed over for a second 4-week treatment period. Subjects were hospitalized at the end of each placebo or active-treatment phase. Their glucose concentrations were recorded at 20 time points over a 24-hour period, and their insulin and C-peptide concentrations were recorded at 16 time points over the same period. Parameters that were calculated included fasting, 24-hour, and postprandial concentrations of glucose, insulin, and C-peptide. RESULTS: One hundred six patients were randomized to receive treatment; 94 completed the entire study. Existing physiologic mechanisms of glucose control were apparently unimpaired by glimepiride treatment. Insulin concentrations increased more during the postprandial glucose peaks than when subjects were fasting. Both twice- and once-daily regimens proved equally effective in reducing concentrations of fasting, postbreakfast, postlunch, and postdinner plasma glucose. Twenty-four-hour mean glucose concentrations showed a slightly greater decrease from baseline for the twice-daily regimen; the difference between the regimens was statistically significant but not clinically meaningful. The incidence of adverse events with glimepiride approximated that obtained with placebo, with both groups reporting only one adverse event, headache, in more than 5% of the subjects. CONCLUSIONS: Glimepiride is equally effective whether administered once or twice daily. Glimepiride seems to stimulate insulin production primarily after meals, when plasma glucose concentrations are highest, but controls blood glucose throughout the day. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9186077 ----K I ----T Pharmacokinetics of oral glyburide in subjects with non-insulin-dependent diabetes mellitus and renal failure. ----A To test the hypothesis that renal failure has no effect on the pharmacokinetics of glyburide, five subjects with non-insulin-dependent diabetes mellitus (NIDDM) and end-stage renal disease requiring hemodialysis, and four NIDDM subjects with normal renal function were studied. On days 0, 1, and 15, subjects consumed 33 carbohydrate grams, and glucose, insulin, and C-peptide were measured for 4 hours. On day 1, subjects received 3 mg glyburide and measured plasma concentrations for 48 hours. On day 3, multiple dosing on 3 mg glyburide daily began. On day 15, plasma concentrations were measured for 48 hours. The pharmacokinetics and pharmacodynamics of glyburide, glucose, insulin, and C-peptide were determined as well as daily fasting blood glucose. Glucose area under the curve (AUC) and daily fasting glucose levels did not change in either controls or hemodialysis subjects. The mean serum glyburide blood levels and pharmacokinetics did not differ after initial or chronic glyburide administration in NIDDM subjects with end-stage renal disease treated with hemodialysis compared with controls. Glyburide half-life averaged 3.3 hours in control subjects and 5.0 hours in hemodialysis subjects. Hemodialysis subjects had increased C-peptide and insulin AUC with chronic dosing. Renal failure does not affect the pharmacokinetics of 3.0 mg oral glyburide. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Kidney_Failure__Chronic_MeSH S_blood_MeSH Kidney_Failure__Chronic_blood_MeSH S_etiology_MeSH Kidney_Failure__Chronic_etiology_MeSH S_therapy_MeSH Kidney_Failure__Chronic_therapy_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Renal_Dialysis_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH M_Time_Factors_MeSH ****** 9195119 ----K E ----T General medicine update: NIDDM, prevention of CAD, & risks & benefits of hormone replacement therapy. ----A ----P Journal_Article Review Review__Tutorial ----M M_Aged_MeSH M_Breast_Neoplasms_MeSH S_epidemiology_MeSH Breast_Neoplasms_epidemiology_MeSH M_Cardiovascular_Diseases_MeSH S_epidemiology_MeSH Cardiovascular_Diseases_epidemiology_MeSH M_Coronary_Disease_MeSH S_prevention_&_control_MeSH Coronary_Disease_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Estrogen_Replacement_Therapy_MeSH S_adverse_effects_MeSH Estrogen_Replacement_Therapy_adverse_effects_MeSH M_Female_MeSH M_Human_MeSH M_Middle_Aged_MeSH ****** 9212313 ----K E ----T Effect of insulin treatment on circulating islet amyloid polypeptide in patients with NIDDM. ----A The objective was to evaluate the effect of insulin treatment on circulating islet amyloid polypeptide (IAPP). Twelve patients with NIDDM and secondary failure were studied on oral agents and then switched to insulin treatment. Fasting and postprandial IAPP concentrations were measured on oral treatment and on insulin treatment. In 5 of the patients no postprandial concentrations were determined. In the 7 patients who were investigated both fasting and postprandially the fasting IAPP concentration was 6.5 +/- 1.2 pmol l(-1) (mean +/- SEM) during oral treatment with a rise to 13.5 +/- 3.1 90 min after breakfast (p = 0.028). On insulin treatment HbA1c decreased from 8.6 +/- 0.5 to 7.5 +/- 0.4% (p< 0.03) and plasma C-peptide concentration was significantly lowered (p< 0.01). There was a close correlation using simple regression between the per cent change of IAPP concentration and the per cent change of C-peptide concentration during this period (r = 0.88; p< 0.01). In the total patient material of 12 patients there was a significant correlation using simple regression analysis between per cent change of IAPP concentration and per cent change of C-peptide concentration using all 48 measurements available (r = 0.58: p< 0.001). These data suggest that secretion of IAPP is lowered when endogenous insulin secretion is lowered by administration of exogenous insulin in patients with NIDDM. Thus, if IAPP secretion has a pathogenetic role in the development of beta cell failure in NIDDM, insulin treatment might delay this deterioration. ----P Journal_Article ----M M_Aged_MeSH M_Aged__80_and_over_MeSH M_Amyloid_MeSH S_blood_MeSH Amyloid_blood_MeSH S_drug_effects_MeSH Amyloid_drug_effects_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_drug_effects_MeSH C-Peptide_drug_effects_MeSH S_metabolism_MeSH C-Peptide_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Fasting_MeSH S_physiology_MeSH Fasting_physiology_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Linear_Models_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Multivariate_Analysis_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9222648 ----K I ----T Glucose tolerance and mortality, including a substudy of tolbutamide treatment. ----A Mortality according to glucose tolerance was studied to determine the prognosis of impaired glucose tolerance. Among 2500 persons tested in a community screening programme in 1962-1965 and followed-up for mortality to the end of 1987, age-sex-adjusted mortality rates were 37.9 +/- 1.9, 53.6 +/- 4.2, and 70.1 +/- 3.6 deaths per 1000 person-years (+/-SE) in those with normal glucose tolerance, impaired glucose tolerance, and diabetes by World Health Organization criteria at baseline. Age-sex-adjusted mortality rates due to ischaemic heart disease were 14.3 +/- 1.1, 16.3 +/- 2.4, and 25.8 +/- 2.0 deaths per 1000 person-years, respectively. Using criteria predating those of the World Health Organization 147 men with abnormal glucose tolerance were entered into a randomized clinical trial in which 49 were treated with tolbutamide for approximately 10 years. Those treated had lower mortality rates from all causes (mortality rate ratio = 0.66, 95% confidence interval = 0.39, 1.10) and from ischaemic heart disease (mortality rate ratio = 0.42, 95% confidence interval = 0.16, 1.12) than those not receiving tolbutamide. Thus mortality rates are increased in persons with impaired glucose tolerance and diabetes, and the small clinical trial suggests that tolbutamide may be beneficial in men with abnormal glucose tolerance. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adolescent_MeSH M_Adult_MeSH M_Age_Factors_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Cause_of_Death_MeSH M_Confidence_Intervals_MeSH M_Diabetes_Mellitus_MeSH S_epidemiology_MeSH Diabetes_Mellitus_epidemiology_MeSH S_mortality_MeSH Diabetes_Mellitus_mortality_MeSH M_Female_MeSH M_Glucose_Intolerance_MeSH S_drug_therapy_MeSH Glucose_Intolerance_drug_therapy_MeSH S_epidemiology_MeSH Glucose_Intolerance_epidemiology_MeSH S_mortality_MeSH Glucose_Intolerance_mortality_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Incidence_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Myocardial_Ischemia_MeSH S_mortality_MeSH Myocardial_Ischemia_mortality_MeSH M_Sex_Characteristics_MeSH M_Sex_Factors_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH M_Tolbutamide_MeSH S_therapeutic_use_MeSH Tolbutamide_therapeutic_use_MeSH M_World_Health_Organization_MeSH ****** 9223393 ----K E ----T Beta cell response to oral glimepiride administration during and following a hyperglycaemic clamp in NIDDM patients. ----A The aim of the present study was to assess the beta cell response to glimepiride, administered orally, during and following a hyperglycaemic clamp in 14 NIDDM patients (7 males), aged 62.5 (St. Dev. 7.7) years with a body mass index of 27.3 (2.8) kg m(-2) and HbA(Ic) of 7.0 (0.7)% at baseline, in a placebo controlled study. All patients were on stable treatment with a second generation sulphonylurea for at least 8 weeks prior to randomization and received placebo (P) or 5 mg glimepiride (G) daily for 7 days and 10 mg prior to a hyperglycaemic clamp (10.9 mmol l(-1) for 60 min, preceded by i.v. insulin infusion to stabilize fasting blood glucose levels at 4.0 mmol l(-1)). The clamp was followed by an observation period of 2 h in 5 subjects and 3.5 h in the next 9 subjects, during which blood glucose and plasma insulin, C-peptide and proinsulin levels were measured at regular intervals to determine the effect of glimepiride on the interaction between changes in glycaemia and plasma levels of beta cell products. Neither G nor P elicited a first phase insulin response. Areas under plasma insulin curve during the 1 h hyperglycaemic clamp were 94.2 (39.5) vs 69.1 (26.5) pmol.h l(-1) in G and P clamps, respectively (p = 0.002). Total areas (AUC) under the plasma insulin curve were 377 (145) vs 271 (113) pmol.h l(-1) in G and P clamps (< 0.05). Total AUCs of C-peptide were 309 (96) and 259 (102 pmol.h.(-1), in G and P clamps, respectively, p = 0.01. Total AUCs of proinsulin were 176 (77) versus 119 (56) pmol.h l(-1) in G and P clamps, respectively, p = 0.004. Five hours after G and P administration blood glucose levels were 4.7) 92.1) mmol(-1) in the G clamp vs 6.2 (1.9) mmol l(-1) in the P clamp (p = 0.001). The number of hypoglycaemic events (blood glucose < 3.0 mmol l(-1)) in the 3.5 h observation period was 3 in G clamps vs 0 in P clamps (p = ns). In conclusion, glimepiride stimulates the second phase insulin and proinsulin secretion. The lowering of blood glucose levels is not accompanied by a commensurate inhibition of the insulin secretion. Further studies are required to compare this new drug with currently available oral hypoglycaemic agents, with respect to glycaemic control and the risk of hypoglycaemia. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH S_drug_effects_MeSH C-Peptide_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH S_drug_effects_MeSH Glucagon_drug_effects_MeSH P_Glucose_Clamp_Technique_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_physiopathology_MeSH Hyperglycemia_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Pharmaceutical_Preparations_MeSH S_metabolism_MeSH Pharmaceutical_Preparations_metabolism_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH S_drug_effects_MeSH Proinsulin_drug_effects_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9239399 ----K E ----T Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance. ----A Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Animals_MeSH M_Chromans_MeSH S_administration_&_dosage_MeSH Chromans_administration_&_dosage_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Glucose_MeSH S_administration_&_dosage_MeSH Glucose_administration_&_dosage_MeSH M_Glucose_Intolerance_MeSH S_drug_therapy_MeSH Glucose_Intolerance_drug_therapy_MeSH S_metabolism_MeSH Glucose_Intolerance_metabolism_MeSH M_Glucose_Tolerance_Test_MeSH M_Guinea_Pigs_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Islets_of_Langerhans_MeSH S_metabolism_MeSH Islets_of_Langerhans_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH P_Thiazolidinediones_MeSH M_Treatment_Outcome_MeSH ****** 9250558 ----K I ----T The influence of bromfenac on the pharmacokinetics and pharmacodynamic responses to glyburide in diabetic subjects. ----A STUDY OBJECTIVE: To assess the effect of bromfenac sodium, a nonnarcotic analgesic drug under development, on the pharmacokinetics and pharmacodynamics of glyburide in patients with type II diabetes. DESIGN: Randomized, double-blind, placebo-controlled, multiple-dose study with a two-period crossover design. PATIENTS: Eleven men and one woman (age 36-64 yrs) whose diabetes was responsive to oral sulfonylurea therapy. INTERVENTIONS: Placebo or bromfenac 50 mg was given as a single oral dose 3 times/day for the first 3 days of the study. On days 4-6, patients received the alternative treatment. For at least 3 months before and during the study, patients took their usual single daily dose of glyburide 10 mg. MEASUREMENTS AND MAIN RESULTS: Bromfenac concentrations were measured by high-performance liquid chromatography with ultraviolet detection. Glyburide concentrations were measured by gas chromatography with nitrogen-phosphorus detection. Glycemia was measured repeatedly on day 3 of each treatment. Pharmacokinetic analysis was performed with noncompartmental techniques. No significant differences in the pharmacokinetics of glyburide or in the pharmacodynamic response of serum glucose levels were observed between placebo and bromfenac. Intersubject variability of concentrations was modest for glyburide and glucose, with a CV of 43% or less. CONCLUSION: Glyburide levels are not changed during concomitant administration of bromfenac. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Analgesics_MeSH S_pharmacology_MeSH Analgesics_pharmacology_MeSH M_Area_Under_Curve_MeSH M_Benzophenones_MeSH S_administration_&_dosage_MeSH Benzophenones_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Benzophenones_pharmacokinetics_MeSH S_pharmacology_MeSH Benzophenones_pharmacology_MeSH M_Biological_Availability_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Bromobenzenes_MeSH S_administration_&_dosage_MeSH Bromobenzenes_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Bromobenzenes_pharmacokinetics_MeSH S_pharmacology_MeSH Bromobenzenes_pharmacology_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Double-Blind_Method_MeSH M_Drug_Interactions_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH M_Half-Life_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Male_MeSH M_Metabolic_Clearance_Rate_MeSH M_Middle_Aged_MeSH ****** 9279533 ----K E ----T Effect of glibenclamide on insulin release at moderate and high blood glucose levels in normal man. ----A Insulin release occurs in two phases; sulphonylurea derivatives may have different potencies in stimulating first- and second-phase insulin release. We studied the effect of glibenclamide on insulin secretion at submaximally and maximally stimulating blood glucose levels with a primed hyperglycaemic glucose clamp. Twelve healthy male subjects, age (mean +/- SEM) 22.5 +/- 0.5 years, body mass index (BMI) 21.7 +/- 0.6 kgm-2, were studied in a randomized, double-blind study design. Glibenclamide 10 mg or placebo was taken before a 4-h hyperglycaemic clamp (blood glucose 8 mmol L-1 during the first 2 h and 32 mmol L-1 during the next 2 h). During hyperglycaemic clamp at 8 mmol L-1, the areas under the delta insulin curve (AUC delta insulin, mean +/- SEM) from 0 to 10 min (first phase) were not different: 1007 +/- 235 vs. 1059 +/- 261 pmol L-1 x 10 min (with and without glibenclamide, P = 0.81). However, glibenclamide led to a significantly larger increase in AUC delta insulin from 30 to 120 min (second phase): 16087 +/- 4489 vs. 7107 +/- 1533 pmol L-1 x 90 min (with and without glibenclamide respectively, P < 0.03). The same was true for AUC delta C-peptide no difference from 0 to 10 min but a significantly higher AUC delta C-peptide from 30 to 120 min on the glibenclamide day (P < 0.01). The M/I ratio (mean glucose infusion rate divided by mean plasma insulin concentration) from 60 to 120 min, a measure of insulin sensitivity, did not change: 0.26 +/- 0.05 vs. 0.22 +/- 0.03 mumol kg-1 min-1 pmol L-1 (with and without glibenclamide, P = 0.64). During hyperglycaemic clamp at 32 mmol L-1, the AUC delta insulin from 120 to 130 min (first phase) was not different on both study days: 2411 +/- 640 vs. 3193 +/- 866 pmol L-1 x 10 min (with and without glibenclamide, P = 0.29). AUC delta insulin from 150 to 240 min (second phase) also showed no difference: 59623 +/- 8735 vs. 77389 +/- 15161 pmol L-1 x 90 min (with and without glibenclamide, P = 0.24). AUC delta C-peptide from 120 to 130 min and from 150 to 240 min were slightly lower on the glibenclamide study day (both P < 0.04). The M/I ratio from 180 to 240 min did not change: 0.24 +/- 0.04 vs. 0.30 +/- 0.07 mumol kg-1 min-1 pmol L-1 (with and without glibenclamide, P = 0.25). In conclusion, glibenclamide increases second-phase insulin secretion only at a submaximally stimulating blood glucose level without enhancement of first-phase insulin release and has no additive effect on insulin secretion at maximally stimulating blood glucose levels. Glibenclamide did not change insulin sensitivity in this acute experiment. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH M_Double-Blind_Method_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_blood_MeSH Glyburide_blood_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_blood_MeSH Hypoglycemia_blood_MeSH S_drug_therapy_MeSH Hypoglycemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9283792 ----K E ----T Glibenclamide, but not acarbose, increases leptin concentrations parallel to changes in insulin in subjects with NIDDM. ----A OBJECTIVE: To hypothesize if glibenclamide, which increases insulin levels, also increases leptin concentrations. RESEARCH DESIGN AND METHODS: Leptin is a hormone that regulates weight in mice. In obese humans, leptin concentrations are increased, suggesting resistance to the effects of this hormone. Although short-term infusion of insulin during the hyperinsulinemiceuglycemic clamp does not increase leptin concentration, the effect of oral antidiabetic agents on leptin concentration is unknown. Differing effects can be expected, since glibenclamide acts via stimulation of insulin secretion, whereas acarbose inhibits alpha-glucosidases of the small intestine and has no direct effect on insulin levels. We examined the effect of acarbose (n = 4), glibenclamide (n = 6), and placebo (n = 6) on insulin and leptin levels during 24-h periods before and after 16 weeks of therapy. RESULTS: We observed a significant diurnal variation in leptin concentrations. This was inversely related to insulin levels during the 24-h follow-up with usual diet. Neither the placebo nor acarbose altered leptin concentrations. However, glibenclamide increased leptin concentrations parallel to insulin levels. There were only minor changes in body weight during the l6-week follow-up: decrease in the placebo group (change -0.5 kg/m2, P = 0.07) and acarbose (change -0.7 kg/m2, P = 0.046) and increase in the glibenclamide group (change 0.8 kg/m2, P = 0.27). However, individual subjects who gained weight had increases in their leptin concentrations. The diurnal variation in leptin concentrations was preserved after glibenclamide. CONCLUSIONS: Glibenclamide increases circadian leptin and insulin concentrations, whereas acarbose does not. This observation may help to explain weight gain in subjects treated with glibenclamide and stable weight in those treated with acarbose in the long run. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acarbose_MeSH M_Analysis_of_Variance_MeSH M_Circadian_Rhythm_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Leptin_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Proteins_MeSH S_analysis_MeSH Proteins_analysis_MeSH S_metabolism_MeSH Proteins_metabolism_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Trisaccharides_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 9290539 ----K E ----T Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions. ----A At least 90% of the 12 to 15 million persons with diabetes mellitus in the United States, half of whose condition remains undiagnosed, have type 2 diabetes. Type 2 diabetes is preceded by a long period of impaired glucose tolerance, a reversible metabolic state associated with increased prevalence of macrovascular complications. Thus, at the time of diagnosis, long-term complications have developed in almost one fourth of patients. Susceptibility to type 2 diabetes requires genetic (most likely polygenic) and acquired factors, and its pathogenesis involves an interplay of progressive insulin resistance and beta-cell failure. The ideal treatment of type 2 diabetes should reverse insulin resistance and beta-cell dysfunction in most treated patients and prevent, delay, or reverse long-term complications. Current strategies are aimed at amelioration of insulin resistance (diet, exercise, weight loss, and metformin and troglitazone therapy), augmentation of insulin supply (sulfonylurea and insulin therapy), or limitation of postprandial hyperglycemia (acarbose therapy). Future therapies probably will target (1) insulin resistance, using a multifaceted approach; (2) hepatic glucose production, using gluconeogenesis inhibitors; (3) excess nonesterified fatty acid production, using lipolysis inhibitors; and (4) fat oxidation, using carnitine palmitoyltransferase I and II inhibitors. Attempts also could be made to stimulate energy expenditure and increase nonoxidative glucose disposal by means of beta 3-adrenoceptor agonists. One promising strategy is an attack on multiple pathophysiological processes by combining antidiabetic agents with disparate mechanisms of action. Thus, we now have unprecedented resources for drug therapy for diabetes, with great opportunity for innovative combinations. It is hoped that these expanded choices will provide the tools necessary for a more efficient management of type 2 diabetes and prevention of its long-term complications. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_etiology_MeSH Hyperglycemia_etiology_MeSH S_prevention_&_control_MeSH Hyperglycemia_prevention_&_control_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Liver_MeSH S_metabolism_MeSH Liver_metabolism_MeSH ****** 9300232 ----K E ----T Monitoring of metabolic control in patients with non-insulin-dependent diabetes mellitus on oral hypoglycaemic agents: value of evening blood glucose determination. ----A Monitoring of metabolic control in patients with non-insulin-dependent (Type 2) diabetes (NIDDM) is usually based upon blood glucose assay in the morning (after an overnight fast) and in the postprandial state (breakfast or lunch). However, this schedule does not seek low blood glucose values, especially in the evening. We have conducted a prospective study of laboratory blood glucose profiles (8 am, 9.30 am after a 35 g carbohydrate breakfast and in the evening between 5 and 7 pm). We have included 58 consecutive NIDDM patients regularly followed in our clinic (39 men, age 60 +/- 11.5 years, diabetes duration 8.6 +/- 6.5 years, BMI 25.5 +/- 3 kg m-2), treated with the sulphonylurea gliclazide, alone (40-320 mg 24 h-1, mean 170 +/- 110 mg) (group 1, n = 32) or in combination with metformin (1000-3000 mg 24 h-1, 2400 +/- 620 mg) (group 2, n = 26). All patients were stable, with no change in dosage for at least 3 months. Mean glycaemic control was good (group 1 HbA1c: 6.5 +/- 1.1%, group 2: 6.9 +/- 0.7%). Evening blood glucose values were the lowest of the day in 26 patients of group 1 (81.3%) and in 22 of group 2 (84.6%). Mean evening blood glucose levels were lower (p = 0.001) than 8 am values (group 1: 5.8 +/- 1.4 vs 6.1 +/- 1.6 mmol l-1, group 2: 6.5 +/- 1.8 vs 6.9 +/- 1.9) and than 9.30 am values (group 1: 7.6 +/- 1.5, group 2: 12.3 +/- 2.8). No blood glucose values in the hypoglycaemic range were observed. HbA1c was strongly correlated (p = 0.002 to 0.0001) in the whole group with 8 am (r = 0.39), 9.30 am (r = 0.56), and evening blood glucose values (r = 0.42). These results indicate that, in patients treated with the sulphonylurea gliclazide, alone or in combination with metformin, the lowest blood glucose values occur in the evening more frequently (4/5) than in the morning. Therefore, evening blood glucose determination should be performed systematically in the course of the metabolic evaluation of NIDDM patients on oral hypoglycaemic agents. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Circadian_Rhythm_MeSH M_Cohort_Studies_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH M_Female_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Prospective_Studies_MeSH ****** 9340472 ----K E ----T [Value of biguanide in therapy of diabetes mellitus] ----A BACKGROUND AND OBJECTIVES: Biguanides have been used in treatment of diabetes mellitus for over 30 years now. Due to frequent occurrence of lactic acidosis, particularly in patients with serious contraindications to biguanide therapy and in cases of non-compliance with dosage instructions, buformin and phenformin were taken off the market in most European countries at the end of the seventies. Metformin continued to be allowed, since the risk of lactic acidosis is 20 times less than with phenformin or buformin due to the different pharmacokinetic properties of the substance. Plenty of clinical experience has been gained with metformin, documented in a large number of reliable long-term studies. FINDINGS: Metformin lowers fasting blood glucose levels by an average of 25% (17 to 37%), postprandial blood glucose by up to 44.5% and HbA1c bei 1.5% (0.8 to 3.1%) Metformin reduces raised plasma insulin levels in cases of metabolic syndrome by as much as 30% and reduces the "insulin requirement" of type 2 insulin-treated diabetics by 15 to 32%. It has well documented effects on various rheological parameters. In overweight type 2 diabetics, metformin shows the same level of hypoglycaemic effect as all of the important sulfonylurea derivatives used in Europe. The active mechanism of these derivatives is, however, concentrated solely on reduction of blood glucose. This mechanism does not take into account the remaining risk constellation involved in insulin resistance. Biguanides, similarly to weight reduction, lead to a reduction of hyperinsulinaemia, which is by contrast exacerbated by sulfonylureas and, in particular, exogenous insulin. CONCLUSION: The risk of lactic acidosis can probably be eliminated entirely if dosage instructions and contraindications are observed carefully. The cause of such neglect in 83% of all cases was limited on renal function (serum creatinine > 1.5 mg%). Regarding morbidity and mortality from lactic acidosis, metformin therapy is no riskier than treatment with the sulfonylurea derivative glibenclamide, taking into account the incidence of fatal hypoglycaemias with the latter. ----P Journal_Article Review Review__Tutorial ----M M_Biguanides_MeSH S_adverse_effects_MeSH Biguanides_adverse_effects_MeSH S_contraindications_MeSH Biguanides_contraindications_MeSH S_therapeutic_use_MeSH Biguanides_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_Resistance_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_contraindications_MeSH Metformin_contraindications_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH ****** 9313749 ----K 3 ----T Relative hyperproinsulinemia of NIDDM persists despite the reduction of hyperglycemia with insulin or sulfonylurea therapy. ----A Subjects with NIDDM have increased plasma proinsulin concentrations, compared with nondiabetic subjects, both in absolute terms and as a proportion of circulating insulin-like molecules. It remains uncertain whether this reflects a primary beta-cell defect in proinsulin processing or is secondary to hyperglycemia. We addressed this question by assessing the effects of reducing hyperglycemia on relative hyperproinsulinemia in subjects with NIDDM. Eight subjects with NIDDM underwent three 8-week periods in a randomized crossover design of therapy with diet alone, sulfonylurea (gliclazide), or insulin (ultralente). The effects on beta-cell peptide concentrations were assessed 1) fasting, 2) in response to hyperglycemic clamping, and 3) in response to an injection of the nonglucose secretogogue arginine and compared with measurements in seven nondiabetic control subjects. Both sulfonylurea and insulin therapy substantially reduced fasting plasma glucose and glycosylated hemoglobin (HbA1e) concentrations, compared with diet therapy alone. The diabetic subjects on diet therapy had relative hyperproinsulinemia, assessed relative to C-peptide concentrations, fasting and in response to hyperglycemic clamping and arginine, compared with control subjects. Neither sulfonylurea nor insulin therapy altered the relative hyperproinsulinemia. Insulin therapy reduced fasting proinsulin concentrations from geometric mean 29.4 (1 SD range, 14.6-59.0) pmol/l on diet therapy to 18.7 (7.3-48.1) pmol/l (P < 0.05). A similar trend was evident with fasting C-peptide concentrations with a reduction from 0.9 (0.6-1.4) nmol/l on diet therapy to 0.6 (0.4-0.9) nmol/l (P = 0.06), so that the relative hyperproinsulinemia, assessed as the ratio of fasting proinsulin to C-peptide, was unchanged by insulin. Similarly, insulin therapy failed to reduce the ratio of proinsulin to C-peptide concentrations in response to a hyperglycemic clamp and in the acute incremental response to arginine. Failure to improve the relative hyperproinsulinemia of NIDDM, despite significant reduction of hyperglycemia with exogenous insulin therapy, supports the hypothesis that relative hyperproinsulinemia in NIDDM is a reflection of a primary beta-cell defect rather than being secondary to hyperglycemia. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Arginine_MeSH S_diagnostic_use_MeSH Arginine_diagnostic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Fasting_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glucose_Clamp_Technique_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9313756 ----K 3 ----T Insulin and sulfonylurea therapy in NIDDM patients. Are the effects on lipoprotein metabolism different even with similar blood glucose control? ----A This study evaluates the effects of insulin versus glibenclamide on lipoprotein metabolism at comparable levels of blood glucose control, in particular on the concentration and distribution of VLDL subfractions and lipolytic enzyme activities in nine NIDDM men (aged 56 +/- 3 years, BMI 26.5 +/- 0.9 kg/m2) (means +/- SE) participating in a crossover study. After a 3-week washout period, patients were randomly assigned to 2-month treatment periods (insulin or glibenclamide); thereafter, each patient crossed to the other treatment. At the end of each period, mean daily blood glucose (MDBG), HbA1e, plasma lipids, lipoproteins (VLDL, LDL, HDL), lipoprotein subfractions (VLDL1, 2, 3; HDL2, HDL3), and post-heparin lipase activities (lipoprotein lipase [LPL], hepatic lipase [HL]) were evaluated. Although glucose control was similar at the end of both periods (MDBG 8.3 +/- 0.3 vs. 7.9 +/- 0.3 mmol/l; HbA1c 7.4 +/- 0.3 vs. 7.0 +/- 0.2%, insulin versus glibenclamide), insulin compared with glibenclamide induced a significant reduction in plasma triglycerides (0.9 +/- 0.1 vs. 1.1 +/- 0.1 mmol/l, P < 0.05), VLDL triglycerides (50.1 +/- 12.2 vs. 63.6 +/- 12.3 mg/dl, P < 0.02), VLDL1 lipid concentration (24.9 +/- 7.5 vs. 39.9 +/- 9.5 mg/dl, P < 0.006), and increased HDL2 cholesterol (25.2 +/- 1.6 vs. 20.3 +/- 1.3 mg/dl, P < 0.03). In terms of VLDL percentage subfraction distribution, with insulin, there was a decrease in the larger subfractions (VLDL1 26.5 +/- 3.0 vs. 37.8 +/- 3.4%, P < 0.02) and an increase in the smallest (VLDL3 47.3 +/- 3.8 vs. 37.3 +/- 3.3%, P < 0.05). Moreover, HL activity was significantly lower after insulin than after glibenclamide (HL 247.2 +/- 22.3 vs. 263.5 +/- 22.6 mU/ml, P < 0.05). In conclusion, compared with glibenclamide, insulin treatment (independent of variations in glucose control) is able to decrease significantly plasma triglycerides, to increase HDL2 cholesterol, and to reduce only the concentration of the larger VLDL subfractions, with a consequent redistribution of their profile. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Fasting_MeSH M_Food_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipoproteins_MeSH S_blood_MeSH Lipoproteins_blood_MeSH M_Lipoproteins__HDL_MeSH S_blood_MeSH Lipoproteins__HDL_blood_MeSH M_Lipoproteins__LDL_MeSH S_blood_MeSH Lipoproteins__LDL_blood_MeSH M_Lipoproteins__VLDL_MeSH S_blood_MeSH Lipoproteins__VLDL_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 9353625 ----K E ----T American Diabetes Association Annual Meeting, 1997. Type 2 diabetes. ----A ----P Congresses News ----M P_Chromans_MeSH S_metabolism_MeSH Chromans_metabolism_MeSH S_pharmacology_MeSH Chromans_pharmacology_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH P_Diabetes_Mellitus_MeSH P_Diabetes_Mellitus__Type_II_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Homeostasis_MeSH M_Human_MeSH P_Hypoglycemic_Agents_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH P_Societies__Medical_MeSH P_Thiazoles_MeSH S_metabolism_MeSH Thiazoles_metabolism_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_United_States_MeSH ****** 9403288 ----K E ----T Concomitant administration of the alpha-glucosidase inhibitor voglibose (AO-128) does not alter the pharmacokinetics of glibenclamide. ----A OBJECTIVE: Voglibose is a new and potent inhibitor of alpha-glucosidases used for treatment of diabetes mellitus. It increases gastro-intestinal motility and could thus affect absorption of other concurrently administered antidiabetic drugs. The aim of this study was to investigate whether or not voglibose modifies the pharmacokinetics of glibenclamide, a widely used oral antidiabetic, and the glibenclamide-induced decrease in fasting serum glucose. METHODS: Twelve healthy male subjects were included in this double-blind cross-over study and received a single 1.75-mg dose of glibenclamide on the 8th day of continuous administration of either placebo (reference) or voglibose 5 mg t.i.d. (test). Blood samples were taken to determine the pharmacokinetic characteristics of glibenclamide and the test/reference ratios were evaluated according to bioequivalence criteria. Additional blood samples were taken to measure serum glucose on the same day. RESULTS: The concentration-time course of glibenclamide under concomitant voglibose administration was similar to that under placebo. The equivalence ratio (test/reference) for the pharmacokinetic characteristics AUCnorm was 1.03 (geometric mean; 0.95-1.11, 90% confidence interval) and Cmax.norm 1.01 (0.94-1.08). The parameters were within the accepted range of 0.8-1.25 (AUC) or 0.7-1.43 (Cmax), thus fulfilling equivalence criteria and indicating no effect of voglibose on glibenclamide kinetics. The glibenclamide-induced decrease in fasting serum glucose concentration was similarly independent of placebo or voglibose co-administration. CONCLUSIONS: Voglibose did not interact with glibenclamide on a pharmacokinetic level. Concomitant treatment was well tolerated and has been proven to be safe for further clinical use. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Double-Blind_Method_MeSH M_Drug_Interactions_MeSH M_Enzyme_Inhibitors_MeSH S_pharmacology_MeSH Enzyme_Inhibitors_pharmacology_MeSH M_Glyburide_MeSH S_blood_MeSH Glyburide_blood_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Inositol_MeSH S_analogs_&_derivatives_MeSH Inositol_analogs_&_derivatives_MeSH S_pharmacology_MeSH Inositol_pharmacology_MeSH M_Male_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 9404682 ----K E ----T Assisting effects of lithium on hypoglycemic treatment in patients with diabetes. ----A In this article, we report the assisting effect of lithium on hypoglycemic treatment in patients with diabetes. Thirty-eight diabetic patients, 15 male and 23 female, aged 20-70 yr, 33 noninsulin-dependent diabetes mellitus (NIDDM) patients, and 5 insulin-dependent diabetes mellitus (IDDM) patients, were recruited in this study. Fasting and 1-h postprandial blood glucose (BG) profiles were undertaken from three groups of patients with diabetes before and after short-term of treatment of lithium carbonate. Group I was treated with diet only, Group II with oral hypoglycemic agents (OHA), and Group III with insulin. The fasting blood glucose (FBG) level and 1-h postprandial blood glucose (1-h PBG) level before and after treatment of lithium were: Group I: FBG: 7.67 +/- 0.48 vs 7.13 +/- 0.82; 1-h PBG 15.13 +/- 0.88 vs 10.33 +/- 0.96; Group II: FBG: 8.84 +/- 0.67 vs 6.04 +/- 0.57; 1-h PBG: 12.33 +/- 0.72 vs 9.95 +/- 0.82; Group III: FBG: 10.87 +/- 0.83 vs 6.83 +/- 0.79; 1-h PBG: 12.45 +/- 0.93 vs 9.17 +/- 1.00 mmol/L, respectively. The FBG and PBG of all three groups decreased significantly after lithium treatment, except the FBG in Group I. These data suggest that combined with other therapy, lithium could improve glucose metabolism in most patients with diabetes. Our results suggest that lithium has an assisting hypoglycemic effect on antidiabetic treatment. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lithium_Carbonate_MeSH S_therapeutic_use_MeSH Lithium_Carbonate_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9405908 ----K E ----T Results of a placebo-controlled study of the metabolic effects of the addition of metformin to sulfonylurea-treated patients. Evidence for a central role of adipose tissue. ----A OBJECTIVE: To define the metabolic effects of metformin in the treatment of NIDDM and to evaluate potential mechanisms for its ability to improve glycemic control. RESEARCH DESIGN AND METHODS: Sulfonylurea-treated patients, with inadequate glycemic control, were treated with metformin in either a placebo-controlled or open fashion. Measurements were made of 1) fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations; 2) glucose appearance and disappearance rates measured overnight with 3-[3H]glucose; and 3) plasma FFA concentrations during a 45-min infusion period at relatively low (approximately 60 pmol/l) insulin concentrations. RESULTS: Mean +/- SE hourly plasma glucose, insulin, and FFA concentrations were similar before and after treatment in the placebo group. In contrast, mean hourly plasma glucose concentrations were significantly lower (P < 0.005) after metformin treatment in both the placebo-controlled and open-label groups (-3.9 +/- 1.0 and -4.4 +/- 0.8 mmol/l, respectively). Similarly, day-long hourly FFA levels were lower (P < 0.005) following metformin in the placebo-controlled and open-label groups (-87 +/- 35 and -136 +/- 31 mumol/l, respectively). Plasma insulin concentrations did not change with treatment in any group. Overnight glucose turnover studies indicated that neither the rate of glucose appearance (hepatic glucose production) or glucose disappearance changed significantly with treatment in the placebo or metformin groups. Because plasma glucose concentration was much lower after metformin treatment, overnight glucose metabolic clearance rate was significantly (P < 0.001) lower in this group. Finally, plasma FFA concentrations in response to a low-dosage insulin infusion (5 mU.m-2.min-1) were significantly lower after metformin as compared with the placebo-treated group (P < 0.001). CONCLUSIONS: Metformin treatment was associated with significantly lower day-long plasma glucose and FFA concentrations. Although overnight hepatic glucose production was unchanged following treatment with metformin, the overnight glucose metabolic clearance rate significantly increased. Given these findings, it is suggested that at least part of the antihyperglycemic effect of metformin is due to an increase in glucose uptake, secondary to a decrease in release of FFA from adipose tissue, and lower circulating FFA concentrations. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adipose_Tissue_MeSH S_drug_effects_MeSH Adipose_Tissue_drug_effects_MeSH S_metabolism_MeSH Adipose_Tissue_metabolism_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Circadian_Rhythm_MeSH S_physiology_MeSH Circadian_Rhythm_physiology_MeSH M_Cohort_Studies_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH S_metabolism_MeSH Fatty_Acids__Nonesterified_metabolism_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_pharmacology_MeSH Glipizide_pharmacology_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Single-Blind_Method_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Time_Factors_MeSH ****** 9463023 ----K E ----T [Pharmacokinetics of hypoglycemic sulfonamides: Ozidia, a new concept] ----A Hypoglycaemic sulfonamides differ in their properties, which vary in clinical importance. The potency of sulfonamide has increased with the generations. However, this potency is compensated in practice by the dose prescribed, which is much smaller for recent generations. The half-life is a far more important property. The effective action period is correlated with half-life but is much longer. The action period for "short-term" sulfonamides is < or = 24 h (tolbutamide, glipizide) and can exceed 24 h for "long-term" sulfonamides (e.g. glibenclamide). Metabolism and elimination reduce the risk of accumulation. All sulfonamides are metabolised more than 95% by the liver. The metabolites are inactive except for one from glibenclamide. As a function of their action period and possibly of intrinsic properties, some sulfonamides more than others (e.g. glibenclamide) affect fasting hepatic glucose production, which is particularly increased early in the day in non-insulin-dependent diabetic patients because of a circadian drop in insulin sensitivity (dawn phenomenon). Finally, in chronic administration, all sulfonamides cause a progressive desensitisation of the beta cell, which responds by an insulin secretion peak only during food intake. This condition indicates the unuselessness of sulfonamide fractionation and, contrary to the classic notion, the low risk of hypoglycaemia after a meal is skipped. The ideal product would be a sulfonamide with high potency and an ultra-short half-life, but capable of maintaining plasma concentrations for 24 h (which might seem incompatible except in continuous administration). Moreover, it would exert its action at relatively low levels of insulinaemia and be completely metabolisable. Glipizide in its osmotic oral form (Ozidia) satisfies all these conditions since it is a very potent sulfonamide with a quite short half-life but with intestinal delivery up to 16 h after administration because of its osmotic principle. It controls fasting glycaema better than ordinary glipizide and at least as well as glibenclamide by acting on hepatic glucose production. Compared to glibenclamide, it has the advantage of generation this effect at lower levels of insulinaemia. In comparison with normal glipizide, it allows identical control for lower postprandial inslinaemias, which is proof of its powerful inductive effect on insulin sensitivity. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Circadian_Rhythm_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_English_Abstract_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glipizide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Liver_MeSH S_drug_effects_MeSH Liver_drug_effects_MeSH S_metabolism_MeSH Liver_metabolism_MeSH ****** 9440664 ----K I ----T A prospective trial of risk factors for sulfonylurea-induced hypoglycemia in type 2 diabetes mellitus. ----A CONTEXT: Retrospective studies have identified oral sulfonylureas, age, and fasting as major risk factors for hypoglycemia in patients with type 2 diabetes. Sulfonylureas may be withheld from elderly patients out of concern for hypoglycemia. OBJECTIVE: To evaluate the hypoglycemic effects of maximum doses of once-daily second-generation sulfonylureas administered to fasting elderly patients. DESIGN: A prospective, randomized, double-blind clinical trial. SETTING: The University of New Mexico General Clinical Research Center. PATIENTS: Fifty-two sulfonylurea-treated subjects with type 2 diabetes with a mean (SD) age of 65.1 (5.7) years. INTERVENTIONS: Subjects were randomly assigned to glyburide or glipizide gastrointestinal therapeutic system (GITS). Each subject participated in three 23-hour fasting studies after the sequential administration of 1 week of placebo and 1 week of 10 mg and 1 week of 20 mg of the assigned sulfonylurea. MAIN OUTCOME MEASURES: Occurrence of hypoglycemia (defined as plasma glucose level <3.33 mmol/L [60 mg/dL]) and hormonal parameters during the final 9 hours of the 23-hour fast in patients who had taken sulfonylureas vs placebo. RESULTS: No hypoglycemia was observed during 156 fasting studies. Plasma glucose level was decreased (nadir, 4.9 mmol/L [88 mg/dL] for a 20-mg dose of glyburide vs 8.3 mmol/L [150 mg/dL] for placebo; nadir, 5.8 mmol/L [105 mg/dL] for a 20-mg dose of glipizide GITS vs 8.7 mmol/L [157 mg/dL] for placebo), and serum insulin was increased in the sulfonylurea studies compared with placebo (P<.001). Plasma glucose parameters did not differ between the 2 sulfonylureas, but C peptide concentrations were increased in the glyburide group compared with glipizide GITS in the 20-mg study (P=.05). Concentrations of epinephrine were increased in the sulfonylurea studies compared with placebo (P<.001). Epinephrine secretion increased when glucose concentration fell below the mean (SD) level of 9.10 (2.66) mmol/L (164 [48] mg/dL) in the 10-mg study and 8.77 (2.83) mmol/L (158 [51] mg/ dL) in the 20-mg study. CONCLUSIONS: Fasting was well tolerated among these elderly patients with type 2 diabetes treated with sulfonylureas. Older age should not be considered a contraindication to sulfonylurea treatment for diabetes. Stimulation of epinephrine secretion at normal or elevated plasma glucose levels appears to be the primary mechanism of protection against hypoglycemia in this study. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Age_Factors_MeSH M_Aged_MeSH M_Analysis_of_Variance_MeSH M_Blood_Chemical_Analysis_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Epinephrine_MeSH S_blood_MeSH Epinephrine_blood_MeSH M_Fasting_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glipizide_adverse_effects_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Peptides_MeSH S_blood_MeSH Peptides_blood_MeSH M_Prospective_Studies_MeSH M_Risk_Factors_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 9447960 ----K I ----T Possible risk of sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus and coronary artery disease. ----A ----P Letter ----M M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Myocardial_Infarction_MeSH S_etiology_MeSH Myocardial_Infarction_etiology_MeSH M_Risk_Factors_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 9454524 ----K I ----T United Kingdom Prospective Diabetes Study 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. United Kingdom Prospective Diabetes Study Group. ----A BACKGROUND: Uncertainty exists about the suitability of oral hypoglycemic drugs and insulin therapy for patients with newly diagnosed type 2 diabetes. OBJECTIVE: To assess and compare response to sulfonylurea, insulin, or metformin over 6 years in patients with newly diagnosed type 2 diabetes in whom disease could and could not be controlled with diet therapy alone. DESIGN: Multicenter, randomized, controlled trial. SETTING: Outpatient diabetes clinics of 15 hospitals in the United Kingdom. INTERVENTION: Sulfonylurea (chlorpropamide or glyburide), insulin, or metformin (if patients were obese). PATIENTS: 458 patients with newly diagnosed type 2 diabetes that could not be controlled with diet and had hyperglycemic symptoms or fasting plasma glucose levels greater than 15 mmol/L during the initial 3 months of diet therapy (primary diet failure group) and 1620 patients in whom disease was controlled by diet therapy and who had fasting plasma glucose levels of 6 to 15 mmol/L and no hyperglycemic symptoms while receiving diet therapy alone. MEASUREMENTS: Fasting plasma levels of glucose and insulin, hemoglobin A1c concentrations, body weight, and therapy required. RESULTS: Compared with the diet-controlled group, the primary diet failure group was younger and less obese and had more retinopathy, lower fasting plasma insulin levels, and reduced beta-cell function. At 6 years, patients allocated to insulin had lower fasting plasma glucose levels than did patients allocated to oral agents, but hemoglobin A1c concentrations were similar. Forty-eight percent (95% CI, 37% to 58%) of patients in the primary diet failure group maintained hemoglobin A1c concentrations less than 0.08. By 6 years, 51% of patients (CI, 42% to 62%) allocated to ultralente insulin required additional short-acting insulin and 66% of patients (CI, 58% to 73%) allocated to sulfonylurea required additional therapy with metformin or insulin to control symptoms and maintain fasting plasma glucose levels less than 15 mmol/L. Patients allocated to insulin gained more weight and had more hypoglycemic attacks than did patients allocated to sulfonylurea. Obese patients allocated to metformin gained the least weight and had the fewest hypoglycemic attacks. For all therapies, control achieved at 6 years was worse in the primary diet failure group than in the diet-controlled group. CONCLUSIONS: Because initial insulin therapy induced more hypoglycemic reactions and weight gain without necessarily providing better control, it may be reasonable to start with oral agents and change to insulin if goals for glycemic levels are not achieved. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Combined_Modality_Therapy_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Great_Britain_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_etiology_MeSH Hypoglycemia_etiology_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_MeSH S_blood_MeSH Obesity_blood_MeSH S_complications_MeSH Obesity_complications_MeSH M_Prospective_Studies_MeSH M_Statistics_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 9469681 ----K E ----T Population pharmacokinetics of glyburide in patients with well-controlled diabetes. ----A STUDY OBJECTIVES: To investigate glyburide pharmacokinetics in patients with well-controlled noninsulin-dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics. METHODS: Prospective, open-label study. SETTING: University-affiliated, internal medicine outpatient clinic. PATIENTS: Fifty-one patients with NIDDM (11 women, 40 men, mean age 56.7 +/- 15.3 yrs) receiving oral glyburide and with well-controlled glycohemoglobin levels 10.0% or below. INTERVENTION: After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5-2 hours, 2-5 hours, and 5-10 hours after dosing. MEASUREMENTS AND MAIN RESULTS: Serum glyburide was assayed by high-performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (> 60 yrs). CONCLUSION: Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Biological_Availability_MeSH M_Cohort_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Glyburide_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metabolic_Clearance_Rate_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH ****** 9492120 ----K E ----T Treatment of NIDDM in youth. ----A This study presents the characteristics of 20 children (17 female) with NIDDM who required oral hypoglycemic agent (OHA) therapy. A family history of NIDDM was present in 55%. None had islet cell antibodies (ICA) or glutamic acid decarboxylase (GAD) antibodies. Tolbutamide was the drug of choice; glibenclamide was introduced if glycemic control was not obtained after 2 to 3 months of tolbutamide therapy. Seven of the patients eventually required insulin therapy. ----P Case_Reports Journal_Article ----M M_Adolescent_MeSH M_Child_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Japan_MeSH M_Male_MeSH M_School_Health_Services_MeSH M_Tolbutamide_MeSH S_therapeutic_use_MeSH Tolbutamide_therapeutic_use_MeSH ****** 9517374 ----K E ----T Molecular effects of sulphonylurea agents in circulating lymphocytes of patients with non-insulin-dependent diabetes mellitus. ----A AIMS: In circulating lymphocytes of NIDDM patients pyruvate dehydrogenase (PDH), the major determinant in glucose consumption through oxidative pathways, is poorly active. The aim of this study is to examine whether sulphonylurea drug treatment revives PDH activity in circulating lymphocytes from NIDDM patients. METHODS: Twenty normal-weight individuals with NIDDM were enrolled in this study. They had maintained their glycaemic levels close to normal by means of a restricted diet that had no longer been successful in the proceeding 2 months. The treatment protocol consisted in 160 mg gliclazide daily for 5 weeks. Twenty healthy subjects, matched for age, body mass index and gender, were enrolled as a control group. Patients, before and after treatment, as well as controls were tested for PDH activity in their circulating lymphocytes. Nine other untreated patients and nine healthy subjects, with the above mentioned characteristics, were recruited for the assay of PDH activity in their circulating lymphocytes before and after exposure, in vitro, to gliclazide, to insulin, and to gliclazide and insulin in combination. RESULTS: In gliclazide-treated NIDDM patients, PDH activity in circulating lymphocytes recovered. In vitro, in circulating lymphocytes of untreated patients and controls insulin at 5 microU ml(-1) was ineffective and highly effective, respectively, in raising enzyme activity; gliclazide at 10 ng ml(-1) was ineffective on PDH in both groups, but in combination with insulin at 5 microU ml(-1) in both groups PDH was as active as in cells of controls exposed to insulin only. In cells of controls, gliclazide alone at 25-50 ng ml(-1) caused enzyme activation, whereas above 50 ng ml(-1) it caused inhibition; in cells of patients below 50 ng ml(-1) it had no effects, but at 50 ng ml(-1) and above raised enzyme activity to the basal level of controls. CONCLUSIONS: This study suggests that free gliclazide concentrations determine recovery of PDH activity in circulating lymphocytes of treated patients through drug-mediated enhanced insulin control over PDH or through the drug alone. ----P Journal_Article ----M M_Adult_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH M_Female_MeSH M_Gliclazide_MeSH S_pharmacology_MeSH Gliclazide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH M_Lymphocytes_MeSH S_drug_effects_MeSH Lymphocytes_drug_effects_MeSH S_enzymology_MeSH Lymphocytes_enzymology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Pyruvate_Dehydrogenase_Complex_MeSH S_blood_MeSH Pyruvate_Dehydrogenase_Complex_blood_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9519749 ----K E ----T Long-term treatment with the dual antithromboxane agent picotamide decreases microalbuminuria in normotensive type 2 diabetic patients. ----A Picotamide both inhibits thromboxane synthetase and acts as a thromboxane antagonist at the receptor level. We investigated the long-term effect of picotamide on urinary albumin excretion (UAE) at rest and induced by exercise in 30 type 2 diabetic patients who were normotensive and had microalbuminuria while at rest. The subjects of our study had a mean age of 52.5 +/- 1.6 years, BMI of 28.5 +/- 0.7 kg/m2, diabetes duration of 9.1 +/- 1.8 years, and HbA1c of 7.0 +/- 0.8%. The study was a randomized double-blind placebo-controlled trial. The patients were randomly allocated to receive for 1 year either picotamide, 300 mg, 3 tablets/day, or placebo, 3 tablets/day. The patients were asked to visit our outpatient clinic after 1, 3, 6, 9, and 12 months of treatment. At all times, blood pressure, microalbuminuria at rest, blood glucose, serum creatinine, serum picotamide, and creatinine clearance were measured; at baseline and after 6 and 12 months, all patients underwent submaximal physical exercise. After 6 months of picotamide, baseline and exercise-induced microalbuminuria were significantly decreased (up to one-third) as compared with the baseline and placebo level, with no further drops at month 12 of picotamide treatment. On placebo treatment, UAE at rest and after exercise was slightly increased compared with baseline values. The effects of picotamide occurred without significant side effects or changes in either blood pressure levels or glycometabolic control. Our study is the first long-term intervention trial in type 2 diabetes showing that an antithromboxane agent is able to decrease microalbuminuria, which in this disease is a dual marker of macro- and microangiopathy. Our findings suggest an important role for thromboxane in the pathophysiology of microalbuminuria in diabetes; moreover, we hypothesize that antithromboxane agents may have a place in the treatment/prevention of both macro- and microvascular complications in type 2 diabetic patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Albuminuria_MeSH S_metabolism_MeSH Albuminuria_metabolism_MeSH S_urine_MeSH Albuminuria_urine_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Cohort_Studies_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_II_prevention_&_control_MeSH M_Diabetic_Nephropathies_MeSH S_drug_therapy_MeSH Diabetic_Nephropathies_drug_therapy_MeSH S_physiopathology_MeSH Diabetic_Nephropathies_physiopathology_MeSH S_prevention_&_control_MeSH Diabetic_Nephropathies_prevention_&_control_MeSH M_Double-Blind_Method_MeSH M_Exercise_MeSH S_physiology_MeSH Exercise_physiology_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Heart_Rate_MeSH S_drug_effects_MeSH Heart_Rate_drug_effects_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phthalic_Acids_MeSH S_administration_&_dosage_MeSH Phthalic_Acids_administration_&_dosage_MeSH S_therapeutic_use_MeSH Phthalic_Acids_therapeutic_use_MeSH M_Platelet_Aggregation_Inhibitors_MeSH S_administration_&_dosage_MeSH Platelet_Aggregation_Inhibitors_administration_&_dosage_MeSH S_therapeutic_use_MeSH Platelet_Aggregation_Inhibitors_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thromboxane_B2_MeSH S_antagonists_&_inhibitors_MeSH Thromboxane_B2_antagonists_&_inhibitors_MeSH S_urine_MeSH Thromboxane_B2_urine_MeSH M_Time_Factors_MeSH ****** 10178657 ----K E ----T A short term cost-effectiveness model for oral antidiabetic medicines in Europe. ----A A short term (6-month) cost-effectiveness model has been developed to simulate current medical practice and disease progression in patients with type 2 (non-insulin-dependent) diabetes mellitus uncontrolled by diet and exercise. The model is based on decision-analytical techniques and includes probabilities of switching between treatments, the reason for the switch and the most common switch options. Effectiveness and economic measures are the 2 main outcomes. In order to assess effectiveness, we use symptom-free days with acceptable control (SFDACs), which represent each day of treatment without adverse events or symptoms, and with acceptable control of glucose and lipids. For the economic evaluation, only incremental costs incurred directly by a health insurance system are considered. This model should prove useful in the evaluation of new oral antidiabetic agents, since the short term aim of antidiabetic therapy is to provide adequate control in the absence of adverse effects and symptoms (a prerequisite for successful long term treatment). Furthermore, short term analysis provides data for comparing initial investment in drug therapy with potential savings over a longer treatment period. ----P Journal_Article ----M M_Comparative_Study_MeSH M_Cost-Benefit_Analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH M_Europe_MeSH M_Glyburide_MeSH S_economics_MeSH Glyburide_economics_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_economics_MeSH Hypoglycemic_Agents_economics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_economics_MeSH Insulin_economics_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_economics_MeSH Metformin_economics_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Models__Economic_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9533980 ----K E ----T Is there a concentration-effect relationship for sulphonylureas? ----A Sulphonylureas have remained the mainstay of oral therapy for type 2 (non-insulin-dependent) diabetes mellitus (NIDDM). They stimulate insulin release from pancreatic beta cells. Pharmacokinetic differences between the various sulphonylureas are of clinical importance in terms of the time to onset of action, timing of drug administration in relation to food intake, magnitude and duration of the glucose-lowering effect and the risk of serious hypoglycaemia. Recent studies with improved analytical sensitivity have shown that the elimination half-life of glibenclamide is longer than previously thought and that 2 metabolites of glibenclamide have significant hypoglycaemic activity. Furthermore, single dose studies in healthy volunteers using an integrated pharmacokinetic-pharmacodynamic model have identified clear concentration-effect relationships for both glibenclamide and its metabolites after oral and intravenous administration. Under multiple dose conditions, kinetic-dynamic relations have been identified with shorter-acting drugs in dosages that give discontinuous sulphonylurea exposure. However, at continuous exposure, i.e. sustained 24-hour therapeutic concentrations in plasma, there is evidence indicating the development of tolerance, which may be caused by downregulation of beta cell sensitivity. As more sophisticated concentration-effect studies appear, it has become evident that currently recommended maximum daily doses of many sulphonylureas are too high. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH ****** 9538962 ----K E ----T The effect of short periods of caloric restriction on weight loss and glycemic control in type 2 diabetes. ----A OBJECTIVE: To determine whether an intermittent very-low-calorie diet (VLCD) improves weight loss and glycemic control more than moderate caloric restriction alone. RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes (n = 54) who were > or = 20% over ideal body weight participated in a 20-week behavioral weight control program. Subjects were randomized to either a standard behavioral therapy (SBT) group or to one of two VLCD groups. SBT subjects received a 1,500-1,800 kcal/day diet throughout. Both VLCD groups followed a VLCD for 5 consecutive days during week 2, followed by either intermittent VLCD therapy for 1 day/week for 15 weeks (1-day) or for 5 consecutive days every 5 weeks (5-day), with a 1,500-1,800 kcal/day diet at other times. RESULTS: Both VLCD groups lost more weight than the SBT group over the 20 weeks (P = 0.04). Although the groups did not differ in fasting plasma glucose (FPG) changes at 20 weeks, more subjects in the 5-day group attained a normal HbA1c when compared with the SBT group (P = 0.04). This benefit was independent of the effects of weight loss. The best predictor of overall change in FPG and HbA1c was the FPG response during the first 3 weeks of the program. CONCLUSIONS: Periodic VLCDs improved weight loss in diabetic subjects. A regimen with intermittent 5-day VLCD therapy seemed particularly promising, because more subjects in this group attained a normal HbA1c. Moreover, the glucose response to a 3-week period of diet therapy predicted glycemic response at 20 weeks, and it was a better predictor of the 20-week response than initial or overall weight loss. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH P_Behavior_Therapy_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH P_Diet__Reducing_MeSH M_Energy_Intake_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_diet_therapy_MeSH Obesity_in_Diabetes_diet_therapy_MeSH S_physiopathology_MeSH Obesity_in_Diabetes_physiopathology_MeSH S_therapy_MeSH Obesity_in_Diabetes_therapy_MeSH M_Regression_Analysis_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Time_Factors_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH P_Weight_Loss_MeSH ****** 9538975 ----K I ----T UKPDS 28: a randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. U.K. Prospective Diabetes Study Group. ----A OBJECTIVE: To assess the efficacy over 3 years of the addition of metformin to maximum sulfonylurea therapy in type 2 diabetes. RESEARCH DESIGN AND METHODS: This multicenter randomized open-controlled trial was conducted in outpatient diabetes clinics in 15 U.K. hospitals. A total of 591 subjects who had already been randomly allocated to sulfonylurea therapy were taking maximum doses with suboptimal glycemic control, i.e., raised fasting plasma glucose (FPG) concentrations of 6-15 mmol/l but no significant hyperglycemic symptoms. The main outcome measures included FPG, glycated hemoglobin, protocol-defined marked hyperglycemia, body weight, blood pressure, fasting plasma lipids, compliance, and hypoglycemia and other side effects. RESULTS: After the addition of metformin, FPG concentrations decreased by mean (95% CI) -0.47 (-0.82 to -0.13) mmol/l over 3 years compared with an increase of 0.44 (0.07-0.81) mmol/l in subjects on sulfonylurea alone (P < 0.00001). Median FPG concentrations at 3 years were 8.6 vs. 9.9 mmol/l, respectively (P < 0.00001), and HbA1c values were 7.5 and 8.1%, respectively (P = 0.006). Adjustment for baseline BMI or FPG concentration did not affect response to therapy. Only 7% of those allocated to sulfonylurea plus metformin developed protocol-defined marked hyperglycemia compared with 36% of those allocated to sulfonylurea alone (P < 0.0001). Fasting plasma lipids, body weight, and blood pressure did not change significantly. The incidence of hypoglycemic episodes did not differ between groups: 4% on sulfonylurea plus metformin and 2% on sulfonylurea alone (NS). CONCLUSIONS: Early addition of metformin improved glycemic control in patients with suboptimal glycemic control while taking maximum sulfonylurea therapy, irrespective of obesity or baseline FPG concentrations. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH M_Chlorpropamide_MeSH S_therapeutic_use_MeSH Chlorpropamide_therapeutic_use_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Clinical_Protocols_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Great_Britain_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Patient_Compliance_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 9545119 ----K E ----T The blood glucose lowering effects of exercise and glibenclamide in patients with type 2 diabetes mellitus. ----A Physical exercise is associated with a fall in serum insulin levels, whereas sulphonylurea administration increases insulin release. To date, the opposing effects of exercise and sulphonylurea administration have not been systematically studied in Type 2 diabetic patients, who are not infrequently treated with sulphonylureas. In this study nine patients with Type 2 diabetes mellitus were subjected to four treatments in random order on separate days: (A) endurance exercise after the administration of 3.5 mg glibenclamide; (B) as A but given only 1.75 mg glibenclamide; (C) as A but with placebo; (D) rest and administration of 1.75 mg glibenclamide. Exercise and placebo resulted in only a small decrease in glycaemia. Rest and administration of 1.75 mg glibenclamide led to a moderate but steady fall in blood glucose concentrations. If glibenclamide administration and exercise were combined, blood glucose concentrations declined more markedly. Serum insulin concentrations showed a physiological decrease during exercise and placebo administration. If patients rested after administration of glibenclamide serum insulin levels rose and remained elevated. When exercise and glibenclamide were combined the rise in serum insulin levels was blunted and insulin levels fell once exercise was begun. Thus, exercise attenuates the glibenclamide induced increase in serum insulin in moderately hyperglycaemic Type 2 diabetic patients. Nevertheless, exercise has a substantial hypoglycaemic effect in glibenclamide treated Type 2 diabetic patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH P_Exercise_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lactic_Acid_MeSH S_blood_MeSH Lactic_Acid_blood_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9551006 ----K I ----T Modeling all-cause mortality: projections of the impact of smoking cessation based on the NHEFS. NHANES I Epidemiologic Follow-up Study. ----A OBJECTIVES: A model that relates clinical risk factors to subsequent mortality was used to simulate the impact of smoking cessation. METHODS: Survivor functions derived from multivariate hazard regressions fitted to data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Followup Study, a longitudinal survey of a representative sample of US adults, were used to project deaths from all causes. RESULTS: Validation tests showed that the hazard regressions agreed with the risk relationships reported by others, that projected deaths for baseline risk factors closely matched observed mortality, and that the projections attributed deaths to the appropriate levels of important risk factors. Projections of the impact of smoking cessation showed that the number of cumulative deaths would be 15% lower after 5 years and 11% lower after 20 years. CONCLUSIONS: The model produced realistic projections of the effects of risk factor modification on subsequent mortality in adults, Comparison of the projections for smoking cessation with estimates of the risk attributable to smoking published by the Centers for Disease Control and Prevention suggests that cessation could capture most of the benefit possible from eliminating smoking. ----P Journal_Article ----M M_Aged_MeSH M_Cause_of_Death_MeSH S_trends_MeSH Cause_of_Death_trends_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Forecasting_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Mortality_MeSH S_trends_MeSH Mortality_trends_MeSH M_Multivariate_Analysis_MeSH M_Nutrition_Surveys_MeSH M_Proportional_Hazards_Models_MeSH M_Reproducibility_of_Results_MeSH M_Risk_Factors_MeSH M_Smoking_MeSH S_mortality_MeSH Smoking_mortality_MeSH S_prevention_&_control_MeSH Smoking_prevention_&_control_MeSH P_Smoking_Cessation_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_United_States_MeSH S_epidemiology_MeSH United_States_epidemiology_MeSH ****** 9561345 ----K I ----T Glimepiride. A review of its use in the management of type 2 diabetes mellitus. ----A Glimepiride is a sulphonylurea agent that stimulates insulin release from pancreatic beta-cells and may act via extrapancreatic mechanisms. It is administered once daily to patients with type 2 (non-insulin-dependent) diabetes mellitus in whom glycaemia is not controlled by diet and exercise alone, and may be combined with insulin in patients with secondary sulphonylurea failure. The greatest blood glucose lowering effects of glimepiride occur in the first 4 hours after the dose. Glimepiride has fewer and less severe effects on cardiovascular variables than glibenclamide (glyburide). Pharmacokinetics are mainly unaltered in elderly patients or those with renal or liver disease. Few drug interactions with glimepiride have been documented. In patients with type 2 diabetes, glimepiride has an effective dosage range of 0.5 to 8 mg/day, although there is little difference in efficacy between dosages of 4 and 8 mg/day. Glimepiride was similar in efficacy to glibenclamide and glipizide in 1-year studies. However, glimepiride appears to reduce blood glucose more rapidly than glipizide over the first few weeks of treatment. Glimepiride and gliclazide were compared in patients with good glycaemic control at baseline in a 14-week study that noted no differences between their effects. Glimepiride plus insulin was as effective as insulin plus placebo in helping patients with secondary sulphonylurea failure to reach a fasting blood glucose target level of < or = 7.8 mmol/L, although lower insulin dosages and more rapid effects on glycaemia were seen with glimepiride. Although glimepiride monotherapy was generally well tolerated, hypoglycaemia occurred in 10 to 20% of patients treated for < or = 1 year and > or = 50% of patients receiving concomitant insulin for 6 months. Pooled clinical trial data suggest that glimepiride may have a lower incidence of hypoglycaemia than glibenclamide, particularly in the first month of treatment. Dosage is usually started at 1 mg/day, titrated to glycaemic control at 1- to 2-week intervals to a usual dosage range of 1 to 4 mg/day (maximum 6 mg/day in the UK or 8 mg/day in the US). CONCLUSIONS: Glimepiride is a conveniently administered alternative to other sulphonylureas in patients with type 2 diabetes mellitus not well controlled by diet alone. Its possible tolerability advantages and use in combination with other oral antidiabetic drugs require further study. Glimepiride is also reported to reduce exogenous insulin requirements in patients with secondary sulphonylurea failure when administered in combination with insulin. ----P Journal_Article Review Review__Tutorial ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Comparative_Study_MeSH M_Controlled_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Combinations_MeSH M_Drug_Interactions_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_metabolism_MeSH Islets_of_Langerhans_metabolism_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Tissue_Distribution_MeSH ****** 9571345 ----K I ----T Response to intensive therapy steps and to glipizide dose in combination with insulin in type 2 diabetes. VA feasibility study on glycemic control and complications (VA CSDM). ----A OBJECTIVE: The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VA CSDM) prospectively studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm during a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS: Five medical centers participated; half of the patients were assigned to the intensive treatment arm aiming for normal HbA1c levels. Age of patients was 60 +/- 6 years, duration of diabetes 8 +/- 3 years, and BMI 30.7 +/- 4 kg/m2. A four-step management technique was used, with patients moving to the next step if the operational goals were not met: Phase I, evening intermediate or long-acting insulin; phase II, added day-time glipizide; phase III, two injections of insulin alone; and phase IV, multiple daily insulin injections. Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases. RESULTS: Baseline HbA1c was 9.3 +/- 1.8%, and fasting plus serum glucose was 11.4 +/- 3.3 mmol/1. Fasting serum glucose fell to near normal in phase I, and remained so in the other treatment phases. An HbA1c separation of 2.1% between the arms was maintained during the course of the study, while the intensive arm kept HbA1c levels below 7.3% (P = 0.001). Most of the decrease in HbA1c occurred with one injection of insulin alone (phase I, -1.4%) or adding day-time glipizide (phase II, -1.9% compared with baseline). HbA1c did not decrease further after substituting two injections of insulin alone, with twice the insulin dose. Multiple daily injections resulted in an additional HbA1c fall (-2.4% compared with baseline). However, two-thirds of the patients were still on one or two injections a day at the end of the study. Changes in home glucose monitoring levels paralleled those of the HbA1c, as did the increments in number of reported hypoglycemic reactions, virtually all either "mild" or "moderate" in character. For the combination of glipizide and insulin (phase II), the only significant effect was obtained with daily doses up to 10 mg a day; there were no significant additional benefits with up to fourfold higher daily doses, and HbA1c levels had an upward trend with doses > 20 mg/day. CONCLUSIONS: A simple regime of a single injection of insulin, alone or with glipizide, seemed sufficient to obtain clinically acceptable levels of HbA1c for most obese, insulin-requiring type 2 diabetes patients. Further decrease of HbA1c demanded multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events. In combination therapy, doses of glipizide > 20 mg/day offered no additional benefit. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Glucose_Self-Monitoring_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glipizide_adverse_effects_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH ****** 10178668 ----K E ----T Evaluation of the potential clinical and economic effects of bodyweight stabilisation with acarbose in patients with type 2 diabetes mellitus. A decision-analytical approach. ----A Bodyweight is an acknowledged independent risk factor for coronary heart disease (CHD). The present model analysis was undertaken to investigate the clinical and economic impact of bodyweight gain in patients with type 2 (non-insulin-dependent) diabetes mellitus and its effects on the development of CHD. Based on a retrospective re-evaluation of data from the Diabetes Intervention Study (DIS), patients with type 2 diabetes mellitus and stable bodyweight (group A) had a significantly lower rate of combined CHD events (30.3%) than patients showing a bodyweight gain (group B; 38.2%) over 10 years. Prevention of bodyweight gain, therefore, appears to be a meaningful strategy in the management of diabetes mellitus. In addition to this clinical advantage, prevention of CHD will also result in economic savings associated with avoided treatment of coronary events. Based on the clinical outcomes from the DIS, the calculated per-patient net savings for a patient with type 2 diabetes mellitus and stable bodyweight amounted to 1085 deutschmarks (DM) when compared with a patient experiencing a bodyweight increase. In a further step, the above situation was projected to current type 2 diabetes mellitus practice. Oral first-line treatment of type 2 diabetes mellitus is usually initiated with glibenclamide (glyburide), which is known to increase bodyweight (reflecting group B). The novel alpha-glucosidase inhibitor acarbose, in contrast, appears to be as effective as glibenclamide, but has the advantage of being bodyweight-neutral (reflecting group A). From the clinical viewpoint, acarbose can thus be considered an alternative to glibenclamide. From the viewpoint of drug costs, monotherapy with acarbose is 4 times as expensive as glibenclamide in Germany, resulting in per-patient incremental costs of DM3527 for acarbose over 10 years. Balanced against the potential 10-year cost saving of DM1085 resulting from the potential of acarbose to prevent CHD, around one-third of the incremental cost of acarbose may be recouped by this single effect. However, further possible benefits of acarbose, including the avoidance of hypoglycaemia and the deferral of costly insulin therapy, may improve the economic value of this novel antidiabetic agent. Given the indirect approach of this evaluation and its many limitations, the above findings need critical appraisal, and comparative trials are urgently required to substantiate our preliminary results. ----P Journal_Article ----M M_Acarbose_MeSH M_Adult_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Decision_Support_Techniques_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH M_Female_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Trisaccharides_MeSH S_economics_MeSH Trisaccharides_economics_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 9585393 ----K E ----T Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. ----A Secondary failure of plasma glucose control following initial successful response to diet therapy may be due to dietary indiscretion, or to progression of the intrinsic diabetic condition. We report a 10-year prospective natural history study of 432 newly diagnosed diabetic patients aged 40-69 years undertaken to assess the effect of intensive dietary management, where patients were transferred to insulin, or oral hypoglycaemic therapy (tolbutamide, metformin) by predetermined criteria of weight and plasma glucose. Secondary failure to diet therapy occurred in 41 patients in years 2-4, 67 patients in years 5-7, and 51 patients in years 8-10; 173 patients remained on diet alone until death or the end of the study. Continuation on diet alone was associated with a lower ongoing fasting plasma glucose, greater beta-cell function assessed by an oral glucose tolerance test at 6 months, and increasing age. The rate of rise of fasting plasma glucose was inversely related to the duration of successful dietary therapy, but mean weight remained constant in all groups while on diet alone. The ongoing fall in beta-cell function assessed by HOMA modelling closely mirrored the progressive rise in fasting plasma glucose: there was no change in mean insulin sensitivity in any of the groups. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_physiopathology_MeSH Islets_of_Langerhans_physiopathology_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Northern_Ireland_MeSH M_Time_Factors_MeSH M_Tolbutamide_MeSH S_therapeutic_use_MeSH Tolbutamide_therapeutic_use_MeSH P_Treatment_Failure_MeSH ****** 9585394 ----K I ----T UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. ----A Patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) on sulphonylurea therapy convert to insulin progressively as the sulphonylureas 'fail'. The rate of failure and the features of those who fail have been poorly described. To assess secondary failure rates of sulphonylureas, we report on the responses in 1305 patients with newly diagnosed Type 2 DM randomly allocated to therapy with either chlorpropamide or glibenclamide in the UK Prospective Diabetes Study (UKPDS). These patients were initially treated by diet for 3 months and had a fasting plasma glucose > 6 mmol l(-1); mean age 53 (SD 9) years; BMI 26.8 (SD 5.0) kg m(-2); and median fasting plasma glucose 9.1 (7.6-12.5 quartiles) mmol l(-1). If their fasting plasma glucose subsequently rose above 15.0 mmol l(-1), or they developed hyperglycaemic symptoms, additional hypoglycaemic therapy was given: metformin, ultratard insulin, and soluble insulin as required. By 6 years, 44% had required additional therapy. Of those randomized to glibenclamide, 48% required additional therapy by 6 years, compared with 40% of those allocated to chlorpropamide (p < 0.01). Sixty-one per cent, 39%, and 23%, respectively, of patients with fasting plasma glucose > or = 10.0 mmol l(-1), > or = 7.8 mmol l(-1) to < 10.0 mmol l(-1) and < 7.8 mmol l(-1) at randomization required additional therapy (p < 0.001). In the initial 3 years, non-obese subjects (BMI < 30 kg m(-2)) were more likely to require additional therapy than obese patients (BMI > or = 30 kg m(-2)) (43% vs 53% at 6 years; p < 0.001). Modelled beta-cell function showed that those with lower function were more likely to fail (p < 0.0001). Thus sulphonylureas fail as a therapeutic agent at rates which are dependent both on the phenotype at presentation and perhaps on the agent used initially. Higher failure rates were found in those with higher glucose concentrations, those who were younger, those with lower beta-cell reserve and those randomized to glibenclamide compared with chlorpropamide. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Chlorpropamide_MeSH S_therapeutic_use_MeSH Chlorpropamide_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Fasting_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Great_Britain_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_physiopathology_MeSH Islets_of_Langerhans_physiopathology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH P_Treatment_Failure_MeSH ****** 9589224 ----K E ----T The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. ----A OBJECTIVE: Hypomagnesemia occurs in 25-38% of patients with type 2 diabetes. Several studies have suggested an association between magnesium (Mg) depletion and insulin resistance and/or reduction of insulin secretion in these cases. Our purpose was to evaluate if Mg supplementation (as magnesium oxide [MgO]) would improve metabolic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 128 patients with type 2 diabetes (32 men, 96 women, aged 30-69 years), treated by diet or diet plus oral antidiabetic drugs, in the Bahia Federal University Hospital, Brazil. Patients at risk for hypomagnesemia or with reduced renal function were excluded. This study was a clinical randomized double-blind placebo-controlled trial. Patients received either placebo, 20.7 mmol MgO, or 41.4 mmol MgO daily (elementary Mg) for 30 days. Mg concentrations were measured in plasma, in mononuclear cells, and in 24-h urine samples. Fasting blood glucose, HbA1, and fructosamine were used as parameters of metabolic control. RESULTS: Of the patients, 47.7% had low plasma Mg, and 31.1% had low intramononuclear Mg levels. Intracellular Mg in patients with diabetes was significantly lower than in the normal population (62 blood donors; 1.4 +/- 0.6 vs. 1.7 +/- 0.6 micrograms/mg of total proteins). No correlation was found between plasma and intracellular Mg concentrations (r = -0.179; P = 0.15) or between Mg concentrations and glycemic control (r = -0.165; P = 0.12). Intracellular Mg levels were lower in patients with peripheral neuropathy than in those without (1.2 +/- 0.5 vs. 1.5 +/- 0.6 micrograms/mg). Similar findings were observed in patients with coronary disease (1.0 +/- 0.5 vs. 1.5 +/- 0.6 micrograms/mg). In the placebo and in the 20.7 mmol Mg groups, neither a change in plasma and intracellular levels nor an improvement in glycemic control were observed. Replacement with 41.4 mmol Mg tended to increase plasma, cellular, and urine Mg and caused a significant fall (4.1 +/- 0.8 to 3.8 +/- 0.7 mmol/l) in fructosamine (normal, 1.87-2.87 mmol/l). CONCLUSIONS: Mg depletion is common in poorly controlled patients with type 2 diabetes, especially in those with neuropathy or coronary disease. More prolonged use of Mg in doses that are higher than usual is needed to establish its routine or selective administration in patients with type 2 diabetes to improve control or prevent chronic complications. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_II_prevention_&_control_MeSH P_Dietary_Supplements_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Fructosamine_MeSH S_metabolism_MeSH Fructosamine_metabolism_MeSH M_Glucose_Tolerance_Test_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH S_prevention_&_control_MeSH Hyperglycemia_prevention_&_control_MeSH M_Magnesium_MeSH S_administration_&_dosage_MeSH Magnesium_administration_&_dosage_MeSH S_blood_MeSH Magnesium_blood_MeSH S_urine_MeSH Magnesium_urine_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Reference_Values_MeSH ****** 9589246 ----K 3 ----T Changes in amylin and amylin-like peptide concentrations and beta-cell function in response to sulfonylurea or insulin therapy in NIDDM. ----A OBJECTIVE: Amylin, a secretory peptide of beta-cells, is the constituent peptide of islet amyloid, which is characteristic of NIDDM, and changes in amylin secretion in response to therapies may influence the rate of production of islet amyloid. The primary objective of this study was to determine whether therapy with sulfonylurea or basal insulin in NIDDM would alter amylin secretion in a way that might affect the formation of islet amyloid. RESEARCH DESIGN AND METHODS: In a randomized crossover design, eight subjects with NIDDM underwent three 8-week periods of therapy with diet alone, sulfonylurea, or exogenous basal insulin, with evaluation of amylin, amylin-like peptide (ALP), and glucose and C-peptide concentrations, both during fasting and after a standard breakfast. Changes in beta-cell function (% beta) were assessed, in the basal state by homeostasis model assessment (HOMA) and in the stimulated state by hyperglycemic clamps. Seven nondiabetic control subjects each underwent a meal profile and hyperglycemic clamp. RESULTS: Both sulfonylurea and insulin therapy reduced basal glucose concentrations compared with diet alone, but neither reduced the increased postprandial glucose increments. Both sulfonylurea and insulin therapy increased basal % beta, assessed by HOMA, but only sulfonylurea increased the second-phase C-peptide responses to the hyperglycemic clamp. Sulfonylurea increased time-averaged mean postprandial amylin and ALP concentrations compared with diet alone (geometric mean [1-SD range] for amylin, 4.9 [2.0-11.8] vs. 3.0 [1.4-6.2] pmol/l, P = 0.003; for ALP, 16.4 [8.5-31.7] vs. 10.1 [4.9-20.8] pmol/l, P = 0.001). Insulin therapy reduced basal ALP concentrations compared with diet alone (2.9 [1.5-5.6] vs. 6.0 [2.6-13.6] pmol/l, P = 0.03), but had no effect on postprandial concentrations of amylin (3.0 [1.3-6.5] pmol/l) or ALP (10.0 [5.5-18.1] pmol/l). CONCLUSIONS: By increasing postprandial concentrations of the constituent peptides of islet amyloid, sulfonylurea therapy might increase the rate of deposition of islet amyloid and thereby accelerate the decline of % beta in NIDDM, compared with diet therapy alone. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Amyloid_MeSH S_blood_MeSH Amyloid_blood_MeSH S_drug_effects_MeSH Amyloid_drug_effects_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH S_drug_effects_MeSH C-Peptide_drug_effects_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Fasting_MeSH M_Female_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Glucose_Clamp_Technique_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_physiopathology_MeSH Islets_of_Langerhans_physiopathology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9594432 ----K E ----T Oxidative stress and metabolic control in non-insulin dependent diabetes mellitus. ----A The aim of this study was to evaluate conjugated dienes in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and its metabolic control. To achieve good metabolic control in addition to dietary management oral hypoglycemic agents such as glibenclamide, gliclazide and metformin were given to patients. Human plasma low-density lipoproteins (LDL) were delipidised and triglycerides (LDL-TG) and cholesterol esters (LDL-CE) were separated. Conjugated dienes in LDL-TG and LDL-CE of subjects with NIDDM (n = 90) and normal glucose tolerance (NGT) (n = 30) were measured using second derivative of uv absorption spectrum. Hypoglycemic agents lowered substantially concentration of cis, trans (c, t) and trans, trans (t, t) conjugated dienes in LDL-CE and LDL-TG. The duration of NIDDM has shown significant correlation (p < 0.001) with conjugated dienes in LDL-TG. Concentration of c, t and t, t-conjugated dienes in LDL-CE and LDL-TG were found significantly higher in subjects with NIDDM than NGT (p < 0.001). In conclusion, NIDDM, status of metabolic control and duration of diabetes have strong positive relation with oxidative stress. ----P Journal_Article ----M M_Adult_MeSH M_Case-Control_Studies_MeSH M_Cholesterol_Esters_MeSH S_chemistry_MeSH Cholesterol_Esters_chemistry_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipoproteins__LDL_MeSH S_chemistry_MeSH Lipoproteins__LDL_chemistry_MeSH M_Middle_Aged_MeSH P_Oxidative_Stress_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_chemistry_MeSH Triglycerides_chemistry_MeSH ****** 9623011 ----K E ----T Effect of acarbose in treatment of type II diabetes mellitus: a double-blind, crossover, placebo-controlled trial. ----A This study evaluated the efficacy of acarbose in improvement of metabolic control in patients with fairly, well controlled non-insulin-dependent diabetes mellitus (NIDDM). Fifteen patients with mean age and duration of diabetes of 57.5 +/- 2.6 (SE) and 7.5 +/- 1.5 years, respectively were recruited and completed our study protocol. This study was a double-blind, crossover, placebo-controlled design consisting of two twelve-week treatments of acarbose and placebo separated by an eight-week washout period. Acarbose was effective in lowering of 1-hour and 2-hour postprandial plasma glucose from 251.7 +/- 10.7 and 205.3 +/- 9.1 mg/dl to 197.4 +/- 7.0 (p = 0.001) and 181.5 +/- 8.5 mg/dl (p = 0.03), respectively. Fasting plasma glucose was slightly decreased but without significant change, from 150.8 +/- 7.3 to 140.8 +/- 6.1 mg/dl (p = 0.07). Overall glycemic control tended to improve during the study period as indicated by the falling of HbA1c levels from 7.7 +/- 0.4 to 7.0 +/- 0.2 per cent (p = 0.05). Serum C-peptide both fasting and postprandial as well as serum lipids were not affected by acarbose. Almost half of the patients treated with acarbose had mild and tolerable gastrointestinal adverse effects. In conclusion, acarbose, as combined therapy with other oral hypoglycemic agents, was effective in improvement of glycemic control particularly postprandial hyperglycemia in fairly, well controlled NIDDM patients with mild and acceptable adverse effects. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Acarbose_MeSH M_Adult_MeSH M_Aged_MeSH M_Analysis_of_Variance_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Trisaccharides_MeSH S_adverse_effects_MeSH Trisaccharides_adverse_effects_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 9653594 ----K E ----T Beginning insulin treatment of obese patients with evening 70/30 insulin plus glimepiride versus insulin alone. Glimepiride Combination Group. ----A OBJECTIVE: This study tested a simple algorithm for beginning insulin for obese patients with type 2 diabetes after sulfonylurea failure, comparing suppertime 70/30 insulin plus continued glimepiride with insulin alone. RESEARCH DESIGN AND METHODS: This was a multicenter ambulatory randomized double-masked parallel comparison. There were 208 subjects with secondary failure to sulfonylureas who took glimepiride titrated to 8 mg b.i.d. for 8 weeks; 145 subjects with fasting plasma glucose (FPG) 180-300 mg/dl (10-16.7 mmol/l) on this treatment were randomized to placebo plus insulin (PI) or glimepiride plus insulin (GI) for 24 weeks. A dosage of 70/30 insulin before supper was titrated, seeking fasting capillary blood glucose (FBG) 120 mg/dl (6.7 mmol/l), equivalent to FPG 140 mg/dl (7.8 mmol/l). Outcome measures included FPG, HbA1c, insulin dosage, weight, serum insulin and lipids, and adverse events. RESULTS: FPG and HbA1c were equivalent at baseline: 261 vs. 250 mg/dl (14.5 vs. 13.9 mmol/l), and 9.9 vs. 9.7%. At 24 weeks, the FPG target was achieved in both groups (136 vs. 138 mg/dl, 7.6 vs. 7.6 mmol/l), and HbA1c values were equal (7.7 vs. 7.6%). However, with GI, control improved faster and fewer subjects dropped out (3 vs. 15%, P < 0.01), and less insulin was needed (49 vs. 78 U/d, P < 0.001). The outcomes were alike in other respects. No subject had severe hypoglycemia. CONCLUSIONS: Injection of 70/30 insulin before supper safely restored glycemic control of type 2 diabetes not controlled by glimepiride alone. Control was restored more rapidly and with less injected insulin when glimepiride was continued. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH S_drug_effects_MeSH C-Peptide_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH S_drug_effects_MeSH Lipoproteins__HDL_Cholesterol_drug_effects_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH S_drug_effects_MeSH Lipoproteins__LDL_Cholesterol_drug_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH M_Patient_Dropouts_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 9653611 ----K E ----T Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study. ----A OBJECTIVE: To determine the efficacy of acarbose, compared with placebo, on the metabolic control of NIDDM patients inadequately controlled on maximal doses of conventional oral agents. RESEARCH DESIGN AND METHODS: In this three-center double-blind study, 90 Chinese NIDDM patients with persistent poor glycemic control despite maximal doses of sulfonylurea and metformin were randomly assigned to receive additional treatment with acarbose 100 mg thrice daily or placebo for 24 weeks, after 6 weeks of dietary reinforcement. Efficacy was assessed by changes in HbA1c, fasting and 1-h postprandial plasma glucose and insulin levels, and fasting lipid levels. RESULTS: Acarbose treatment was associated with significantly greater reductions in HbA1c (-0.5 +/- 0.2% vs. placebo 0.1 +/- 0.2% [means +/- SEM], P = 0.038), 1-h postprandial glucose (-2.3 +/- 0.4 mmol/l vs. placebo 0.7 +/- 0.4 mmol/l, P < 0.001) and body weight (-0.54 +/- 0.32 kg vs. placebo 0.42 +/- 0.29 kg, P < 0.05). There was no significant difference between the two groups regarding changes in fasting plasma glucose and lipids or fasting and postprandial insulin levels. Flatulence was the most common side effect (acarbose vs. placebo: 28/45 vs. 11/44, P < 0.05). One patient on acarbose had asymptomatic elevations in serum transaminases that normalized in 4 weeks after acarbose withdrawal. Another patient on acarbose developed severe hypoglycemia; glycemic control was subsequently maintained on half the baseline dosage of sulfonylurea. CONCLUSIONS: In NIDDM patients inadequately controlled on conventional oral agents, acarbose in moderate doses resulted in beneficial effects on glycemic control, especially postprandial glycemia, and mean body weight. Additional use of acarbose can be considered as a useful alternative in such patients if they are reluctant to accept insulin therapy. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Acarbose_MeSH M_Administration__Oral_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_China_MeSH S_ethnology_MeSH China_ethnology_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH M_Double-Blind_Method_MeSH M_Drug_Resistance_MeSH M_Fasting_MeSH M_Female_MeSH M_Flatulence_MeSH S_chemically_induced_MeSH Flatulence_chemically_induced_MeSH M_Gastrointestinal_Diseases_MeSH S_chemically_induced_MeSH Gastrointestinal_Diseases_chemically_induced_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Hong_Kong_MeSH S_epidemiology_MeSH Hong_Kong_epidemiology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH S_drug_effects_MeSH Lipoproteins__HDL_Cholesterol_drug_effects_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Patient_Compliance_MeSH M_Placebos_MeSH M_Postprandial_Period_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Transaminases_MeSH S_drug_effects_MeSH Transaminases_drug_effects_MeSH S_metabolism_MeSH Transaminases_metabolism_MeSH M_Treatment_Outcome_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_Trisaccharides_MeSH S_adverse_effects_MeSH Trisaccharides_adverse_effects_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 9685916 ----K E ----T Accelerated oral absorption of gliclazide in human subjects from a soft gelatin capsule containing a PEG 400 suspension of gliclazide. ----A Whether a rapid elevation of serum gliclazide concentration in human subjects can be achieved through an acceleration of dissolution of gliclazide from a formulation was examined. A soft gelatin capsule containing PEG 400, PEG 4000, Tween 20 and glycerin was prepared as a formulation that may accelerate dissolution of gliclazide. The in vitro dissolution of gliclazide at pH 7.2 was identical for the soft capsule and conventional tablets, Diamicron and Diberin. However, at pH 1, 2 and 4.0 the dissolution from the soft capsule was more rapid compared to the tablets. When bioavailability parameters were compared following oral administration of the soft capsule and Diamicron to 16 healthy Korean male subjects, the parameters representing the amount of adsorption (i.e. the area under the serum gliclazide concentration vs. time curve up to 24 h, AUC24, and the peak serum concentration Cmax) were not statistically different for both formulations. However, the time required to reach the peak (Tmax) was significantly shorter for the soft capsule than for the Diamicron. Our results, therefore, indicate that a rapid elevation of serum gliclazide concentration following oral administration of a formulation can be achieved by accelerating the in vitro dissolution of gliclazide from the formulation into the acidic buffers. Thus, the rate of gastrointestinal absorption of gliclazide appears to be dependent on its in vivo dissolution rate in gastric fluid. A soft capsule containing a PEG 400 suspension of gliclazide appears to be an appropriate formulation for accelerating the dissolution. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Area_Under_Curve_MeSH M_Capsules_MeSH P_Drug_Delivery_Systems_MeSH M_Gelatin_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_blood_MeSH Gliclazide_blood_MeSH S_pharmacokinetics_MeSH Gliclazide_pharmacokinetics_MeSH M_Glycerol_MeSH M_Human_MeSH M_Hydrogen-Ion_Concentration_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Intestinal_Absorption_MeSH S_physiology_MeSH Intestinal_Absorption_physiology_MeSH M_Korea_MeSH P_Polyethylene_Glycols_MeSH M_Polysorbates_MeSH M_Solubility_MeSH M_Support__Non-U_S__Gov't_MeSH M_Therapeutic_Equivalency_MeSH ****** 9702849 ----K I ----T A placebo-controlled, randomized study of glimepiride in patients with type 2 diabetes mellitus for whom diet therapy is unsuccessful. ----A This multicenter, randomized, placebo-controlled study of glimepiride, a new oral sulfonylurea, was conducted in patients with type 2 diabetes for whom dietary treatment was unsuccessful (fasting plasma glucose [FPG] = 151-300 mg/dL) during a 1-week screening period. Patients were randomized to receive glimepiride (n = 123) or placebo (n = 126) once daily for a 10-week dose-titration period, then maintained on an individually determined optimal dose (1-8 mg of glimepiride or placebo) for 12 weeks. Glimepiride lowered FPG by 46 mg/dL, hemoglobin A1C (HbA1C) by 1.4%, and 2-hour postprandial glucose by 72 mg/dL more than placebo. Glimepiride improved postprandial insulin and C-peptide responses without producing clinically meaningful increases in fasting insulin or C-peptide levels. Good glycemic control (HbA1C < or = 7.2%) was achieved by 69% of the patients taking glimepiride versus 32% of those taking placebo. The overall incidence of adverse events was similar in both groups. No clinically noteworthy abnormal laboratory values or hypoglycemia (blood glucose < 60 mg/dL) occurred. Glimepiride is safe and effective for treatment of patients with type 2 diabetes for whom diet therapy is unsuccessful. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_metabolism_MeSH C-Peptide_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Diet_Therapy_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH S_metabolism_MeSH Fasting_metabolism_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9702426 ----K E ----T Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older women and men. The Rancho Bernardo Study. ----A OBJECTIVE: To determine whether diabetes defined by isolated postchallenge hyperglycemia (IPH) (2-h postchallenge plasma glucose > or = 11.1 mmol/l with fasting plasma glucose [FPG] < 7.0 mmol/l) increases the risk of fatal cardiovascular disease (CVD) in older women and men. RESEARCH DESIGN AND METHODS: In a prospective study, we followed 769 men and 1,089 women, aged 50-89 years, who had no history of diabetes or myocardial infarction and demonstrated no fasting hyperglycemia (i.e., FPG < 7.0 mmol/l) when they underwent oral glucose tolerance testing at baseline in 1984-1987. RESULTS: At baseline, 70% of 125 women and 48% of 133 men with previously undiagnosed diabetes had IPH. Over the next 7 years, women with IPH had a significantly increased risk of fatal CVD and heart disease compared with nondiabetic women. This increased risk was not observed in men with IPH. This association was independent of age, hypertension, central obesity, cigarette smoking, HDL cholesterol, and triglycerides (multiply adjusted hazard ratio and 95% CI: 2.6 and 1.4-4.7 for CVD; 2.9 and 1.3-6.4 for heart disease). CONCLUSIONS: Diabetes defined by IPH alone is common in older adults and more than doubles the risk of fatal CVD and heart disease in older women. Because the prevalence of IPH increases with age, the use of fasting glucose alone for diabetes screening or diagnosis may fail to identify most older adults at high risk for CVD and should be reevaluated. ----P Journal_Article Multicenter_Study ----M M_Adult_MeSH M_Age_Factors_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Alcohol_Drinking_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Constitution_MeSH M_Body_Mass_Index_MeSH M_California_MeSH S_epidemiology_MeSH California_epidemiology_MeSH M_Cardiovascular_Diseases_MeSH S_mortality_MeSH Cardiovascular_Diseases_mortality_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Cohort_Studies_MeSH M_Europe_MeSH S_ethnology_MeSH Europe_ethnology_MeSH M_European_Continental_Ancestry_Group_MeSH M_Fasting_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_epidemiology_MeSH Hyperglycemia_epidemiology_MeSH M_Hypertension_MeSH S_epidemiology_MeSH Hypertension_epidemiology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Risk_Factors_MeSH M_Sex_Factors_MeSH M_Smoking_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 9727892 ----K E ----T Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group. ----A OBJECTIVE: To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone. RESEARCH DESIGN AND METHODS: There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed. RESULTS: Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy CONCLUSIONS: Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Body_Weight_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Chromans_MeSH S_administration_&_dosage_MeSH Chromans_administration_&_dosage_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Treatment_Outcome_MeSH ****** 9732337 ----K E ----T Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. ----A OBJECTIVE: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. DESIGN: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg. SETTING: 20 hospital based clinics in England, Scotland, and Northern Ireland. SUBJECTS: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years. MAIN OUTCOME MEASURES: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography. RESULTS: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P=0.0046), 32% in deaths related to diabetes (6% to 51%) (P=0.019), 44% in strokes (11% to 65%) (P=0.013), and 37% in microvascular end points (11% to 56%) (P=0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P=0.0004) and a 47% reduced risk (7% to 70%) (P=0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures. CONCLUSION: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adrenergic_beta-Antagonists_MeSH S_therapeutic_use_MeSH Adrenergic_beta-Antagonists_therapeutic_use_MeSH M_Albuminuria_MeSH S_etiology_MeSH Albuminuria_etiology_MeSH M_Angiotensin-Converting_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Angiotensin-Converting_Enzyme_Inhibitors_therapeutic_use_MeSH M_Antihypertensive_Agents_MeSH S_therapeutic_use_MeSH Antihypertensive_Agents_therapeutic_use_MeSH M_Atenolol_MeSH S_therapeutic_use_MeSH Atenolol_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Captopril_MeSH S_therapeutic_use_MeSH Captopril_therapeutic_use_MeSH M_Cerebrovascular_Disorders_MeSH S_prevention_&_control_MeSH Cerebrovascular_Disorders_prevention_&_control_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH M_Diabetic_Angiopathies_MeSH S_physiopathology_MeSH Diabetic_Angiopathies_physiopathology_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Diabetic_Retinopathy_MeSH S_prevention_&_control_MeSH Diabetic_Retinopathy_prevention_&_control_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Human_MeSH M_Hypertension_MeSH S_prevention_&_control_MeSH Hypertension_prevention_&_control_MeSH M_Hypoglycemia_MeSH S_etiology_MeSH Hypoglycemia_etiology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Myocardial_Infarction_MeSH S_prevention_&_control_MeSH Myocardial_Infarction_prevention_&_control_MeSH M_Patient_Compliance_MeSH M_Peripheral_Vascular_Diseases_MeSH S_prevention_&_control_MeSH Peripheral_Vascular_Diseases_prevention_&_control_MeSH M_Prospective_Studies_MeSH M_Proteinuria_MeSH S_etiology_MeSH Proteinuria_etiology_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Visual_Acuity_MeSH M_Weight_Gain_MeSH S_drug_effects_MeSH Weight_Gain_drug_effects_MeSH ****** 9739505 ----K E ----T Repaglinide. ----A Repaglinide is a novel insulin secretagogue being developed for the management of type 2 (non-insulin-dependent) diabetes mellitus. It stimulates release of insulin from the pancreatic beta-cell, but appears to bind to a different receptor site from sulphonylureas. Repaglinide lowers fasting and postprandial blood glucose levels in animals, healthy volunteers and patients with type 2 diabetes mellitus. Repaglinide is rapidly absorbed and eliminated, which may allow a relatively fast onset and offset of action. Excretion occurs almost entirely by non-renal mechanisms. In comparative clinical trials in patients with type 2 diabetes mellitus, repaglinide 0.5 to 4 mg twice or 3 times daily before meals provided similar glycaemic control to glibenclamide (glyburide) 2.5 to 15 mg/day. Addition of repaglinide to existing metformin therapy resulted in improved glycaemic control. In contrast with glibenclamide, use of repaglinide allowed patients to miss a meal without apparently increasing the risk of hypoglycaemia. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Experimental_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Experimental_drug_therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Randomized_Controlled_Trials_MeSH M_Stereoisomerism_MeSH ****** 9742976 ----K I ----T Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. ----A BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED) ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Chlorpropamide_MeSH S_therapeutic_use_MeSH Chlorpropamide_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Female_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prospective_Studies_MeSH M_Risk_Factors_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 9742977 ----K E ----T Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. ----A BACKGROUND: In patients with type 2 diabetes, intensive blood-glucose control with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks. This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage. METHODS: Of 4075 patients recruited to UKPDS in 15 centres, 1704 overweight (>120% ideal bodyweight) patients with newly diagnosed type 2 diabetes, mean age 53 years, had raised fasting plasma glucose (FPG; 6.1-15.0 mmol/L) without hyperglycaemic symptoms after 3 months' initial diet. 753 were included in a randomised controlled trial, median duration 10.7 years, of conventional policy, primarily with diet alone (n=411) versus intensive blood-glucose control policy with metformin, aiming for FPG below 6 mmol/L (n=342). A secondary analysis compared the 342 patients allocated metformin with 951 overweight patients allocated intensive blood-glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). The primary outcome measures were aggregates of any diabetes-related clinical endpoint, diabetes-related death, and all-cause mortality. In a supplementary randomised controlled trial, 537 non-overweight and overweight patients, mean age 59 years, who were already on maximum sulphonylurea therapy but had raised FPG (6.1-15.0 mmol/L) were allocated continuing sulphonylurea therapy alone (n=269) or addition of metformin (n=268). FINDINGS: Median glycated haemoglobin (HbA1c) was 7.4% in the metformin group compared with 8.0% in the conventional group. Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017), and 36% for all-cause mortality (9-55, p=0.011). Among patients allocated intensive blood-glucose control, metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint (p=0.0034), all-cause mortality (p=0.021), and stroke (p=0.032). Early addition of metformin in sulphonylurea-treated patients was associated with an increased risk of diabetes-related death (96% increased risk [95% CI 2-275], p=0.039) compared with continued sulphonylurea alone. A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related endpoints (risk reduction 19% [2-33], p=0.033). Epidemiological assessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin (risk reduction 5% [-33 to 32], p=0.78). INTERPRETATION: Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Chlorpropamide_MeSH S_therapeutic_use_MeSH Chlorpropamide_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_blood_MeSH Obesity_in_Diabetes_blood_MeSH M_Prospective_Studies_MeSH M_Risk_Factors_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 9750481 ----K E ----T [Pitfalls in treatment with oral antidiabetic agents] ----A In the treatment of type 2 diabetes (NIDDM) we possess three groups of oral hypoglycaemic drugs: sulfonyl urea derivatives, biguanides (metformin) and alpha-glucosidase (acarbose) inhibitors. Oral treatment of diabetes has a favourable impact on the patients metabolic deviations but it involves also certain dangers and pitfalls. The side-effects of oral antidiabetics can be reduced to a minimum by respecting consequentially contraindications of administration of different preparations, knowledge of their mechanism of action and individual selection of a suitable antidiabetic for every patient. ----P Journal_Article Review Review__Tutorial ----M M_Acarbose_MeSH M_Administration__Oral_MeSH M_Biguanides_MeSH S_administration_&_dosage_MeSH Biguanides_administration_&_dosage_MeSH S_adverse_effects_MeSH Biguanides_adverse_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH M_Trisaccharides_MeSH S_administration_&_dosage_MeSH Trisaccharides_administration_&_dosage_MeSH S_adverse_effects_MeSH Trisaccharides_adverse_effects_MeSH ****** 9762378 ----K E ----T Issues surrounding tight glycemic control in people with type 2 diabetes mellitus. ----A OBJECTIVE: To review the prospective evidence surrounding the issue of tight glycemic control in people with type 2 diabetes mellitus and resultant long-term complications. DATA SOURCE: Conference proceedings and a MEDLINE search (1966-February 1998) identified pertinent English-language publications on type 2 diabetes in humans. Key search terms included insulin resistance, diabetes mellitus, non-insulin-dependent, macrovascular complications, microvascular complications, and intensive glycemic control. STUDY SELECTION: Selection of prospective epidemiologic and clinical studies were limited to those focusing on the management of type 2 diabetes. All articles with pertinent information relevant to the scope of this article were reviewed. DATA SYNTHESIS: The pathophysiology of type 1 and type 2 diabetes differ; however, both share chronic complications that significantly affect morbidity and mortality. People with type 1 diabetes have an absolute deficiency of insulin, whereas people with type 2 diabetes have varying degrees of insulin resistance and an inadequate compensatory insulin secretory response. The Diabetes Control and Complications Trial (DCCT) has clearly indicated that intense control of blood glucose in type 1 diabetes prevents and slows the progression of microvascular (i.e., retinopathy, nephropathy) and neuropathic complications. The Kumamoto study showed similar results in nonobese patients with type 2 diabetes. Intense insulin therapy in both populations has proven advantageous, thus supporting a common pathophysiologic process for the microvascular and neuropathic complications. Trends were seen toward fewer macrovascular (atherosclerotic disease) complications in the intensive insulin arm of the DCCT. Conversely, trends were seen toward an increase in macrovascular complications in the VA Cooperative study in people with type 2 diabetes using intensive insulin therapy. This may suggest a discordance in the pathophysiology of macrovascular disease between type 1 and type 2 diabetes. Additionally, it remains uncertain whether tight glycemic control prevents the onset or slows the progression of macrovascular disease. Two studies (the University Group Diabetes Program and the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes) to date have examined pharmacotherapy options for patients with type 2 diabetes and resultant macrovascular complications. It has yet to be determined whether any therapeutic intervention will decrease the morbidity and mortality of macrovascular disease in this population. CONCLUSIONS: In type 2 diabetes, limited prospective evidence does support tight glycemic control to help prevent or slow the progression of microvascular and neuropathic complications. It is uncertain whether tight glycemic control decreases macrovascular complications and which pharmacotherapeutic agent(s) is/are the best options. However, therapy that improves glucose control in combination with aggressive risk factor management should be initiated and enforced in patients with type 2 diabetes in an effort to reduce long-term complications. ----P Journal_Article Review Review__Tutorial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Human_MeSH M_Insulin_Resistance_MeSH M_MEDLINE_MeSH M_Randomized_Controlled_Trials_MeSH ****** 9789590 ----K E ----T [New therapies in type 2 diabetes] ----A The progress of knowledge relating to non-insulin-dependent diabetes mellitus (NIDDM) is associated with new therapeutic developments. Their different respective targets allow to classify them in drugs stimulating insulin secretion (glimepiride, repaglinide, glucagon-like peptide 1), medications reducing insulin resistance (thiazolidinediones) or in insulinmimetic agents (vanadium). Alpha glucosidase inhibitors, available in France since 1993, constitute another therapeutic approach, reducing postprandial hyperglycemia by delaying the digestion of complex carbohydrates. These new medications, safer and sometimes effective in a single daily administration, represent an alternative to classic oral antidiabetic agents allowing therapeutic combinations and a more global management of NIDDM. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Enzyme_Inhibitors_therapeutic_use_MeSH M_Human_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Insulin_Resistance_MeSH M_Secretory_Rate_MeSH S_drug_effects_MeSH Secretory_Rate_drug_effects_MeSH M_Structure-Activity_Relationship_MeSH M_Vanadium_MeSH S_therapeutic_use_MeSH Vanadium_therapeutic_use_MeSH M_alpha-Glucosidases_MeSH S_antagonists_&_inhibitors_MeSH alpha-Glucosidases_antagonists_&_inhibitors_MeSH ****** 9797183 ----K E ----T Effects of glibenclamide on blood pressure and cardiovascular responsiveness in non-insulin dependent diabetes mellitus. ----A OBJECTIVE: To compare the effects of chronic glibenclamide therapy and placebo on blood pressure and cardiovascular responsiveness in patients with non-insulin-dependent diabetes. DESIGN AND METHODS: Fourteen patients with non-insulin-dependent diabetes mellitus, seven of whom were receiving angiotensin converting enzyme inhibitor therapy, received glibenclamide or placebo for 1 month in a double-blind, randomized crossover study. At the end of each treatment period patients attended for studies of forearm vascular responsiveness to intra-brachial arterial infusions of angiotensin II, acetylcholine, sodium nitroprusside and noradrenaline, responses of blood pressure to intravenous infusions of noradrenaline and angiotensin II and 24 h ambulatory blood pressure monitoring. RESULTS: Administration of glibenclamide produced significantly better glycaemic control than placebo (fasting blood glucose level 8.5 +/- 2.4 versus 13.5 +/- 4.5 mmol/l, P < 0.001) and plasma insulin levels were significantly higher during glibenclamide treatment than they were with placebo (12.9 +/- 4.4 versus 9.2 +/- 4.1 mU/l, P < 0.05). Body weights at the ends of the glibenclamide treatment and placebo phases were similar (92.1 +/- 14.3 versus 91.1 +/- 14.3 kg, P = 0.085). Night-time systolic blood pressures were significantly higher during glibenclamide treatment than they were with placebo (128 +/- 17 versus 118 +/- 10 mmHg, P < 0.05) due to there being a smaller day-night difference in systolic blood pressure during glibenclamide treatment that appeared to occur mainly in patients receiving angiotensin converting enzyme inhibitors. Responses of diastolic blood pressure to intravenous infusion of angiotensin II and forearm vascular responses to intra-brachial arterial infusion of angiotensin II were significantly greater during glibenclamide treatment than they were with placebo (P < 0.05). However, the enhancement of forearm vascular responses during glibenclamide treatment appeared to be restricted to patients receiving angiotensin converting enzyme inhibitors. Responses of blood pressure to intravenous infusion of noradrenaline and forearm vascular responses to infusions of noradrenaline, acetylcholine and nitroprusside did not differ between glibenclamide treatment and placebo; neither did basal forearm vascular resistance. CONCLUSIONS: Glibenclamide therapy is associated with greater responses of blood pressure and forearm vascular responses to infusion of angiotensin and higher nocturnal blood pressures. This effect appears to be influenced by concomitant angiotensin converting enzyme inhibition. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acetylcholine_MeSH S_pharmacology_MeSH Acetylcholine_pharmacology_MeSH M_Adult_MeSH M_Aged_MeSH M_Angiotensin_II_MeSH S_pharmacology_MeSH Angiotensin_II_pharmacology_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Forearm_MeSH S_blood_supply_MeSH Forearm_blood_supply_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Nitroprusside_MeSH S_pharmacology_MeSH Nitroprusside_pharmacology_MeSH M_Norepinephrine_MeSH S_pharmacology_MeSH Norepinephrine_pharmacology_MeSH M_Regional_Blood_Flow_MeSH S_drug_effects_MeSH Regional_Blood_Flow_drug_effects_MeSH M_Vasoconstriction_MeSH S_drug_effects_MeSH Vasoconstriction_drug_effects_MeSH M_Vasoconstrictor_Agents_MeSH S_pharmacology_MeSH Vasoconstrictor_Agents_pharmacology_MeSH ****** 9802740 ----K I ----T A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes. ----A OBJECTIVE: The objective of the study was to assess the efficacy and safety of repaglinide compared with placebo in the treatment of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a phase II multicenter, double-blind, placebo-controlled, randomized, dose-adjustment and maintenance trial. After screening and a 2-week washout period, 99 patients were randomized to receive either repaglinide (n = 66) or placebo (n = 33). Patients underwent 6 weeks of dose adjustment followed by 12 weeks of dose maintenance. Fasting and stimulated glycosylated hemoglobin (HbA1c), plasma glucose, insulin, and C-peptide were measured at predetermined intervals. Adverse events and hypoglycemic episodes were recorded. RESULTS: From baseline to last visit, mean HbA1c decreased from 8.5 to 7.8% in patients treated with repaglinide and increased from 8.1 to 9.3% in patients receiving placebo, with a statistically significant difference of - 1.7% (P < 0.0001) between treatment groups at the last visit. Mean fasting plasma glucose and postprandial glucose increased in patients receiving placebo and decreased in patients treated with repaglinide, with statistically significant (P < 0.01) differences between groups at the last visit. Concentrations of fasting and postprandial insulin and C-peptide were lower at the last visit compared with baseline for patients treated with placebo and higher for patients treated with repaglinide, and the differences between groups were statistically significant (P < 0.05). Overall, repaglinide was well tolerated. CONCLUSIONS: This study demonstrated that repaglinide was safe and efficacious in lowering blood glucose concentrations. In addition to overall improvement in glycemic control noted with repaglinide in both sulfonylurea-treated patients and oral hypoglycemic agent-naive patients, repaglinide had a potent glucose-lowering effect in the postprandial period. ----P Clinical_Trial Clinical_Trial__Phase_II Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9802745 ----K E ----T Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure. ----A OBJECTIVE: Glucagon-like peptide 1 (GLP-1) has glucose-dependent insulinotropic and glucagonostatic actions in type 2 diabetic patients on diet and on oral agents. It is not known, however, whether after secondary sulfonylurea failure, GLP-1 is still effective. RESEARCH DESIGN AND METHODS: Therefore, 10 type 2 diabetic patients (6 women, 4 men; age 65+/-10 years, BMI 30.4+/-5.1 kg/m2, HbA1c 8.2+/-1.5%, 6+/-3 [2-13] years after starting insulin treatment) were examined in the fasting state after discontinuing NPH insulin on the evening before the two study days. GLP-1 (1.2 pmol x kg(-1) x min(-1) or placebo (NaCl with 1% human serum albumin) were infused over 6 h. Plasma glucose (glucose oxidase) insulin (IMx), and C-peptide (enzyme-linked immunosorbent assay) were measured. Statistical analysis was performed using repeated measures analysis of variance. RESULTS: Fasting plasma glucose was 9.4+/-0.5 mmol/l and was reduced by GLP-1 to 5.3+/-0.3 (3.9-7.3) mmol/l (placebo: 8.2+/-0.7 mmol/l; P < 0.0001). GLP-1 transiently increased insulin (from 115+/-31 to 222+/-64 pmol/l at 150 min; P < 0.0001) and C-peptide (from 1.00+/-0.12 to 1.90+/-0.23 nmol/l at 120 min; P < 0.0001) with no effect of placebo. Glucagon and free fatty acids were lowered transiently. After normalization of plasma glucose, insulin and C-peptide concentrations became lower again during the ongoing administration of exogenous GLP-1, and no hypoglycemia occurred. CONCLUSIONS: It is concluded that exogenous GLP-1 effectively lowers plasma glucose concentrations in advanced type 2 diabetes long after sulfonylurea secondary failure. These findings may broaden the applicability of GLP-1-derived drugs as a new treatment to nearly all type 2 diabetic patients. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Calorimetry__Indirect_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Enzyme-Linked_Immunosorbent_Assay_MeSH M_Fasting_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH S_therapeutic_use_MeSH Glucagon_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Peptide_Fragments_MeSH S_therapeutic_use_MeSH Peptide_Fragments_therapeutic_use_MeSH M_Postprandial_Period_MeSH M_Proinsulin_MeSH S_blood_MeSH Proinsulin_blood_MeSH M_Protein_Precursors_MeSH S_therapeutic_use_MeSH Protein_Precursors_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 9812648 ----K E ----T [Clinical study of glibenclamide in combination with kelening treatment in non-insulin dependent diabetes mellitus] ----A OBJECTIVE: To asses the efficacy of combination therapy of glibenclamide and Kelening in treating the non-insulin dependent diabetes mellitus (NIDDM). METHODS: Sixty-five patients with NIDDM were randomly divided into two groups. One group was treated with both glibenclamide and Kelening, the other with glibenclamide alone. RESULTS: After treatment for 12 weeks, the levels of fasting blood glucose (FBG), postprandial blood glucose (PBG) and HBAIC were reduced significantly in glibenclamide-Kelening group. In both groups, the degree dropped of the levels of FBG were almost the same, but the levels of PBG and HBAIC in glibenclamide-Kelening group were reduced more significantly than those in glibenclamide group, and the incidence of hyperinsulinemia had dropped considerably. CONCLUSION: Glibenclamide in combination with Kelening in the treatment of NIDDM is more effective and less toxic, and the combination may reduce the dosage of glibenclamide in NIDDM. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Combinations_MeSH M_Drugs__Chinese_Herbal_MeSH S_therapeutic_use_MeSH Drugs__Chinese_Herbal_therapeutic_use_MeSH M_English_Abstract_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH ****** 9833950 ----K E ----T Reduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes. ----A To assess in vivo effects of antioxidants on vascular cell adhesion molecule (VCAM)-1 expression, circulating soluble VCAM-1 and intraerythrocytic reduced glutathione (GSH) and GSH disulphide (GSSG) concentrations were evaluated in non-insulin-dependent diabetic patients without complications (9 men, 6 women, 48 +/- 6 years old) before and after 1 month of either oral N-acetyl-L-cysteine (1.200 mg/day) or placebo treatments, given in randomized, cross-over, double-blind fashion. Ten healthy subjects (7 men, 3 women, 52 +/- 4 years old) served as control subjects. Baseline plasma VCAM-1 concentrations were higher (p = 0.007) in non-insulin-dependent diabetic patients (707.9 +/- 52.5 ng/ml) than in control subjects (627.3 +/- 84.6 ng/ml). Intraerythrocytic GSSG content was higher (non-insulin dependent diabetic patients: 0.618 +/- 0.185 micromol/g Hb; control subjects: 0.352 +/- 0.04 micromol/g Hb, p = 0.0002), whereas intraerythrocytic GSH concentrations were lower (p = 0.001) in non-insulin dependent diabetic patients (6.0 +/- 0.7 micromol/g Hb) than in control subjects (7.1 +/- 0.5 micromol/g Hb). The mean GSH:GSSG ratio was also lower (p = 0.0001) in the first (10.9 +/- 4.5) than in the second group (20.2 +/- 1.4). Circulating VCAM-1 and intraerythrocytic GSH concentrations were negatively correlated in non-insulin diabetic patients (r = 0.605, p = 0.01). Treatment with N-acetyl-L-cysteine decreased plasma VCAM-1 (p = 0.01) and intraerythrocytic GSSG (p = 0.006) but increased GSH concentrations (p = 0.04) and the GSH:GSSG ratio (p = 0.004) in non-insulin dependent diabetic patients. Our data indicate that the vascular endothelium is activated in non-insulin dependent diabetes. Antioxidant treatment counterbalanced such endothelial activation. Thus, antioxidant agents might protect against oxidant-related upregulation of endothelial adhesion molecules and slow down the progression of vascular damage in non-insulin dependent diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acetylcysteine_MeSH S_administration_&_dosage_MeSH Acetylcysteine_administration_&_dosage_MeSH S_pharmacology_MeSH Acetylcysteine_pharmacology_MeSH S_therapeutic_use_MeSH Acetylcysteine_therapeutic_use_MeSH M_Administration__Oral_MeSH M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH M_Erythrocytes_MeSH S_drug_effects_MeSH Erythrocytes_drug_effects_MeSH S_metabolism_MeSH Erythrocytes_metabolism_MeSH M_Female_MeSH M_Free_Radical_Scavengers_MeSH S_administration_&_dosage_MeSH Free_Radical_Scavengers_administration_&_dosage_MeSH S_pharmacology_MeSH Free_Radical_Scavengers_pharmacology_MeSH S_therapeutic_use_MeSH Free_Radical_Scavengers_therapeutic_use_MeSH M_Glutathione_Disulfide_MeSH S_blood_MeSH Glutathione_Disulfide_blood_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Oxidative_Stress_MeSH S_drug_effects_MeSH Oxidative_Stress_drug_effects_MeSH S_physiology_MeSH Oxidative_Stress_physiology_MeSH M_Reference_Values_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH M_Vascular_Cell_Adhesion_Molecule-1_MeSH S_blood_MeSH Vascular_Cell_Adhesion_Molecule-1_blood_MeSH ****** 9834926 ----K 5 ----T High-fat versus high-carbohydrate enteral formulae: effect on blood glucose, C-peptide, and ketones in patients with type 2 diabetes treated with insulin or sulfonylurea. ----A Recently, two commercial enteral formulae for diabetic patients have been made available in Spain: a high-complex-carbohydrate, low-fat formulation (HCF) and a low-carbohydrate formulation (RCF). This study compares the effects of the two enteral nutritional formulae in patients with non-insulin-dependent diabetes mellitus (type 2 diabetes) treated with sulfonylurea or insulin. Fifty-two type 2 diabetes patients were randomly assigned to receive one of the two enteral formulae. Test enteral formula breakfast (250 cc) were consumed at approximately 0900 h after routine medications (insulin or oral agents) had been taken. Venous blood samples were obtained during fasting, before medication, and at 30 and 120 min after the start of the meal. The glycemic response of patients to the HCF was significantly greater than to RCF, but lower than in the sulfonyl type 2 diabetes treated groups. The incremental glucose response was within acceptable levels except in insulin treatment type 2 diabetes patients given HCF. Glucose, insulin, and C-peptide responses were higher in HCF than RCF groups. Two-factor analysis of variance on mean increments of blood glucose and C-peptide from basal levels to 30 min show the type of enteral nutrition as the main factor (P = 0.0010 and P = 0.0005, respectively). The RCF formula supplies 50.0% of energy as fat and 33.3% as carbohydrates, so it may be a ketogenic diet. It was found that both ketone bodies were higher after RCF than after HCF ingestion, but without statistical significance. We conclude that the partial replacement of complex digestible carbohydrates with monounsaturated fatty acids in the enteral formulae for supplementation of oral diet may improve glycemic control in patients with type 2 diabetes. The long-term effects of enteral diets high in monounsaturated fatty acids need further evaluation in patients with type 2 diabetes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dietary_Carbohydrates_MeSH S_administration_&_dosage_MeSH Dietary_Carbohydrates_administration_&_dosage_MeSH M_Dietary_Fats_MeSH S_administration_&_dosage_MeSH Dietary_Fats_administration_&_dosage_MeSH M_Energy_Intake_MeSH P_Enteral_Nutrition_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH M_Ketones_MeSH S_blood_MeSH Ketones_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Statistics__Nonparametric_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH ****** 9836523 ----K E ----T Previous episodes of hypoglycemic coma are not associated with permanent cognitive brain dysfunction in IDDM patients on intensive insulin treatment. ----A Intensive insulin treatment of IDDM is associated with increased frequency of hypoglycemic coma. The extent of possible cerebral sequelae after recovery is still unknown. We studied the impact of previous hypoglycemic coma on neurophysiological measures of cognitive brain function in 108 patients with adult-onset IDDM receiving intensive insulin treatment. In the study, 55 IDDM patients (age 38 +/- 14 years, mean +/- SD) who had a history of > or =1 (median 3, range 1-35) comatose hypoglycemic event were compared with 53 IDDM patients (age 34 +/- 12 years) with no history of hypoglycemic events using P300 event-related potentials and psychometric tests (the Mini-Mental State Exam and trailmaking test, part A). Findings on these patients were compared with those from 108 matched healthy control subjects. No difference was observed in P300 latencies and psychometric tests between patients with and without a history of hypoglycemic coma (P300 latency, 346 vs. 342 ms; trailmaking test, 31 vs. 30 s; Mini-Mental State Exam, 29.5 vs. 29.6; NS). In diabetic patients, however, P300 latencies were delayed compared with those of healthy control subjects (344 vs. 332 ms; P < 0.001) and were correlated to diabetes duration but not to total hypoglycemic episodes. Scores on the Mini-Mental State Exam (29.5 vs. 29.6; P = 0.59) and trailmaking test (31 vs. 28 s; P = 0.10) were not different between patients and control subjects. In conclusion, previous episodes of hypoglycemic coma are not associated with permanent impairment of cognitive brain function in patients with adult-onset IDDM receiving intensive insulin treatment compared with patients without such episodes. Cognitive brain function, however, is subclinically impaired in relation to duration of diabetes. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Albuminuria_MeSH S_blood_MeSH Albuminuria_blood_MeSH M_Brain_MeSH S_drug_effects_MeSH Brain_drug_effects_MeSH S_physiopathology_MeSH Brain_physiopathology_MeSH M_Cognition_Disorders_MeSH S_chemically_induced_MeSH Cognition_Disorders_chemically_induced_MeSH S_physiopathology_MeSH Cognition_Disorders_physiopathology_MeSH M_Cross-Sectional_Studies_MeSH M_Data_Interpretation__Statistical_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Diabetic_Neuropathies_MeSH S_blood_MeSH Diabetic_Neuropathies_blood_MeSH M_Diabetic_Retinopathy_MeSH S_blood_MeSH Diabetic_Retinopathy_blood_MeSH M_Electroencephalography_MeSH M_Evoked_Potentials_MeSH S_drug_effects_MeSH Evoked_Potentials_drug_effects_MeSH S_physiology_MeSH Evoked_Potentials_physiology_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_blood_MeSH Hypoglycemia_blood_MeSH S_physiopathology_MeSH Hypoglycemia_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Insulin_Coma_MeSH S_blood_MeSH Insulin_Coma_blood_MeSH S_physiopathology_MeSH Insulin_Coma_physiopathology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Psychometrics_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9836525 ----K E ----T Impact of nocturnal hypoglycemia on hypoglycemic cognitive dysfunction in type 1 diabetes. ----A To test the hypothesis that glycemic thresholds for cognitive dysfunction during hypoglycemia, like those for autonomic and symptomatic responses, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM), 15 patients were studied on two occasions. Cognitive functions were assessed during morning hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) after, in random sequence, nocturnal (2330-0300) hypoglycemia (48 +/- 2 mg/dl) on one occasion and nocturnal euglycemia (109 +/- 1 mg/dl) on the other. Compared with nondiabetic control subjects (n = 12), patients with T1DM had absent glucagon (P = 0.0009) and reduced epinephrine (P = 0.0010), norepinephrine (P = 0.0001), and neurogenic symptom (P = 0.0480) responses to hypoglycemia; the epinephrine (P = 0.0460) and neurogenic symptom (P = 0.0480) responses were reduced further after nocturnal hypoglycemia. After nocturnal hypoglycemia, in contrast to nocturnal euglycemia, there was less deterioration of cognitive function overall (P = 0.0065) during hypoglycemia based on analysis of the sum of standardized scores (z-scores). There was relative preservation of measures of pattern recognition and memory (the delayed non-match to sample task, P = 0.0371) and of attention (the Stroop arrow-word task, P = 0.0395), but not of measures of information processing (the paced serial addition task) or declarative memory (the delayed paragraph recall task), after nocturnal hypoglycemia. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, like those for autonomic and symptomatic responses to hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia in patients with T1DM. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Analysis_of_Variance_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH P_Circadian_Rhythm_MeSH M_Cognition_MeSH S_drug_effects_MeSH Cognition_drug_effects_MeSH S_physiology_MeSH Cognition_physiology_MeSH M_Cognition_Disorders_MeSH S_etiology_MeSH Cognition_Disorders_etiology_MeSH S_physiopathology_MeSH Cognition_Disorders_physiopathology_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_blood_MeSH Diabetes_Mellitus__Type_I_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_I_physiopathology_MeSH M_Epinephrine_MeSH S_blood_MeSH Epinephrine_blood_MeSH M_Female_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH S_drug_effects_MeSH Glucagon_drug_effects_MeSH M_Glucose_MeSH S_administration_&_dosage_MeSH Glucose_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glucose_therapeutic_use_MeSH M_Glucose_Clamp_Technique_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH S_complications_MeSH Hypoglycemia_complications_MeSH S_physiopathology_MeSH Hypoglycemia_physiopathology_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_blood_MeSH Insulin_blood_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Neuropsychological_Tests_MeSH M_Norepinephrine_MeSH S_blood_MeSH Norepinephrine_blood_MeSH M_Pancreatic_Polypeptide_MeSH S_blood_MeSH Pancreatic_Polypeptide_blood_MeSH S_drug_effects_MeSH Pancreatic_Polypeptide_drug_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 9853636 ----K E ----T Restricting home glucose-monitoring strips in patients taking oral antidiabetic agents. ----A ----P Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Arizona_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Glucose_Self-Monitoring_MeSH S_instrumentation_MeSH Blood_Glucose_Self-Monitoring_instrumentation_MeSH S_standards_MeSH Blood_Glucose_Self-Monitoring_standards_MeSH M_Creatinine_MeSH S_blood_MeSH Creatinine_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Utilization_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A_MeSH S_metabolism_MeSH Hemoglobin_A_metabolism_MeSH M_Hospitals__Veterans_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Prescriptions__Drug_MeSH S_standards_MeSH Prescriptions__Drug_standards_MeSH ****** 9881243 ----K E ----T Insulin treatment of elderly type 2 diabetic patients: effects on retinopathy. ----A Insulin treatment is reportedly associated with the transient progression of retinopathy, possibly with the development of macular oedema in middle-aged Type 2 diabetic patients. The purpose of this study was to investigate the effect of insulin treatment on eye-grounds in elderly (> 65-year-old) Type 2 diabetic patients with secondary failure of oral antidiabetic-drug therapy. Eye examinations were performed in 37 patients randomized to insulin (n = 19) or sulphonylurea (n = 16) treatment and re-investigated after one year. Insulin treatment reduced HbA1c from 9.3% to 7.3% (p < 0.001) after one year. In the sulphonylurea-treated group, HbA1c did not change (9.1 vs. 9.3%). At the start, 65% of the patients had retinopathy, and after one year progression was noted in 7/35 patients (20%; 5 insulin- and 2 sulphonylurea-treated). In the insulin-treated group, the 5 patients with progression had higher initial fasting blood-glucose levels than other patients in the group (15.8 vs 13.1 mmol/L, p < 0.05). Initial HbA1c levels did not differ between the groups (9.8 vs. 9.1%, n.s.), nor the reduction of HbA1c levels during treatment (2.2 vs. 1.3% n.s.). Thus, diabetic retinopathy in this study was common among elderly Type 2 diabetic patients. The progression of retinopathy may in fact be associated with insulin treatment or improvement of metabolic control. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Retinopathy_MeSH S_etiology_MeSH Diabetic_Retinopathy_etiology_MeSH M_Fasting_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Risk_Factors_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9932219 ----K E ----T Effects of regular insulin or insulin LISPRO on glucose metabolism after an oral glucose load in patients with type 2 diabetes mellitus. ----A Seven obese Type 2 diabetic patients were studied for two 4-h periods after ingestion of a glucose load to determine the effects of preprandial subcutaneous injection of Insulin Lispro (5 min before the meal) or regular insulin (20 min before the meal) on glucose metabolism. Glucose production and utilisation were measured using a dual isotope method. After Lispro, the mean postprandial increase in plasma glucose was 29% lower and the increase in insulin concentration 25% higher than after regular insulin (p < 0.05). Suppression of endogenous glucose production was similar with both types of insulin. Thus, preprandial injection of Lispro reduced postprandial glucose increments in Type 2 diabetic patients as compared to regular insulin. This effect is best explained by the increased postprandial bioavailability of Lispro. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glucose_MeSH S_pharmacology_MeSH Glucose_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 9972673 ----K E ----T Efficacy of combined treatments in NIDDM patients with secondary failure to sulphonylureas. Is it predictable? ----A The treatment of NIDDM patients with secondary failure to sulphonylurea is a common problem. We performed a crossover study in 50 NIDDM patients with secondary failure to glibenclamide by comparing the addition to sulphonylurea of either a low-dose bedtime NPH insulin or a t.i.d. oral metformin and by analyzing treatment efficacy in relation to patient and disease characteristics. Both combined therapies clearly improved glycaemic control. HbA1 c were similarly reduced by the addition of either bedtime NPH insulin (7.6+/-0.34 vs 8.7+/-0.35, p<0.01) or metformin (7.6+/-0.22 vs 8.6+/-0.31, p<0.01). Also fasting plasma glucose (FPG) and post-prandial plasma glucose (PPPG) significantly decreased (p<0.01) with both treatments. Bed-time NPH insulin was more effective on FPG reduction than metformin (-36+/-2% vs -25+/-2%, p<0.01); in contrast, metformin addition was more effective on PPPG reduction than bedtime NPH insulin addition (-30+/-2% vs 20+/-3%, p<0.01). Serum cholesterol was marginally but significantly decreased after metformin (5.49+/-0.19 vs 5.91 +/-0.18 mM, p<0.05) but not after NPH insulin. Body weight increase was significantly greater after insulin addition than after metformin (1.47+/-0.25 Kg vs 0.64+/-0.17 p=0.02). All patients preferred the addition of metformin rather than NPH insulin. None of the measured clinical and metabolic variables (before treatment FPG and PPPG, HbA1 c, post-glucagon C-peptide levels, insulin sensitivity, patient age, BMI and diabetes duration) significantly correlated to the efficacy of the two combined treatments studied. In conclusion, in NIDDM patients with secondary failure to sulphonylureas the addition of either low-dose bedtime NPH insulin or t.i.d. metformin is similarly effective in improving glycaemic control. Metformin is better accepted by patients and provides a modest advantage in terms of body weight and cholesterol levels.The most common clinical and metabolic variables are not useful for predicting the efficacy of these two combined treatments. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH P_Drug_Resistance_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH M_Female_MeSH M_Food_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 9989540 ----K I ----T Drug-induced hypoglycemic coma in 102 diabetic patients. ----A BACKGROUND: Hypoglycemic coma is a continuous threat for diabetic patients treated with insulin and/or oral hypoglycemic agents; it may be associated with substantial morbidity and mortality. METHODS: We retrospectively reviewed our clinical experience with drug-induced hypoglycemic coma during a 7-year period. RESULTS: The study consisted of 102 patients and included 61 females and 41 males. The median age was 72 years. Ninety-two patients suffered from type 2 diabetes mellitus; 10 patients had type 1 diabetes mellitus. The median lowest blood glucose level was 1.77 mmol/L (32 mg/dL). Drug-induced hypoglycemic coma occurred in 99 patients out of the hospital, while 3 patients developed it during hospitalization. Drug-induced hypoglycemic coma occurred in patients undergoing treatment with insulin, glyburide, and combined therapy with insulin and glyburide, insulin and metformin, or glyburide and metformin. Ninety-three patients had at least 1 of the following risk factors: age older than 60 years, renal dysfunction, decreased intake of energy, and infection. Fourteen patients concomitantly received drugs that potentiated hypoglycemia. Forty patients responded to treatment within the first 12 hours, while 62 patients had protracted hypoglycemia of 12 to 72 hours' duration. Morbidity included physical injuries in 7 patients, myocardial ischemia in 2 patients, and stroke in 1 patient. Death occurred in 5 patients. CONCLUSIONS: Hypoglycemic coma is a serious and not an uncommon problem among elderly patients with diabetes mellitus and treated with insulin and/or oral hypoglycemic drugs. Risk factors contribute substantially to the morbidity and mortality of patients with drug-induced hypoglycemic coma. Enhanced therapeutic monitoring may be warranted when hypoglycemic drugs are administered to an elderly patient with the above predisposing factors and potentiating drugs for hypoglycemia. ----P Journal_Article ----M M_Adolescent_MeSH M_Adult_MeSH M_Age_Factors_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Coma_MeSH S_chemically_induced_MeSH Coma_chemically_induced_MeSH M_Diabetes_Mellitus_MeSH S_blood_MeSH Diabetes_Mellitus_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus_drug_therapy_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Retrospective_Studies_MeSH ****** 10068412 ----K E ----T Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. ----A BACKGROUND: Compared with other insulin regimens, combination therapy with oral hypoglycemic agents and bedtime insulin produces similar improvement in glycemic control but induces less weight gain. OBJECTIVE: To determine whether bedtime insulin regimens differ with respect to their effects on weight gain in patients with type 2 diabetes. DESIGN: Randomized, controlled trial. SETTING: Four outpatient clinics at central hospitals. PATIENTS: 96 patients (mean age, 58 +/- 1 years; mean body mass index, 29 +/- 1 kg/m2) whose type 2 diabetes was poorly controlled with sulfonylurea therapy (mean glycosylated hemoglobin value, 9.9% +/- 0.2%; mean fasting plasma glucose level, 11.9 +/- 0.3 mmol/L [214 +/- 5 mg/dL]). INTERVENTION: Random assignment to 1 year of treatment with bedtime intermediate-acting insulin plus glyburide (10.5 mg) and placebo, metformin (2 g) and placebo, glyburide and metformin, or a second injection of intermediate-acting insulin in the morning. Patients were taught to adjust the bedtime insulin dose on the basis of fasting glucose measurements. MEASUREMENTS: Body weight, biochemical and symptomatic hypoglycemias, and indices of glycemic control. RESULTS: At 1 year, body weight remained unchanged in patients receiving bedtime insulin plus metformin (mean change, 0.9 +/- 1.2 kg; P < 0.001 compared with all other groups) but increased by 3.9 +/- 0.7 kg, 3.6 +/- 1.2 kg, and 4.6 +/- 1.0 kg in patients receiving bedtime insulin plus glyburide, those receiving bedtime insulin plus both oral drugs, and those receiving bedtime and morning insulin, respectively. The greatest decrease in the glycosylated hemoglobin value was observed in the bedtime insulin and metformin group (from 9.7% +/- 0.4% to 7.2% +/- 0.2% [difference, -2.5 +/- 0.4 percentage points] at 1 year; P < 0.001 compared with 0 months and P < 0.05 compared with other groups). This group also had significantly fewer symptomatic and biochemical cases of hypoglycemia (P < 0.05) than the other groups. CONCLUSIONS: Combination therapy with bedtime insulin plus metformin prevents weight gain. This regimen also seems superior to other bedtime insulin regimens with respect to improvement in glycemic control and frequency of hypoglycemia. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Albuminuria_MeSH S_urine_MeSH Albuminuria_urine_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Follow-Up_Studies_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Weight_Gain_MeSH S_drug_effects_MeSH Weight_Gain_drug_effects_MeSH ****** 10082152 ----K I ----T Effects of K(ATP) channel blockade by glibenclamide on the warm-up phenomenon. ----A AIMS: The increased tolerance to myocardial ischaemia observed during the second of two sequential exercise tests, i.e. the warm-up phenomenon, has been proposed as a clinical model of ischaemic preconditioning. As ATP-sensitive K+ channels appear to be a mediator of ischaemic preconditioning in both experimental and clinical studies, the aim of this study was to investigate the role of K(ATP) channels in the warm-up phenomenon. METHODS AND RESULTS: Twenty-six patients with coronary artery disease were randomized to receive 10 mg oral glibenclamide, a selective ATP-sensitive K+ channel blocker, or placebo. Sixty minutes after glibenclamide or placebo administration, patients were given an infusion of 10% dextrose (8 ml x min(-1)) to correct glucose plasma levels or, respectively, an infusion of saline at the same infusion rate. Thirty minutes after the beginning of the infusions, both patient groups underwent two consecutive treadmill exercise tests, with a recovery period of 15 min to re-establish baseline conditions. Before exercise tests, blood glucose levels were similar in placebo and glibenclamide groups (96 +/- 10 vs 105 +/- 22 mg x 100 ml(-1), P=ns). After placebo administration, rate-pressure product at 1.5 mm ST-segment depression significantly increased during the second exercise test compared to the first (220 +/- 41 vs 186 +/- 29 beats x min(-1) x mmHg x 10(2), P<0.01), but it did not change after glibenclamide (191 +/- 34 vs 187 +/- 42 beats x min(-1) x mmHg x 10(2), P=ns), with a significant drug-test interaction (P=0.0091, at two-way ANOVA). CONCLUSIONS: Glibenclamide, at a dose previously shown to abolish ischaemic preconditioning during coronary angioplasty, prevents the increase of ischaemic threshold observed during the second of two sequential exercise tests. These findings confirm that ischaemic preconditioning plays a key role in the warm-up phenomenon and that in this setting is, at least partially, mediated by activation of ATP-sensitive K+ channels. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adenosine_Triphosphate_MeSH S_antagonists_&_inhibitors_MeSH Adenosine_Triphosphate_antagonists_&_inhibitors_MeSH M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Comparative_Study_MeSH M_Coronary_Disease_MeSH S_diagnosis_MeSH Coronary_Disease_diagnosis_MeSH S_drug_therapy_MeSH Coronary_Disease_drug_therapy_MeSH S_enzymology_MeSH Coronary_Disease_enzymology_MeSH M_Electrocardiography_MeSH M_Exercise_Test_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH P_Ischemic_Preconditioning__Myocardial_MeSH M_Male_MeSH M_Middle_Aged_MeSH P_Potassium_Channel_Blockers_MeSH M_Single-Blind_Method_MeSH M_Treatment_Outcome_MeSH ****** 10085698 ----K E ----T [Short-term intensive insulin therapy as a method of overcoming secondary failure of sulfonylureas in patients with type 2 diabetes (non-insulin-dependent)] ----A The study group comprised 56 patients (25 males and 31 females) with type 2 diabetes in whom the secondary failure to sulphonylurea derivates (SU) had developed. All patients were submitted for 14 days to therapy with 5 injections of insulin per day in total dose of insulin permitting to decrease the mean daily glycaemia below 8.8 mmol/l (160 mg/dl). After the termination of the intensive insulin therapy (IIT) the patients with insulin requirement below 44 U daily were alternatively qualified to treatment with SU (glybenclamide) alone or with this SU plus biguanide derivate (BG: phenformin), and those who needed more than 44 U daily continued conventional therapy with insulin alone or with insulin plus SU (glybenclamide). There was a marked reduction of fasting and postprandial blood glucose during the IIT and over the subsequent 15 months of the follow-up. The mean glycaemia which initially was in fasting state 12.5 +/- 2.4 mmol/l (225 +/- 43 mg/dl) and 2 hours after breakfast 18.1 +/- 2.8 mmol/l (325 +/- 50 mg/dl) decreased significantly and was in four groups between 8.0 +/- 0.3 mmol/l (144 +/- 5 mg/dl) and 10.8 +/- 0.5 mmol/l (194 +/- 9 mg/dl) in fasting state and between 10.5 +/- 0.3 (189 +/- 5 mg/dl) and 11.2 +/- 0.4 mmol/l (201 +/- 7 mg/dl) after breakfast. The least hypoglycaemic effect was found in patients who after IIT were treated exclusively with insulin (mean daily dose 53 +/- 2 IU) while the decrease of glycaemia was most evident in patients treated with SU given as a single drug or in combination with BG or with insulin (mean daily dose 19 +/- 1 IU). In all studied patients basal and stimulated (1 mg glucagon i.v.) C-peptide secretion markedly decreased during IIT, and greatly increased after its termination, and this increase persisted over following 15 months of observation, correlating with the initial values. CONCLUSIONS: The short-term IIT in patients with NIDDM and secondary failure to SU is effective in reducing hyperglycaemia, and in most of them makes possible to continue the oral antidiabetic treatment with SU. The secretion of endogenous insulin seems to have only limited influence on the metabolic control of the patients treated with four different pharmacological regiments after IIT. ----P Clinical_Trial Journal_Article ----M M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Resistance_MeSH M_Drug_Therapy__Combination_MeSH M_English_Abstract_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenformin_MeSH S_administration_&_dosage_MeSH Phenformin_administration_&_dosage_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Treatment_Failure_MeSH ****** 10097930 ----K I ----T A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group. ----A OBJECTIVE: Repaglinide is a newly developed oral blood glucose-lowering agent that exerts its effect by stimulating insulin secretion. This multicenter study was designed to compare the efficacy and safety of this drug with glyburide in a 1-year randomized double-blind study of outpatients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 424 subjects (154 women, 270 men) participated and had the following characteristics: age, 61 +/- 9 years; duration of diabetes. 8 years (range 0.5-35); BMI, 28.3 +/- 3.5 kg/m2; HbA1c, 7.1 +/- 1.4%; and fasting plasma glucose, 10.8 +/- 3.1 mmol/l. The majority of the subjects (91%) were previously treated with sulfonylurea, alone or in combination with metformin. The patients were randomized to a 2:1 ratio of repaglinide (0.5-4 mg t.i.d.) or glyburide (1.75-10.5 mg daily) treatment. The study protocol included a screening visit to assess patient eligibility; a titration period of 6-8 weeks, during which the dosages of repaglinide and glyburide were optimized; and a subsequent 12-month treatment period on fixed, optimal dosages. RESULTS: The trial was completed by 320 subjects, 211 (74%) in the repaglinide and 109 (78%) in the glyburide group. HbA1c initially decreased in both groups and then increased during the second half-year of the maintenance period to a similar extent in the repaglinide and glyburide subjects (0.58 and 0.45% vs. at screening, respectively). In the small group of subjects who previously controlled their condition with diet only (n = 37), a sustained improvement of metabolic control could be observed with both drugs, which was slightly better with glyburide than with repaglinide (theta HbA1c -2.4 vs. -1.0%; P < 0.05). The same trends were seen with fasting plasma glucose. There were no changes in serum lipids. Over the course of the study, 15% of the repaglinide-treated and 13% of glyburide-treated subjects withdrew due to adverse events, mostly hyperglycemia. No differences in adverse events between both drugs were reported. There were no differences in incidences of hypoglycemia. CONCLUSIONS: Repaglinide is a safe and efficacious oral blood glucose-lowering agent, with a potency similar to that of glyburide. Its rapid onset of action and hepatic clearance allows meal-related administration, including in subjects with impaired kidney function. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Carbamates_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH S_blood_MeSH Fasting_blood_MeSH M_Female_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH ****** 10193691 ----K E ----T Troglitazone: a review of its use in the management of type 2 diabetes mellitus. ----A Troglitazone is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is indicated for the treatment of patients with type 2 (non-insulin-dependent) diabetes mellitus. Troglitazone acts by enhancing the effects of insulin at peripheral target sites and, unlike the sulphonylurea drugs, is not associated with hypoglycaemia when administered as monotherapy. Clinical trials with troglitazone (usually 200 to 600 mg/day) in patients with type 2 diabetes mellitus consistently showed marked improvement in glycaemic control, as well as reductions in fasting serum insulin, C-peptide and triglyceride levels. Comparative studies with either glibenclamide (glyburide) or metformin indicated similar glycaemic control with troglitazone or these agents. Serum insulin levels were lower with troglitazone than with glibenclamide. Clinical trials of up to approximately 2 years' duration showed that glycaemic control is maintained with troglitazone on a long term basis. In general, troglitazone is well tolerated by the majority of patients. However, discontinuation of troglitazone because of elevated liver enzyme levels occurs in approximately 2% of patients receiving the drug, and frequent monitoring of liver enzymes is required (e.g. at least 11 times during the first year of therapy). Among patients who started troglitazone therapy in 1998 (after the incorporation of a boxed warning and increased monitoring requirements in the product labelling), the estimated risk of liver-related death is approximately 1 in 100,000. CONCLUSIONS: Troglitazone improves the ability of target cells to respond to insulin. The drug has been shown to improve glycaemic control in patients with type 2 diabetes mellitus when used as monotherapy or in combination with other oral antidiabetic drugs or insulin, and its efficacy is similar to that of glibenclamide or metformin. Although troglitazone is generally well tolerated, close monitoring of liver enzyme function is required to minimise the rare occurrence of serious hepatic dysfunction. Drug acquisition and liver function monitoring costs, as well as potential adverse effects, are important factors that may ultimately determine the precise place of troglitazone in the management of type 2 diabetes mellitus. Nevertheless, as the first member of a new class of oral antidiabetic agents, the thiazolidinediones, troglitazone offers an effective treatment option in patients with type 2 diabetes mellitus through its action of improving insulin sensitivity. ----P Journal_Article Review Review__Tutorial ----M M_Adult_MeSH M_Aged_MeSH M_Animals_MeSH M_Area_Under_Curve_MeSH M_Chromans_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH S_pharmacology_MeSH Chromans_pharmacology_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Interactions_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Half-Life_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Randomized_Controlled_Trials_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 10199430 ----K I ----T Relationship between fasting plasma glucose and glycosylated hemoglobin: potential for false-positive diagnoses of type 2 diabetes using new diagnostic criteria. ----A CONTEXT: New criteria for the diagnosis of type 2 diabetes mellitus have recently been introduced that lowered the diagnostic fasting plasma glucose (FPG) concentration from 7.8 to 7.0 mmol/L (140 to 126 mg/dL). OBJECTIVE: To determine if individuals with diabetes diagnosed by the new FPG concentration criterion would have excessive glycosylation (elevated hemoglobin [HbA1c] levels). DEFINITIONS: We determined the distribution of HbA1c levels in individuals using 4 classifications: (1) normal by the new criterion (FPG concentration <6.1 mmol/L [110 mg/dL]); (2) impaired fasting glucose by the new criterion (FPG concentration of 6.1-6.9 mmol/L [110-125 mg/dL]); (3) diabetes diagnosed solely by the new FPG concentration criterion of 7.0 through 7.7 mmol/L (126-139 mg/dL); and (4) diabetes diagnosed by the previous FPG concentration criterion of 7.8 mmol/L (140 mg/dL) or higher. DESIGN: Cross-sectional analysis of 2 large data sets (NHANES III and Meta-Analysis Research Group [MRG] on the Diagnosis of Diabetes Using Glycated Hemoglobin) that contained individuals in whom FPG concentrations, 2-hour glucose concentrations using an oral glucose tolerance test, and an HbA1c level were simultaneously measured. We cross-tabulated FPG concentrations (<6.1 mmol/L [110 mg/dL], 6.1-6.9 mmol/L [110-125 mg/dL], 7.0-7.7 mmol/L [126-139 mg/dL], and > or =7.8 mmol/L [140 mg/dL]) and HbA1c levels separated into 3 intervals: normal, less than the upper limit of normal (ULN); slightly elevated, ULN to ULN plus 1%; and high, higher than ULN plus 1%. RESULTS: Among subjects with normal FPG concentrations, HbA1c levels in the NHANES III (and the MRG) data sets were normal in 97.3% (96.2%), slightly elevated in 2.7% (3.6%), and high in 0.1% (0.2%). Among individuals with impaired fasting glucose, HbA1c concentrations were normal in 86.7% (81.4%), slightly elevated in 13.1% (16.4%), and high in 0.2% (2.2%). Among diabetic patients diagnosed by the new FPG criterion only, HbA1c levels were normal in 60.9% (59.6%), slightly elevated in 35.8% (32.8%), and high in 3.4% (7.6%). In diabetic patients diagnosed by the former FPG criterion, HbA1c levels were normal in 18.6% (16.7%), slightly elevated in 32.5% (21.0%), and high in 48.9% (62.3%). CONCLUSIONS: About 60% of the new cohort of diabetic patients in both data sets have normal HbA1c levels. We believe that diabetes should not be diagnosed in those with FPG concentrations less than 7.8 mmol/L (140 mg/dL) unless excessive glycosylation is evident. Individuals without excessive glycosylation but with moderate elevations of FPG concentrations (6.1-7.7 mmol/L [110-139 mg/dL]) should be diagnosed as having impaired fasting glucose and treated with an appropriate diet and exercise. This diagnostic labeling achieves the goal of early intervention without subjecting these persons to the potentially negative insurance, employment, social, and psychological consequences of a diagnosis of diabetes mellitus. ----P Journal_Article ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Cross-Sectional_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diagnosis_MeSH Diabetes_Mellitus__Type_II_diagnosis_MeSH M_False_Positive_Reactions_MeSH M_Fasting_MeSH S_blood_MeSH Fasting_blood_MeSH M_Glucose_Tolerance_Test_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH ****** 10213347 ----K E ----T Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide. ----A AIMS: Glimepiride is a new sulfonylurea for diabetes treatment which is supposed to impact less on extra-pancreatic ATP-dependent K+ channels than the conventional drug glibenclamide. This study was performed to evaluate whether this results in a better maintenance of ATP-dependent K+ channel mediated ischaemic myocardial preconditioning. METHODS AND RESULTS: In a double-blind placebo-controlled study the period of total coronary occlusion during balloon angioplasty of high grade coronary artery stenoses was used as a model to compare the effects of both drugs. Quantification of myocardial ischaemia was achieved by recording the intracoronary ECG and the time to the occurrence of angina during vessel occlusion. All patients underwent three dilatations. The first dilatation (dilatation 1) served to determine the severity of ischaemia during vessel occlusion. During dilatation 2, baseline values were recorded. Thereafter, glimepiride (15 patients: 1.162 mg), glibenclamide (15 patients: 2.54 mg) or placebo (15 patients) were intravenously administered over 12 min. Dilatation 3 started 10 min after the beginning of the drug administration. Mean ST segment shifts in the placebo group decreased by 35% (dilatation 2: 0.23; dilatation 3:0.15 mV; CI -0.55 to 0.00 mV; P=0.049). A similar reduction also occurred in the glimepiride group, in which repetitive balloon occlusion led to a 34% reduction (dilatation 2: 0.35; dilatation 3: 0.23 mV; CI -0.21 to -0.02 mV; P=0.01). There was little influence however, on mean ST segment shifts in the glibenclamide group (dilatation 2 and dilatation 3: 0.24 mV; CI -0.10 to 0.25 mV; P=0.34). Accordingly, time to angina during balloon occlusion slightly increased (by 30%) in the placebo group (dilatation 2: 37 s; dilatation 3: 48 s; CI 0.0 to 15.0 s; P=0.16); increased by 13% in the glimepiride group (dilatation 2: 40 s; dilatation 3: 45 s; CI 0.0 to 14.0 s; P=0023); and remained unchanged in the glibenclamide group (dilatation 2 and dilatation 3: 30 s; CI -7.5 to 7.5 s; P=0.67). CONCLUSION: These results show that glimepiride maintains myocardial preconditioning, while glibenclamide might be able to prevent it. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Angioplasty__Transluminal__Percutaneous_Coronary_MeSH M_Comparative_Study_MeSH M_Coronary_Disease_MeSH S_therapy_MeSH Coronary_Disease_therapy_MeSH M_Double-Blind_Method_MeSH M_Electrocardiography_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Injections__Intravenous_MeSH M_Ischemic_Preconditioning_MeSH S_methods_MeSH Ischemic_Preconditioning_methods_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH ****** 10229308 ----K E ----T The effect of gliclazide on plasma insulin, intact and 32/33 split proinsulin in South Asian subjects with Type 2 diabetes mellitus. ----A AIMS: Previous studies have shown that in Caucasian subjects with Type 2 diabetes mellitus (DM), the sulphonylurea glibenclamide increased insulin secretion without causing an increase in 32/33 split proinsulin secretion. South Asian subjects with Type 2 DM are thought to be more insulin resistant and the effect of sulphonylureas may be different. We therefore investigated the effect of sulphonylurea therapy with gliclazide on beta-cell function in South Asian subjects with newly diagnosed Type 2 DM. METHODS: Glucose, insulin, and intact and 32/33 split proinsulin were measured at diagnostic oral glucose tolerance test (OGTT). After 8-12 weeks on a conventional diet, subjects with a fasting glucose > 6 mmol/l (n = 16) were commenced on gliclazide. RESULTS: At diagnosis, those requiring gliclazide were more hyperglycaemic but there was no difference in weight or fasting insulin concentration than in the diet group. Following diet, in the gliclazide group, weight fell (P < 0.04) with no change in fasting glucose concentration. Fasting intact proinsulin, insulin and 32/33 split proinsulin remained unchanged. After gliclazide therapy weight remained unchanged, but fasting glucose fell (P < 0.003). Fasting insulin and intact proinsulin remained unchanged but 32/33 split proinsulin fell (P < 0.05). Fasting insulin to glucose ratio significantly improved after gliclazide (P < 0.006). CONCLUSIONS: In South Asian subjects treated with gliclazide the reduction in fasting glucose concentrations appears to be due to an improvement in insulin sensitivity as well as in beta-cell function. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Asia__Southeastern_MeSH S_ethnology_MeSH Asia__Southeastern_ethnology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Great_Britain_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_secretion_MeSH Islets_of_Langerhans_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Proinsulin_MeSH S_secretion_MeSH Proinsulin_secretion_MeSH M_Protein_Precursors_MeSH S_secretion_MeSH Protein_Precursors_secretion_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10332683 ----K I ----T A double-blind randomized comparison of meal-related glycemic control by repaglinide and glyburide in well-controlled type 2 diabetic patients. ----A OBJECTIVE: This study was designed to compare diurnal blood glucose excursions and the effects of accidental dietary noncompliance in type 2 diabetic patients who are well-controlled on either repaglinide or glyburide treatment. RESEARCH DESIGN AND METHODS: This single-center double-blind randomized study comprised type 2 diabetic patients whose mean fasting blood glucose value after repaglinide/glyburide titration and stabilization was in the range of 90-140 mg/dl. The study consisted of an initial screening day, a titration period of 3 weeks, a 1-week stabilization period, a study period, and an end-of-study day. During the 3-day study period, half the patients of each group received two meals on the first day and three meals on the next 2 days, and in the other half, this sequence was reversed. Repaglinide was administered preprandially with each meal, and glyburide was administered as recommended in current labeling, i.e., either one or two daily doses before breakfast and dinner, regardless of whether lunch had been omitted. The diurnal blood glucose excursions on a day in which three meals were eaten were compared between the two groups, and the minimum blood glucose concentration (BGmin) measurements were compared between lunch and dinner on days with three and two meals. RESULTS: Of the 83 randomized patients, 43 entered into the 3-day study period and completed the trial. The results showed no significant differences between the repaglinide and glyburide groups in average blood glucose excursions from fasting blood glucose (P = 0.44). The influence on the mean BGmin of omitting a meal differed significantly between the repaglinide and glyburide groups (P = 0.014). In the latter group, BGmin decreased from 77 to 61 mg/dl as a result of omitting lunch, whereas in the repaglinide group, BGmin was unchanged for the two-meal day (78 mg/dl) and the three-meal day (76 mg/dl). All hypoglycemic events (n = 6) occurred in the glyburide group on the two-meal day, in connection with omitting lunch. No hypoglycemic events were recorded in the repaglinide group. CONCLUSIONS: These results suggest that treatment with repaglinide in well-controlled type 2 diabetic patients who miss or delay a meal is superior to treatment with longer-acting sulfonylurea drugs (such as glyburide) with respect to the risk of hypoglycemic episodes. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Diet_MeSH M_Double-Blind_Method_MeSH M_Drug_Administration_Schedule_MeSH M_Eating_MeSH M_Energy_Intake_MeSH M_Fasting_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH ****** 10333912 ----K I ----T Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. ----A OBJECTIVE: To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period. RESULTS: In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05). CONCLUSIONS: Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Australia_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH M_Fatty_Acids__Nonesterified_MeSH S_blood_MeSH Fatty_Acids__Nonesterified_blood_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 10333939 ----K E ----T The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. ----A OBJECTIVE: To assess the relationship between nondiabetic glucose levels and cardio vascular risk. RESEARCH DESIGN AND METHODS: Three independent searches using MEDLINE (1966-1996), followed by a manual search of the references from each retrieved article, were conducted by two physicians and one medical librarian. Data had to be reported in at least three quantiles or intervals so that the nature of the relationship between glucose and cardiovascular events (i.e., linear or nonlinear) could be explored, and to ensure that any incremental cardiovascular risk was consistent across quantiles or intervals. RESULTS: Analyzed studies comprised 95,783 people (94% male) who had 3,707 cardiovascular events over 12.4 years (1,193,231 person-years). Studies reporting fasting glucose levels (n = 6), 2-h glucose levels (n = 7), 1-h glucose levels (n = 5), and casual glucose levels (n = 4) were included. The glucose load used varied from 50 to 100 g. The highest glucose interval for most studies included glucose values in the diabetic range. The relationship between glucose levels and the risk of a cardiovascular event was modeled for each study and the beta-coefficients were combined. Compared with a glucose level of 4.2 mmol/l (75 mg/dl), a fasting and 2-h glucose level of 6.1 mmol/dl (110 mg/dl) and 7.8 mmol/l (140 mg/dl) was associated with a relative cardiovascular event risk of 1.33 (95% CI 1.06-1.67) and 1.58 (95% CI 1.19-2.10), respectively. CONCLUSIONS: The progressive relationship between glucose levels and cardiovascular risk extends below the diabetic threshold. ----P Journal_Article Meta-Analysis ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cardiovascular_Diseases_MeSH S_epidemiology_MeSH Cardiovascular_Diseases_epidemiology_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus_MeSH S_complications_MeSH Diabetes_Mellitus_complications_MeSH S_epidemiology_MeSH Diabetes_Mellitus_epidemiology_MeSH M_Female_MeSH M_Glucose_Intolerance_MeSH S_complications_MeSH Glucose_Intolerance_complications_MeSH S_epidemiology_MeSH Glucose_Intolerance_epidemiology_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Incidence_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Regression_Analysis_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10333958 ----K E ----T American Diabetes Association Annual Meeting, 1998. More on the treatment of type 2 diabetes. ----A ----P Congresses News ----M M_Diabetes_Mellitus__Type_II_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH ****** 10337452 ----K E ----T Effect of oral antidiabetic agents on plasma amylin level in patients with non-insulin-dependent diabetes mellitus (type 2). ----A The purpose of the study was the comparison of the effect of the oral therapy of non-insulin-dependent diabetes mellitus (NIDDM) with either a sulphonylurea or biguanide derivative on plasma amylin level. In 10 healthy individuals the fasting plasma amylin level was 1.56 +/- 0.27 pmol/l (mean +/- SEM) and 6 min after i.v. injection of 1 mg glucagon a fourfold increase was observed. In 10 patients with NIDDM receiving glibenclamide (CAS 10238-21-8) the fasting plasma amylin level was twofold higher than in healthy control (2.72 +/- 0.38 pmol/l; p < 0.025) but following glucagon administration it increased only twofold. In 15 patients treated with metformin (CAS 657-24-9) the fasting plasma amylin level was similar to that in healthy individuals (1.64 +/- 0.25 pmol/l), but after glucagon stimulation the increment of plasma amylin was minimal and the relevant mean value was significantly lower when compared with those in healthy individuals and with NIDDM patients treated with glibenclamide. In 10 untreated obese patients with newly diagnosed NIDDM the administration of glibenclamide (14 days) resulted in the increase of basal (2.47 +/- 0.23 and 3.16 +/- 0.29 pmol/l; p < 0.1), and glucagon stimulated (3.34 +/- 0.39 and 4.56 +/- 0.38; p < 0.05) plasma amylin concentrations, whereas other 10 patients receiving metformin showed a decrease in fasting plasma level of this peptide before (2.64 +/- 0.59 and 1.28 +/- 0.38 pmol/l; p < 0.1), and after glucagon injection (5.02 +/- 0.55 and 2.83 +/- 0.65 pmol/l; p < 0.02). With the respect to the trophic effect of amyloid deposits in the pancreatic islets and to a hypothetic effect of amylin increasing insulin resistance, the present results emphasize the particular usefulness of metformin in the pharmacological treatment of NIDDM. All contraindications and side effects of metformin should be taken into account before drug administration. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Amyloid_MeSH S_blood_MeSH Amyloid_blood_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Cross-Sectional_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10359389 ----K I ----T Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. ----A CONTEXT: Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. OBJECTIVE: To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. DESIGN: Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. SETTING: Outpatient diabetes clinics in 15 UK hospitals. PATIENTS: A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. INTERVENTIONS: After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. MAIN OUTCOME MEASURES: Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. RESULTS: The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. CONCLUSIONS: Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Combined_Modality_Therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diet__Fat-Restricted_MeSH M_Dietary_Carbohydrates_MeSH M_Dietary_Fiber_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Logistic_Models_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Multivariate_Analysis_MeSH M_Prospective_Studies_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 10363530 ----K E ----T [Morning blood glucose determination in the monitoring of metabolic control in type 2 elderly diabetic cases treated by oral hypoglycemic agents] ----A Daily blood glucose profiles were measured in 163 Type 2 elderly diabetic cases to evaluate whether a fasting (before breakfast) or a post-prandial (after breakfast) blood glucose concentration is able to predict blood glucose values throughout the day. In the diet-treated alone group (n = 61), the percentage of daily blood glucose profiles having plasma glucose values less than the 08:00 hours (before breakfast) value were as follows: 59.0%, 32.8%, 59.0%, and 55.7% at 18.00 (before supper), 24.00, 03.00, 06.00 hours, respectively. In group treated by oral hypoglycemic agents (OHA) (n = 102), these were as follows: 45.1%, 26.5%, 52.9%, and 67.6%, respectively. In the OHA group, the mean plasma glucose value at 08:00 hours was significantly higher in patients with the lowest plasma glucose levels between 60-79 mg/dl than in patients with these levels between 80-99 mg/dl (103.7 +/- 19.6 vs 118.7 +/- 16.9 mg/dl, p < 0.01), but that at 10:00 hours was similar in the two groups (218.8 +/- 43.9 vs 214.5 +/- 40.1 mg/dl). In patients with lowest plasma glucose levels of between 60-99 mg/dl, the 08:00 hours value correlated positively with that of 24:00 (r = 0.40), 03.00 (r = 0.53), and the 06.00 hours value (r = 0.69), but no correlation was observed with the 18.00 hours value. On the other hand, the 10:00 hours value was not associated with these time-points values. Our results reveal that before breakfast plasma glucose values are more predictive of low blood glucose values in the night during sleep than after-breakfast blood glucose values, but do not predict low blood glucose values before supper in patients on OHA. ----P Clinical_Trial Journal_Article ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Blood_Glucose_Self-Monitoring_MeSH P_Circadian_Rhythm_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Fasting_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10372240 ----K E ----T Effect of troglitazone on body fat distribution in type 2 diabetic patients. ----A OBJECTIVE: Troglitazone was recently reported to specifically promote the differentiation of pre-adipocytes into adipocytes in vitro in subcutaneous fat only, indicating a relation to insulin-resistance-improving action of troglitazone. To expand on this finding, we investigated at the clinical level how long-term administration of troglitazone influences the body fat distribution in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Troglitazone (400 mg/day) was administered for 6 months to 30 type 2 diabetic patients whose glycemic control was poor. A total of 18 patients received diet therapy alone (in the single-treatment group, BMI 26.0 +/- 4.6, HbA1c 8.2 +/- 1.7%), and 12 patients concomitantly received glibenclamide (1.25-7.5 mg/day) (in the concomitant sulfonylurea group, BMI 25.4 +/- 4.7, HbA1c 9.2 +/- 1.2%). BMI, HbA1c, serum lipid level, and body fat distribution, which were determined by computed tomography (CT) scan at the umbilical level, were measured and compared before and after troglitazone treatment. RESULTS: During the 6-month troglitazone treatment, HbA1c levels decreased and BMI increased in both groups. As for body fat distribution in the single-treatment group, visceral fat area (VFA) decreased (from 118.3 +/- 54.3 to 101.1 +/- 50.8 cm2; P < 0.001), and subcutaneous fat area (SFA) increased (from 189.7 +/- 93.3 to 221.6 +/- 101.6 cm2; P < 0.001), resulting in a decrease in visceral/subcutaneous (V/S) ratio (from 0.74 +/- 0.48 to 0.50 +/- 0.32; P < 0.001). In the concomitant sulfonylurea group, VFA was unchanged (from 108.1 +/- 53.5 to 112.5 +/- 59.9 cm2), while SFA increased (from 144.6 +/- 122.0 to 180.5 +/- 143.5 cm2; P < 0.01), thereby decreasing the V/S ratio (from 0.91 +/- 0.46 to 0.77 +/- 0.44; P < 0.01). The serum triglyceride level and the area under glucose curve during the 75-g oral glucose tolerance test decreased significantly in the single-treatment group. CONCLUSIONS: According to our data, troglitazone appears to promote fat accumulation in the subcutaneous adipose tissue rather than in the visceral adipose tissue in mildly obese Japanese people with type 2 diabetes. This shift of energy accumulation from the visceral to subcutaneous adipose tissue may greatly contribute to the troglitazone-mediated amelioration of insulin resistance. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Abdomen_MeSH M_Adipose_Tissue_MeSH S_anatomy_&_histology_MeSH Adipose_Tissue_anatomy_&_histology_MeSH S_drug_effects_MeSH Adipose_Tissue_drug_effects_MeSH S_radiography_MeSH Adipose_Tissue_radiography_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH M_Body_Mass_Index_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glucose_Tolerance_Test_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Skin_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Tomography__X-Ray_Computed_MeSH M_Viscera_MeSH ****** 10379630 ----K I ----T A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. ----A OBJECTIVE: To compare the efficacy and safety of repaglinide, a novel oral prandial glucose regulator, with that of glibenclamide, an oral hypoglycaemic agent, in the treatment of patients with type 2 diabetes. METHODS: This was a 14-week, double-blind, parallel-group trail in which a total of 195 type 2 diabetic patients treated with oral hypoglycaemic agents were randomized to receive either repaglinide, administered preprandially three times daily, or glibenclamide, given preprandially once or twice daily, as per manufacturer's recommendations. RESULTS: By the end of the study, the 2-h postprandial blood glucose values were lower in the repaglinide group than in the glibenclamide group, with the difference approaching statistical significance (repaglinide, 8.1 (0.6) mol x l(-1) vs glibenclamide, 9.1 (0.6)mmol x l(-1); P = 0.07). There was no statistically significant difference in the mean blood glucose level at the end of the study between the two groups (repaglinide, 7.1 (0.5) mmol x l(-1) vs glibenclamide, 7.4 (0.5) mmol x l(-1); P = 0.42), and baseline HbA1c values had decreased to the same degree in both the repaglinide [7.8% (0.1%) to 7.5% 0.1%)] and the glibenclamide groups [8.0 (0.1%) to 7.6 (0.1%)]. There are no significant differences between the repaglinide and glibenclamide treatment groups in the levels of fasting blood glucose, fructosamine, fasting C-peptide, insulin and proinsulin. Neither treatment group showed any clinically significant changes in blood lipid profiles. Repaglinide and glibenclamide were both well tolerated. No significant differences were observed between the two treatment groups with respect to adverse events, including hypoglycaemic episodes and weight change. No accumulation of repaglinide was apparent during the maintenance period. CONCLUSION: Repaglinide is as well tolerated as glibenclamide and is equally effective in the management of type 2 diabetes. Repaglinide may, however, offer an improvement in postprandial blood glucose control compared with glibenclamide, thereby helping to reduce the relative long-term risk of diabetic complications. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 10388978 ----K I ----T Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37). U.K. Prospective Diabetes Study Group. ----A OBJECTIVE: To determine in patients with type 2 diabetes the effects on quality of life (QOL) of therapies for improving blood glucose control and for improving blood pressure (BP) control, diabetic complications, and hypoglycemic episodes. RESEARCH DESIGN AND METHODS: We performed two cross-sectional studies of patients enrolled in randomized controlled trials of 1) an intensive blood glucose control policy compared with a conventional blood glucose control policy, and 2) a tight BP control policy compared with a less tight BP control policy. Also undertaken was a longitudinal study of patients in a randomized controlled trial of an intensive blood glucose control policy compared with a conventional blood glucose control policy. Subjects' QOL was assessed before or at the time of randomization and from 6 months to 6 years after randomization. Two cross-sectional samples of type 2 diabetic patients were randomized to therapies for blood glucose control: 1) 2,431 patients, mean age 60, duration from randomization 8.0 years, completed a "specific" questionnaire covering four aspects of QOL, and 2) 3,104 patients, mean age 62, duration from randomization 11 years, completed a "generic" QOL measure. Of these samples, 628 and 747 patients, respectively, were also randomized to therapies for BP control. A sample of 122 non-diabetic control subjects, average age 62, were also given the specific questionnaire. A longitudinal sample of 374 type 2 diabetic patients randomized to either intensive or conventional blood glucose policies, mean age at randomization 52, were given the specific questionnaire. Sample-sizes at 6 months and 1, 2, 3, 4, 5, and 6 years after randomization were 322, 307, 280, 253, 225, 163, and 184, respectively. The specific questionnaire assessed specific domains of QOL, including mood disturbance (Profile of Mood State), cognitive mistakes (Cognitive Failures Questionnaire), symptoms, and work satisfaction; the generic questionnaire (EQ5D) assessed general health. Both questionnaires were self-administered. RESULTS: The cross-sectional studies showed that allocated therapies were neutral in effect, with neither improvement nor deterioration in QOL scores for mood, cognitive mistakes, symptoms, work satisfaction, or general health. The longitudinal study also showed no difference in QOL scores for the specific domains assessed, other than showing marginally more symptoms in patients allocated to conventional than to intensive policy. In the cross-sectional studies, patients who had had a macrovascular complication in the last year had worse general health, as measured by the generic questionnaire, than those without complications, with scale scores median 60 and 78 respectively (P = 0.0006) and tariff scores median 0.73 and 0.83 respectively (P = 0.0012); more problems with mobility, 64 and 36%, respectively (P < 0.0001); and more problems with usual activities, 48 and 28% respectively (P = 0.0023). As measured by the specific questionnaire, they also showed reduced vigor (P = 0.0077). Patients who had had a microvascular complication in the last year reported more tension (P = 0.0082) and total mood disturbance (P = 0.0054), as measured by the specific questionnaire, than patients without complications. Patients treated with insulin who had had two or more hypoglycemic episodes during the previous year reported more tension (P = 0.0023), more overall mood disturbance (P = 0.0009), and less work satisfaction (P = 0.0042), as measured by the specific questionnaire, than those with no hypoglycemic attacks, after adjusting for age, duration from randomization, systolic BP, HbA1c, and sex in a multivariate polychotomous regression. CONCLUSIONS: In patients with type 2 diabetes, complications of the disease affected QOL, whereas therapeutic policies shown to reduce the risk of complications had no effect on QOL. It cannot be discerned whether frequent hypoglycemic episodes affect QOL, or whether patients with certain p ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Affect_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Glucose_Self-Monitoring_MeSH P_Blood_Pressure_MeSH M_Cognition_MeSH M_Cross-Sectional_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_psychology_MeSH Diabetes_Mellitus__Type_II_psychology_MeSH M_Female_MeSH M_Health_Status_MeSH M_Human_MeSH M_Job_Satisfaction_MeSH M_Longitudinal_Studies_MeSH M_Male_MeSH M_Middle_Aged_MeSH P_Quality_of_Life_MeSH P_Questionnaires_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_United_States_MeSH ****** 10400405 ----K E ----T Rosiglitazone. ----A Rosiglitazone, a thiazolidinedione antidiabetic agent, improves insulin resistance, a key underlying metabolic abnormality in most patients with type 2 (non-insulin-dependent) diabetes mellitus. In animal models of insulin resistance, rosiglitazone decreased plasma glucose, insulin and triglyceride levels and also attenuated or prevented diabetic nephropathy and pancreatic islet cell degeneration. In contrast with troglitazone, rosiglitazone does not induce cytochrome P4503A4 metabolism. It does not interact significantly with nifedipine, oral contraceptives, metformin, digoxin, ranitidine or acarbose. In clinical trials in patients with type 2 diabetes mellitus, rosiglitazone 2 to 12 mg/day (as a single daily dose or 2 divided daily doses) improved glycaemic control, as shown by decreases in fasting plasma glucose and glycosylated haemoglobin (HbA1c). Addition of rosiglitazone 2 to 8 mg/day to existing sulphonylurea, metformin or insulin therapy achieved further reductions in fasting plasma glucose and HbA1c. Oral combinations improved insulin sensitivity and beta-cell function according to a homeostasis model assessment. Consistent with its mechanism of action, rosiglitazone appears to be associated with a low risk of hypoglycaemia (<2% of patients receiving monotherapy). There is no evidence to date that rosiglitazone shares the hepatotoxicity of troglitazone. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH M_Polypharmacy_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 10406828 ----K E ----T Vasodilatory effects of troglitazone improve blood pressure at rest and during mental stress in type 2 diabetes mellitus. ----A The present study examined the hemodynamic mechanisms of blood pressure (BP) lowering by troglitazone in patients with type 2 diabetes mellitus (DM) at rest and during a mental arithmetic test (MAT). Twenty-two patients with DM with normal to high-normal BP and 12 controls matched for age, gender, glucose tolerance, and BP were studied. DM subjects showed significantly higher systolic BP response during MAT than controls (157 versus 139 mm Hg; P<0.01). All 22 DM patients and 5 of 12 controls had systolic BP >140 mm Hg during MAT. Heart rate and diastolic BP were not significantly different between the 2 groups. The DM group was then randomized to receive troglitazone (n=10; 400 mg/d) or glyburide (n=12; 20 mg/d). MAT was repeated after 6 months of treatment. Both treatments reduced glucose equally (-1.7 mmol/L for troglitazone and -1.5 mmol/L for glyburide), but only troglitazone reduced insulin (-15 microU/mL; P<0.001) and C-peptide (-0.9 ng/mL; P<0.02) levels. Troglitazone significantly reduced BP at baseline (P<0.05) and systolic BP response to MAT (P<0.01), whereas glyburide did not affect BP at baseline or during MAT. Stroke volume and cardiac output did not change with either drug, but troglitazone decreased peripheral vascular resistance (-112 dyne. s. cm(-5); P<0.05). Improved insulin resistance rather than an improved glycemic control is associated with lower resting and stress BP values in patients with DM. A reduction in vascular resistance may be a primary hemodynamic mechanism of the manner in which troglitazone lowers BP. Insulin sensitizers may offer potential therapeutic advantage in subjects with DM with elevated BP. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Chromans_MeSH S_pharmacology_MeSH Chromans_pharmacology_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Hemodynamic_Processes_MeSH S_drug_effects_MeSH Hemodynamic_Processes_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Reference_Values_MeSH M_Rest_MeSH M_Stress__Psychological_MeSH S_physiopathology_MeSH Stress__Psychological_physiopathology_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Thiazoles_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH P_Thiazolidinediones_MeSH M_Vasodilation_MeSH S_drug_effects_MeSH Vasodilation_drug_effects_MeSH ****** 10416947 ----K E ----T High-dose biotin, an inducer of glucokinase expression, may synergize with chromium picolinate to enable a definitive nutritional therapy for type II diabetes. ----A Glucokinase (GK), expressed in hepatocyte and pancreatic beta cells, has a central regulatory role in glucose metabolism. Efficient GK activity is required for normal glucose-stimulated insulin secretion, postprandial hepatic glucose uptake, and the appropriate suppression of hepatic glucose output and gluconeogenesis by elevated plasma glucose. Hepatic GK activity is subnormal in diabetes, and GK may also be decreased in the beta cells of type II diabetics. In supraphysiological concentrations, biotin promotes the transcription and translation of the GK gene in hepatocytes; this effect appears to be mediated by activation of soluble guanylate cyclase. More recent evidence indicates that biotin likewise increases GK activity in islet cells. On the other hand, high-dose biotin suppresses hepatocyte transcription of phosphoenolpyruvate carboxykinase, the rate-limiting enzyme for gluconeogenesis. Administration of high-dose biotin has improved glycemic control in several diabetic animals models, and a recent Japanese clinical study concludes that biotin (3 mg t.i.d. orally) can substantially lower fasting glucose in type II diabetics, without side-effects. The recently demonstrated utility of chromium picolinate in type II diabetes appears to reflect improved peripheral insulin sensitivity--a parameter which is unlikely to be directly influenced by biotin. Thus, the joint administration of supranutritional doses of biotin and chromium picolinate is likely to combat insulin resistance, improve beta-cell function, enhance postprandial glucose uptake by both liver and skeletal muscle, and inhibit excessive hepatic glucose production. Conceivably, this safe, convenient, nutritional regimen will constitute a definitive therapy for many type II diabetics, and may likewise be useful in the prevention and management of gestational diabetes. Biotin should also aid glycemic control in type I patients. ----P Journal_Article Review Review__Tutorial ----M M_Biotin_MeSH S_therapeutic_use_MeSH Biotin_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Synergism_MeSH M_Enzyme_Induction_MeSH S_drug_effects_MeSH Enzyme_Induction_drug_effects_MeSH M_Gene_Expression_Regulation__Enzymologic_MeSH S_drug_effects_MeSH Gene_Expression_Regulation__Enzymologic_drug_effects_MeSH M_Glucokinase_MeSH S_biosynthesis_MeSH Glucokinase_biosynthesis_MeSH S_genetics_MeSH Glucokinase_genetics_MeSH M_Iron_Chelating_Agents_MeSH S_therapeutic_use_MeSH Iron_Chelating_Agents_therapeutic_use_MeSH M_Picolinic_Acids_MeSH S_therapeutic_use_MeSH Picolinic_Acids_therapeutic_use_MeSH ****** 10426848 ----K E ----T Late recovery of ventricular function in children with idiopathic dilated cardiomyopathy. ----A BACKGROUND: The prognosis for children with idiopathic dilated cardiomyopathy (IDC) is variable. Patients who fail to exhibit improvement in left ventricular (LV) function have a high 1-year mortality rate, whereas improvement in LV fractional shortening (LVFS) to >15% is associated with better survival. However, complete recovery of LV performance to normal has not been examined. METHODS AND RESULTS: The clinical features and echocardiograms of 63 children with IDC were reviewed. Sixteen patients (group 1) were identified who demonstrated progressive improvement in LVFS, ultimately recovering to within the normal range. They were compared with 47 patients (group 2) in whom LVFS remained depressed. Group 1 LVFS at first examination was 13.6% +/- 5.1%, z = -10.8 +/- 4.0, and improved to within the normal range (33.7% +/- 3.4%, z = -0.9 +/- 1. 4, P <.001). Group 2 initial LVFS was 13.6 +/- 2.3, z = -8.9 +/- 3.2 and did not change significantly (15.7% +/- 7.3%, z = -7.3 +/- 1.6). The LV was dilated at initial examination in all patients (z = 6.9 +/- 3.0). Recovery in group 1 was associated with a decrease in LV dimension to within the normal range (z = 1.3 +/- 1.6, P <.001), whereas the LV dimension in group 2 patients remained increased (z = 6.2 +/- 3.4). The mean follow-up time at which LV function was noted to be normal was 4.5 +/- 3.6 years (range 0.3 to 14 years). The total duration of follow-up was 6.5 +/- 5.2 years (range 1 to 16 years). CONCLUSIONS: Complete recovery of LV function is possible in children with IDC. Recovery may occur within the first year after initial examination in some patients, but longer periods are needed in the majority of patients in whom LV function ultimately returned to normal. ----P Journal_Article ----M M_Cardiomyopathy__Congestive_MeSH S_physiopathology_MeSH Cardiomyopathy__Congestive_physiopathology_MeSH M_Child_MeSH M_Child__Preschool_MeSH M_Human_MeSH M_Infant_MeSH M_Infant__Newborn_MeSH M_Prognosis_MeSH M_Retrospective_Studies_MeSH P_Ventricular_Function__Left_MeSH ****** 10427465 ----K E ----T Clinical pharmacokinetics and pharmacodynamics of bromfenac. ----A Bromfenac is a nonsteroidal anti-inflammatory drug whose peak plasma concentration is reached 0.5 hours after oral administration. Bromfenac binds extensively to plasma albumin. The area under the plasma concentration-time curve is linearly proportional to the dose for oral doses up to 150 mg. The relationship between the total plasma and analgesic effect has been established. Only small amounts of bromfenac are eliminated unchanged, with the remaining drug being biotransformed into glucuronide metabolites which are excreted in urine and bile. Rapid elimination occurs in healthy individuals (half-life 0.5 to 4.0 h). Renal disease, hepatic disease and aging alter the disposition kinetics of bromfenac, and dosage adjustment may be advisable. Bromfenac modestly decreases free phenytoin concentrations. Bromfenac can cause idiosyncratic hepatic toxicity and has been withdrawn by its manufacturer pending further investigation of these case reports. ----P Journal_Article Review Review__Tutorial ----M M_Analgesics_MeSH S_adverse_effects_MeSH Analgesics_adverse_effects_MeSH S_pharmacokinetics_MeSH Analgesics_pharmacokinetics_MeSH S_pharmacology_MeSH Analgesics_pharmacology_MeSH M_Anti-Inflammatory_Agents__Non-Steroidal_MeSH S_adverse_effects_MeSH Anti-Inflammatory_Agents__Non-Steroidal_adverse_effects_MeSH S_pharmacokinetics_MeSH Anti-Inflammatory_Agents__Non-Steroidal_pharmacokinetics_MeSH S_pharmacology_MeSH Anti-Inflammatory_Agents__Non-Steroidal_pharmacology_MeSH M_Benzophenones_MeSH S_adverse_effects_MeSH Benzophenones_adverse_effects_MeSH S_pharmacokinetics_MeSH Benzophenones_pharmacokinetics_MeSH S_pharmacology_MeSH Benzophenones_pharmacology_MeSH M_Bromobenzenes_MeSH S_adverse_effects_MeSH Bromobenzenes_adverse_effects_MeSH S_pharmacokinetics_MeSH Bromobenzenes_pharmacokinetics_MeSH S_pharmacology_MeSH Bromobenzenes_pharmacology_MeSH M_Drug_Interactions_MeSH M_Human_MeSH ****** 10436254 ----K I ----T A comparison of preconstituted, fixed combinations of low-dose glyburide plus metformin versus high-dose glyburide alone in the treatment of type 2 diabetic patients. ----A In the present study we assessed and compared the effectiveness and safety of preconstituted, fixed, combinations of low-dose glyburide plus metformin with higher-dose glyburide monotherapy in patients with type 2 diabetes. This randomized, double-blind, cross-over study comprised 40 patients. After a 30-day run-in period of dietary treatment, patients received combined glyburide (5, 7.5 or 10 mg/day) and metformin (800, 1,200 or 1,600 mg/day) as preconstitued, fixed combinations, or glyburide alone (5, 10 or 15 mg/day). The dose was increased stepwise so as to have 1 (T1), 2 (T2) and 3 (T3) months of treatment for any given regimen (6 months in total). After 2 weeks of washout (T4), the groups were then crossed over (T5, T6, T7 periods). Body weight, fasting plasma glucose, HbA(1c), blood lactate, total cholesterol and HDL-cholesterol, and triglycerides were measured at the beginning and end of T1 and T5, and end of T2, T3, T6 and T7; postprandial plasma glucose, fasting and postprandial plasma insulin and C-peptide were evaluated at the beginning of T1 and T5, and end of T3 and T7. At these latter time points additional assessments included routine clinical chemistry measurements, ECG, and ophthalmoscopic examination. Statistical analysis was performed by the paired Student's t-test and analysis of variance for cross-over studies. Thirty-three patients completed the study. Fasting plasma glucose, postprandial plasma glucose and HbA(1c) levels improved significantly during combined treatment with glyburide at lower doses plus metformin. This effect was achieved without any major change of insulin and C-peptide concentrations. Circulating lactate concentrations increased during the regimen including metformin, but they remained well within the reference values for normal subjects. Plasma total cholesterol and triglycerides levels remained substantielly unchanged throughout the study, whereas HDL-cholesterol concentrations increased slightly, but significantly, with glyburide plus metformin therapy. Routine clinical chemistry measurements, ECG and ophthalmoscopic examinations did not change during the study. These results demonstrate that improved metabolic control can be achieved with preconstituted, fixed combinations of low-dose glyburide plus metformin in patients with type 2 diabetes, compared to higher doses of the sulphonylurea alone. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Combinations_MeSH M_Fasting_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 10436259 ----K E ----T Effects of combination of insulin and acarbose compared with insulin and gliclazide in type 2 diabetic patients. ----A In this prospective study we aimed to compare insulin plus acarbose with insulin plus gliclazide with respect to their effect on insulin requirement, lipid profiles and body mass index (BMI) while achieving good glycemic control. Forty patients with type 2 diabetes mellitus who were on conventional insulin therapy (subcutaneous insulin therapy consisting of regular and NPH insulin, two times a day) were included in the study. They were randomized to double blind treatment with insulin in combination with gliclazide or acarbose for 6 months. For both groups, acceptable glycemic control was achieved at the end of study period. The mean HbA(1c) levels decreased from 8.32+/-0.26 to 7.13+/-0.18% in acarbose group and 8. 6+/-0.15 to 7.48+/-0.21% in the gliclazide group. The difference between groups was not significant (P 0.29). In the acarbose group, total cholesterol and LDL concentration decreased significantly while other parameters did not change. In the gliclazide group, HDL levels decreased significantly from 46.6+/-2.48 mg/dl to 41.3+/-2.09 mg/dl (P 0.001) BMI increased significantly from 27.60+/-1.21 kg/m(2) to 28.69+/-1.26 kg/m(2). (P 0.003) Total daily insulin dose was not changed in the acarbose group significantly, but increased from 42.6+/-2.73 to 49.27+/-3.58 U/day, which was significant in gliclazide group of (P 0.016). In the acarbose group, there were no significant differences between responders and nonresponders with respect to fasting and stimulated C-peptide, HbA(1c) levels and baseline BMI values. But in the gliclazide group, baseline BMI values were significantly higher in the nonresponding group compared to responders (P 0.02). In conclusion, combination of insulin with acarbose can be a good alternative for type 2 diabetic patients on insulin therapy; seems more beneficial than combination with gliclazide; may have advantage of achieving good glycemic control without increasing insulin dose and BMI; also may have the advantage of providing a decrease in LDL level, which are all important to prevent atherosclerosis. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acarbose_MeSH S_therapeutic_use_MeSH Acarbose_therapeutic_use_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Prospective_Studies_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 10454950 ----K I ----T Pharmacologic therapy for type 2 diabetes mellitus. ----A Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided. ----P Journal_Article Review Review__Academic ----M M_Acarbose_MeSH M_Administration__Oral_MeSH M_Algorithms_MeSH M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Chromans_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Evidence-Based_Medicine_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Trisaccharides_MeSH S_therapeutic_use_MeSH Trisaccharides_therapeutic_use_MeSH ****** 10445835 ----K I ----T Higher incidence of severe hypoglycaemia leading to hospital admission in Type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas. ----A AIMS: A comparison of the frequency of severe hypoglycaemia leading to hospital admission in people with Type 2 diabetes mellitus (DM) treated with long vs. short-acting sulphonylureas. METHODS: A community based study over a 12-year period in the population of the city of Basle, Switzerland. The number of diabetic patients treated with oral hypoglycaemic agents was established on the basis of tablet consumption and a defined daily dose, e.g. 7.5 mg for glibenclamide, and 50 mg for glibornuride. RESULTS: Twenty-eight Type 2 diabetic patients were admitted for severe hypoglycaemia, with a median age of 73 years. There were no deaths. Sixteen of these admissions were patients treated with long-acting sulphonylureas and 12 were patients treated with short-acting forms. Only 23.5% of the population with Type 2 DM in Basle were treated with long-acting sulphonylureas. With 30345 person-years of observation, the incidence of severe hypoglycaemia was 2.24 per 1000 person-years for long-acting sulphonylureas vs. 0.75 per 1000 person-year for short-acting forms, odds ratio 3.01 (95% confidence interval 1.35-6.77). Decreased food intake (nine patients) was a major contributing factor. CONCLUSIONS: Severe hypoglycaemia leading to hospital admission is more common in elderly Type 2 diabetic patients treated with long-acting compared to short-acting sulphonylureas. Such long-acting sulphonylureas should be avoided. ----P Journal_Article ----M M_Aged_MeSH M_Aged__80_and_over_MeSH M_Case-Control_Studies_MeSH M_Comparative_Study_MeSH M_Confidence_Intervals_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Emergencies_MeSH M_Female_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH M_Hospitals__University_MeSH S_statistics_&_numerical_data_MeSH Hospitals__University_statistics_&_numerical_data_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH S_epidemiology_MeSH Hypoglycemia_epidemiology_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Incidence_MeSH M_Inpatients_MeSH S_statistics_&_numerical_data_MeSH Inpatients_statistics_&_numerical_data_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Odds_Ratio_MeSH M_Retrospective_Studies_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH M_Switzerland_MeSH S_epidemiology_MeSH Switzerland_epidemiology_MeSH ****** 10430816 ----K E ----T Type 2 diabetes: an overview. ----A Type 2 diabetes is a heterogeneous disorder. Clinical expression of the disorder requires both genetic and environmental factors. One theory concerning its etiology is that it is the result of the evolution of a thrifty genotype that had survival benefits in the past but is detrimental in the current environment. An opposing theory is that it represents an adult metabolic response to fetal malnutrition. Hyperglycemia in type 2 diabetes results from absolute or relative insulin deficiency. Most often relative insulin deficiency is attributable to an inability to adequately compensate for insulin resistance. Insulin resistance may be caused by a variety of genetic or metabolic factors. The most common etiological factor in insulin resistance is central obesity. Insulin resistance is associated with a cluster of metabolic abnormalities that include glucose intolerance, hypertension, a unique dyslipidemia, a procoagulant state, and an increase in macrovascular disease. Clinical intervention studies have demonstrated that reduction in the chronic microvascular and macrovascular complications of type 2 diabetes requires treatment of hyperglycemia to achieve hemoglobin A1c <7.0%, blood pressure </=130/80 mmHg, and plasma LDL-cholesterol </=2.6 mmol/L (</=100 mg/dL). Oral antihyperglycemic agents increase endogenous insulin secretion, decrease insulin resistance, or lower postprandial plasma glucose rise by delaying absorption of complex carbohydrates. Long-term glycemic control in type 2 diabetes requires progressive, stepwise, combination treatment with oral agents and eventually combination treatment with oral agents and insulin. ----P Journal_Article Review Review__Tutorial ----M M_Cardiovascular_Diseases_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH P_Diabetes_Mellitus__Type_II_MeSH S_classification_MeSH Diabetes_Mellitus__Type_II_classification_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_Resistance_MeSH M_Obesity_MeSH S_etiology_MeSH Obesity_etiology_MeSH M_Risk_Factors_MeSH ****** 10466661 ----K E ----T Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. ----A BACKGROUND: The American Diabetes Association (ADA) recommend that fasting glucose alone with the oral glucose tolerance test should be used to diagnose diabetes mellitus. We assessed mortality associated with the ADA fasting-glucose criteria compared with the WHO 2 h post-challenge glucose criteria. METHODS: We assessed baseline data on glucose concentrations at fasting and 2 h after the 75 g oral glucose tolerance test from 13 prospective European cohort studies, which included 18,048 men and 7316 women aged 30 years or older. Mean follow-up was 7.3 years. We assessed the risk of death according to the different diagnostic glucose categories. FINDINGS: Compared with men who had normal fasting glucose (< 6.1 mmol/L), men with newly diagnosed diabetes mellitus by the ADA fasting criteria (> or = 7.0 mmol/L) had a hazard ratio for death of 1.81 (95% CI 1.49-2.20); for women the hazard ratio was 1.79 (1.18-2.69). For impaired fasting glucose (6.1-6.9 mmol/L), the hazard ratios were 1.21 (1.05-1.41) and 1.08 (0.70-1.66). For the WHO criteria (> or = 11.1 mmol/L), the ratios for newly diagnosed diabetes were 2.02 (1.66-2.46) in men and 2.77 (1.96-3.92) in women, and for impaired glucose tolerance (7.8-11.1 mmol/L) were 1.51 (1.32-1.72) and 1.60 (1.22-2.10). Within each fasting-glucose classification, mortality increased with increasing 2 h glucose. However, for 2 h glucose classifications of impaired glucose tolerance, and diabetes, there was no trend for increasing fasting glucose concentrations. INTERPRETATION: Fasting-glucose concentrations alone do not identify individuals at increased risk of death associated with hyperglycaemia. The oral glucose tolerance test provides additional prognostic information and enables detection of individuals with impaired glucose tolerance, who have the greatest attributable risk of death. ----P Journal_Article Multicenter_Study ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus_MeSH S_blood_MeSH Diabetes_Mellitus_blood_MeSH S_diagnosis_MeSH Diabetes_Mellitus_diagnosis_MeSH S_mortality_MeSH Diabetes_Mellitus_mortality_MeSH M_Fasting_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH P_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_mortality_MeSH Hyperglycemia_mortality_MeSH M_Male_MeSH M_Practice_Guidelines_MeSH M_Proportional_Hazards_Models_MeSH M_Risk_Factors_MeSH M_Societies__Medical_MeSH M_Support__Non-U_S__Gov't_MeSH M_United_States_MeSH M_World_Health_Organization_MeSH ****** 10465860 ----K E ----T Hypoglycemia associated with high doses of sertraline and sulphonylurea compound in a noninsulin-dependent diabetes mellitus patient. ----A Unlike other selective serotonin reuptake inhibitors (SSRIs), sertraline has linear pharmacokinetics so that increases in dose lead to proportional increases in drug concentration. The half-life of sertraline is about 26 h so that it reaches a steady state in one week, according to the product monograph. Hypoglycemia associated with sertraline and coadministration of oral hypoglycemics belonging to the sulphonylurea derivatives has rarely been reported. A patient with schizoaffective disorder with non-insulin-dependent diabetes mellitus (NIDDM) treated with sertraline, risperidone and glyburide who developed hypoglycemia is presented. The article highlights that inhibition of P450 enzymes can be affected by several different factors. Interactions are possible whenever a patient concomitantly receives two drugs that bind to the same P450 system Greater inhibition was likely induced at doses higher than those recommended. This process was reversed within 10 days of discontinuing the sertraline. Good glycemic control followed discontinuation of psychotropic drugs and the oral hypoglycemic agent. Knowledge of the individual P450 enzymes is important in the metabolism of individual drugs, together with an understanding of the patient's drug metabolizing ability. These factors may lead to more appropriate prescribing and further research into specific P450 enzymes responsible for metabolism of particular drugs, which remains unclear. ----P Case_Reports Journal_Article ----M M_Adult_MeSH M_Antidepressive_Agents__Second-Generation_MeSH S_administration_&_dosage_MeSH Antidepressive_Agents__Second-Generation_administration_&_dosage_MeSH S_adverse_effects_MeSH Antidepressive_Agents__Second-Generation_adverse_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Interactions_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH S_complications_MeSH Hypoglycemia_complications_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Male_MeSH M_Psychotic_Disorders_MeSH S_complications_MeSH Psychotic_Disorders_complications_MeSH S_drug_therapy_MeSH Psychotic_Disorders_drug_therapy_MeSH M_Sertraline_MeSH S_administration_&_dosage_MeSH Sertraline_administration_&_dosage_MeSH S_adverse_effects_MeSH Sertraline_adverse_effects_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH ****** 10476312 ----K E ----T Reduced glucose effectiveness as a feature of glucose intolerance: evidence in elderly type-2 diabetic subjects. ----A One of the factors determining glucose tolerance is glucose disappearance independent from the dynamic insulin (glucose effectiveness); the debate on its role in the development of Type-2 diabetes is still open. The aim of the present study was to evaluate insulin delivery, insulin sensitivity (SI), and glucose effectiveness (SG) in a group of elderly Type-2 diabetic patients (D, 4/6 F/M, age 67 +/- 2 years, 64 +/- 2 kg, BMI 23.8 +/- 0.5 kg/m2), compared to young controls (C, 4/6 F/M, 25 +/- 2 years, 72 +/- 4 kg, 23.7 +/- 1.1 kg/m2) and elderly controls (E, 2/4 F/M, 73 +/- 3 years, 63 +/- 4 kg, 23.1 +/- 0.5 kg/m2). We performed oral (OGTT) and intravenous (FSIGT) glucose tolerance tests. The OGTT showed that C and E were normotolerant, while D had a markedly reduced glucose tolerance. This was also confirmed in the FSIGT where the glucose tolerance index (KG) was 0.6 +/- 0.1% min-1 in D vs 1.8 +/- 0.2 in C and 1.5 +/- 0.2 in E (p < 0.0002). Total insulin area of D and the overall insulin delivery were not different from those of the control groups. The early phase area was instead significantly reduced (0.19 +/- 0.02 mU min/mL vs 0.61 +/- 0.06 of C and 0.46 +/- 0.06 of E, p < 0.001) given the reduction in the dynamic first-phase insulin delivery (0.86 +/- 0.17 min(microU/mL)/(mg/dL) vs 3.95 +/- 0.61 in C (p < 0.005) and 2.61 +/- 0.66 (p < 0.001) in E). SI of D was 3.4 +/- 0.4 10(-4) min-1/(microU/mL), not different from that of C (4.7 +/- 0.6) and E (3.5 +/- 0.2). This study showed a marked difference between SG of D and that of both control groups [0.010 +/- 0.001 min-1 vs 0.026 +/- 0.004 (p < 0.001) of C and 0.020 +/- 0.003 (p < 0.002) of E], mostly due to the zero-insulin component GEZI which was 0.006 +/- 0.001 in D vs 0.021 +/- 0.004 in C and 0.016 +/- 0.003 in E (p < 0.003). In the elderly groups, when taken together, SG exhibited a positive correlation with the area under insulin concentration during the early phase and with KG (r = 0.69, p = 0.0032 and r = 0.90, p = 0.0001, respectively), demonstrating the importance of the first-phase insulin delivery in modulating glucose effectiveness and glucose tolerance. ----P Journal_Article ----M M_Adult_MeSH M_Age_Factors_MeSH M_Aged_MeSH M_Aging_MeSH S_metabolism_MeSH Aging_metabolism_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Fasting_MeSH M_Female_MeSH M_Glucose_Intolerance_MeSH S_drug_therapy_MeSH Glucose_Intolerance_drug_therapy_MeSH S_metabolism_MeSH Glucose_Intolerance_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Insulin_Resistance_MeSH M_Male_MeSH M_Support__Non-U_S__Gov't_MeSH M_Tolbutamide_MeSH S_administration_&_dosage_MeSH Tolbutamide_administration_&_dosage_MeSH ****** 10480768 ----K E ----T Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu Heart Program. ----A OBJECTIVE: The associations between glucose intolerance measured at the study entry date and the 23-year incidence of coronary heart disease (CHD), CHD mortality, and total mortality were examined at the Honolulu Heart Program. RESEARCH DESIGN AND METHODS: This prospective study followed a cohort of 8,006 Japanese-American men who were 45-68 years old and living on the island of Oahu, HI, in 1965. Baseline glucose was measured in a nonfasting state 1 h after a 50-g glucose load. History and use of medication for diabetes was obtained during an interview. The cohort was divided into four categories of glucose tolerance: low-normal, high-normal, asymptomatic hyperglycemia, and known diabetes. RESULTS: During the 23 years of follow-up, 864 incident cases of CHD, 384 deaths from CHD, and 2,166 total deaths occurred. The relative risks (RRs) were obtained using Cox proportional hazards modeling, with the low-normal category as a reference. The RRs were adjusted for age only, as well as for age, BMI, hypertension, cholesterol, triglycerides, smoking, alcohol, and a Japanese diet index. The age-adjusted and risk factor-adjusted RRs for all outcomes were significant for the asymptomatic hyperglycemic and known diabetes groups (P<0.05). The age-adjusted RRs for CHD incidence and total mortality were marginally significant in the high-normal group, but the RRs were not significant when adjusted for risk factors. CONCLUSIONS: These results suggest a dose-response relation of glucose intolerance at baseline with CHD incidence, CHD mortality, and total mortality, independent of other risk factors, in this cohort of middle-aged and older Japanese-American men. ----P Clinical_Trial Controlled_Clinical_Trial Journal_Article ----M M_Aged_MeSH M_Coronary_Disease_MeSH S_blood_MeSH Coronary_Disease_blood_MeSH S_epidemiology_MeSH Coronary_Disease_epidemiology_MeSH S_mortality_MeSH Coronary_Disease_mortality_MeSH M_Diabetes_Mellitus_MeSH S_blood_MeSH Diabetes_Mellitus_blood_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH P_Glucose_Intolerance_MeSH M_Hawaii_MeSH S_epidemiology_MeSH Hawaii_epidemiology_MeSH M_Human_MeSH M_Incidence_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Proportional_Hazards_Models_MeSH M_Risk_Assessment_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 10483287 ----K 5 ----T [Controversial aspects regarding metformin in type 2 diabetic patient: reduction of late complications in early, single drug administration; increased risk of death in later administration in combination with sulfonylurea compounds] ----A ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_mortality_MeSH Diabetes_Mellitus__Type_II_mortality_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_drug_therapy_MeSH Obesity_in_Diabetes_drug_therapy_MeSH S_mortality_MeSH Obesity_in_Diabetes_mortality_MeSH M_Risk_Factors_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH M_Survival_Rate_MeSH ****** 10487540 ----K E ----T Carnitine transport and its inhibition by sulfonylureas in human kidney proximal tubular epithelial cells. ----A The kidney plays an important role in the homeostasis of carnitine by its ability to reabsorb carnitine almost completely from the glomerular filtrate. The transport process responsible for this reabsorption has been investigated thus far only in laboratory animals. Here we report on the characteristics of carnitine uptake in a proximal tubular epithelial cell line derived from human kidney. The uptake process was found to be obligatorily dependent on Na+ with no involvement of anions. The process was saturable, with a Michaelis-Menten constant of 14 +/- 1 microM. The Na+:carnitine stoichiometry was 1:1. The same process also was found to be responsible for the uptake of acetylcarnitine and propionylcarnitine, two acyl esters of carnitine with potential for therapeutic use in humans. The uptake process was specific for carnitine and its acyl esters. Betaine, a structural analog of carnitine, interacted with the uptake process to a significant extent. The present studies also showed that sulfonylureas, oral hypoglycemic agents currently used in the management of type 2 diabetes, inhibited the carnitine uptake system. Among the sulfonylureas tested, glibenclamide was the most potent inhibitor. The inhibition was competitive. Glibenclamide inhibited the uptake not only of carnitine but also of acetylcarnitine and propionylcarnitine. The inhibition most likely was the result of direct interaction of the compound with the carnitine transporter because the inhibition could be demonstrated in purified rat kidney brush border membrane vesicles. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Animals_MeSH M_Biological_Transport_MeSH S_drug_effects_MeSH Biological_Transport_drug_effects_MeSH M_Carnitine_MeSH S_analogs_&_derivatives_MeSH Carnitine_analogs_&_derivatives_MeSH S_metabolism_MeSH Carnitine_metabolism_MeSH M_Cell_Line_MeSH M_Cell_Membrane_MeSH S_drug_effects_MeSH Cell_Membrane_drug_effects_MeSH S_metabolism_MeSH Cell_Membrane_metabolism_MeSH M_Epithelial_Cells_MeSH S_drug_effects_MeSH Epithelial_Cells_drug_effects_MeSH S_metabolism_MeSH Epithelial_Cells_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Kidney_Tubules__Proximal_MeSH S_drug_effects_MeSH Kidney_Tubules__Proximal_drug_effects_MeSH S_metabolism_MeSH Kidney_Tubules__Proximal_metabolism_MeSH M_Microvilli_MeSH S_drug_effects_MeSH Microvilli_drug_effects_MeSH S_metabolism_MeSH Microvilli_metabolism_MeSH M_Rats_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH ****** 10491414 ----K E ----T The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. ----A The pathogenesis of type 2 diabetes involves abnormalities in insulin action, insulin secretion, and endogenous glucose output (EGO). However, the sequence with which these abnormalities develop and their relative contributions to the deterioration in glucose tolerance remain unclear in the absence of a detailed longitudinal study. We measured insulin action, insulin secretion, and EGO longitudinally in 17 Pima Indians, in whom glucose tolerance deteriorated from normal (NGT) to impaired (IGT) to diabetic over 5.1 +/- 1.4 years. Transition from NGT to IGT was associated with an increase in body weight, a decline in insulin-stimulated glucose disposal, and a decline in the acute insulin secretory response (AIR) to intravenous glucose, but no change in EGO. Progression from IGT to diabetes was accompanied by a further increase in body weight, further decreases in insulin-stimulated glucose disposal and AIR, and an increase in basal EGO. Thirty-one subjects who retained NGT over a similar period also gained weight, but their AIR increased with decreasing insulin-stimulated glucose disposal. Thus, defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes. Intervention to prevent diabetes should target both abnormalities. ----P Journal_Article ----M M_Adult_MeSH M_Anthropometry_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Glucose_MeSH S_metabolism_MeSH Glucose_metabolism_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Insulin_MeSH S_secretion_MeSH Insulin_secretion_MeSH P_Insulin_Resistance_MeSH M_Male_MeSH M_Obesity_MeSH S_complications_MeSH Obesity_complications_MeSH M_Sex_Factors_MeSH ****** 10496299 ----K E ----T Clinical pharmacokinetics of troglitazone. ----A Troglitazone is a new thiazolidinedione oral antidiabetic agent approved for use to improve glycaemic control in patients with type 2 diabetes. It is rapidly absorbed with an absolute bioavailability of between 40 and 50%. Food increases the absorption by 30 to 80%. The pharmacokinetics of troglitazone are linear over the clinical dosage range of 200 to 600 mg once daily. The mean elimination half-life ranges from 7.6 to 24 hours, which facilitates a once daily administration regimen. The pharmacokinetics of troglitazone are similar between patients with type 2 diabetes and healthy individuals. In humans, troglitazone undergoes metabolism by sulfation, glucuronidation and oxidation to form a sulfate conjugate (M1), glucuronide conjugate (M2) and quinone metabolite (M3), respectively. M1 and M3 are the major metabolites in plasma, and M2 is a minor metabolite. Age, gender, type 2 diabetes, renal impairment, smoking and race do not appear to influence the pharmacokinetics of troglitazone and its 2 major metabolites. In patients with hepatic impairment the plasma concentrations of troglitazone, M1 and M3 increase by 30%, 4-fold, and 2-fold, respectively. Cholestyramine decreases the absorption of troglitazone by 70%. Troglitazone may enhance the activities of cytochrome P450 (CYP) 3A and/or transporter(s) thereby reducing the plasma concentrations of terfenadine, cyclosporin, atorvastatin and fexofenadine. It also reduces the plasma concentrations of the oral contraceptive hormones ethinylestradiol, norethindrone and levonorgestrel. Troglitazone does not alter the pharmacokinetics of digoxin, glibenclamide (glyburide) or paracetamol (acetaminophen). There is no pharmacodynamic interaction between troglitazone and warfarin or alcohol (ethanol). Pharmacodynamic modelling showed that improvement in fasting glucose and triglyceride levels increased with dose from 200 to 600 mg. Knowledge of systemic troglitazone exposure within a dose group does not improve the prediction of glucose lowering response or adverse effects beyond those based on the administered dose. ----P Journal_Article Review Review__Tutorial ----M M_Biological_Availability_MeSH M_Biological_Markers_MeSH S_analysis_MeSH Biological_Markers_analysis_MeSH M_Chromans_MeSH S_pharmacokinetics_MeSH Chromans_pharmacokinetics_MeSH S_pharmacology_MeSH Chromans_pharmacology_MeSH M_Clinical_Trials_MeSH M_Comorbidity_MeSH M_Drug_Interactions_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Thiazoles_MeSH S_pharmacokinetics_MeSH Thiazoles_pharmacokinetics_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH P_Thiazolidinediones_MeSH ****** 10501822 ----K E ----T Absorption, metabolism and excretion of a single oral dose of (14)C-repaglinide during repaglinide multiple dosing. ----A OBJECTIVE: The present study was designed to assess the disposition of (14)C-repaglinide in whole blood, plasma, urine and faeces, and to measure the total recovery of drug-related material in urine and faeces after a single 2-mg oral dose of (14)C-repaglinide during multiple dosing.METHODS: In this single-centre, open-label, phase-I trial, six healthy male volunteers received 2 mg of the prandial glucose regulator, repaglinide, four times daily for 13 days, 15 min before meals. On the morning of day 7, breakfast was omitted and the dose was given as an oral solution containing 2 mg of (14)C-repaglinide.RESULTS: After oral dosing, a mean peak plasma concentration of repaglinide of 27.74 ng. ml(-1) (range: 16.84-36.65 ng. ml(-1)) was observed with a time to peak concentration of 0.5 h. Approximately 20% of repaglinide and its associated metabolites were distributed into red blood cells. No measurable (14)C-radioactivity was present in whole blood samples 6 h after dosing. Within 96 h of dosing with (14)C-repaglinide, 90% of the administered dose appeared in the faeces and 8% was excreted in urine. In the plasma, the major compound was repaglinide (61%). In the urine, the major metabolites were unidentified polar compounds, the aromatic amine (M(1)) (24%), and the dicarboxylic acid (M(2)) (22%). In the faeces, the major metabolite was M(2) (66% of administered dose). Therefore, repaglinide was excreted predominantly as metabolites and the major in vivo metabolite of repaglinide in humans was M(2). During regular dosing for 6 days, the morning plasma trough levels of repaglinide were, with very few exceptions, almost always too low to measure, indicating the absence of accumulation at this dose of 2 mg four times daily. Repaglinide was well tolerated, and there were no episodes of hypoglycaemia.CONCLUSION: After oral dosing with repaglinide, the mean peak plasma concentration was rapidly attained and, thereafter, plasma concentrations decreased promptly. The major route of excretion was via the faeces. These properties make repaglinide a suitable insulin secretagogue for all patients with type-2 diabetes who retain sufficient beta-cell function. ----P Clinical_Trial Clinical_Trial__Phase_I Journal_Article ----M M_Absorption_MeSH M_Administration__Oral_MeSH M_Adolescent_MeSH M_Adult_MeSH M_Area_Under_Curve_MeSH M_Carbamates_MeSH S_metabolism_MeSH Carbamates_metabolism_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH M_Carbon_Radioisotopes_MeSH S_diagnostic_use_MeSH Carbon_Radioisotopes_diagnostic_use_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Erythrocytes_MeSH S_metabolism_MeSH Erythrocytes_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH M_Metabolic_Clearance_Rate_MeSH M_Piperidines_MeSH S_metabolism_MeSH Piperidines_metabolism_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH M_Tissue_Distribution_MeSH ****** 10510156 ----K E ----T Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. ----A AIMS: To identify the human cytochrome P450 enzyme(s) involved in the in vitro metabolism of rosiglitazone, a potential oral antidiabetic agent for the treatment of type 2 diabetes-mellitus. Method The specific P450 enzymes involved in the metabolism of rosiglitazone were determined by a combination of three approaches; multiple regression analysis of the rates of metabolism of rosiglitazone in human liver microsomes against selective P450 substrates, the effect of selective chemical inhibitors on rosiglitazone metabolism and the capability of expressed P450 enzymes to mediate the major metabolic routes of rosiglitazone metabolism. Result The major products of metabolism following incubation of rosiglitazone with human liver microsomes were para-hydroxy and N-desmethyl rosiglitazone. The rate of formation varied over 38-fold in the 47 human livers investigated and correlated with paclitaxel 6alpha-hydroxylation (P<0.001). Formation of these metabolites was inhibited significantly (>50%) by 13-cis retinoic acid, a CYP2C8 inhibitor, but not by furafylline, quinidine or ketoconazole. In addition, both metabolites were produced by microsomes derived from a cell line transfected with human CYP2C8 cDNA. There was some evidence for CYP2C9 playing a minor role in the metabolism of rosiglitazone. Sulphaphenazole caused limited inhibition (<30%) of both pathways in human liver microsomes and microsomes from cells transfected with CYP2C9 cDNA were able to mediate the metabolism of rosiglitazone, in particular the N-demethylation pathway, albeit at a much slower rate than CYP2C8. Rosiglitazone caused moderate inhibition of paclitaxel 6alpha-hydroxylase activity (CYP2C8; IC50=18 microm ), weak inhibition of tolbutamide hydroxylase activity (CYP2C9; IC50=50 microm ), but caused no marked inhibition of the other cytochrome P450 activities investigated (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A and 4A). Conclusion CYP2C8 is primarily responsible for the hydroxylation and N-demethylation of rosiglitazone in human liver; with minor contributions from CYP2C9. ----P Journal_Article ----M P_Aryl_Hydrocarbon_Hydroxylases_MeSH M_Cytochrome_P-450_Enzyme_System_MeSH S_genetics_MeSH Cytochrome_P-450_Enzyme_System_genetics_MeSH S_metabolism_MeSH Cytochrome_P-450_Enzyme_System_metabolism_MeSH M_DNA__Complementary_MeSH S_genetics_MeSH DNA__Complementary_genetics_MeSH M_Enzyme_Inhibitors_MeSH S_pharmacology_MeSH Enzyme_Inhibitors_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH M_Kinetics_MeSH M_Microsomes__Liver_MeSH S_enzymology_MeSH Microsomes__Liver_enzymology_MeSH S_metabolism_MeSH Microsomes__Liver_metabolism_MeSH P_Steroid_16-alpha-Hydroxylase_MeSH M_Steroid_Hydroxylases_MeSH S_genetics_MeSH Steroid_Hydroxylases_genetics_MeSH S_metabolism_MeSH Steroid_Hydroxylases_metabolism_MeSH M_Thiazoles_MeSH S_metabolism_MeSH Thiazoles_metabolism_MeSH P_Thiazolidinediones_MeSH M_Transfection_MeSH M_Tumor_Cells__Cultured_MeSH ****** 10558125 ----K E ----T A short-term cost-of-treatment model for type 2 diabetes: comparison of glipizide gastrointestinal therapeutic system, metformin, and acarbose. ----A OBJECTIVE: To compare, from a managed care perspective, the 3-year costs of 3 first-line monotherapy strategies in type 2 diabetes patients: glipizide gastrointestinal therapeutic system (GITS), metformin, and acarbose. STUDY DESIGN: A Markov model, with a Monte Carlo simulation, was developed to compare the costs to achieve full glycemic control (hemoglobin A1c of < or = 7%) with each first-line strategy. PATIENTS AND METHODS: The patient population for the model was assumed to be all newly diagnosed type 2 diabetes patients eligible for monotherapy with an oral agent. Each monotherapy could be succeeded by add-on treatments. The model included the costs of routine medical care and supplies, medication, adverse events, and treatment failures. RESULTS: Using a Monte Carlo simulation, the mean 3-year cumulative costs per patient were $4971, $5273, and $5311 for glipizide GITS, metformin, and acarbose first-line strategies, respectively. The main cost drivers were drug prices. Mean 3-year cost savings for first-line glipizide GITS were $301 over metformin and $340 over acarbose. Between 83% and 85% of all simulations showed cost savings with glipizide GITS compared with the other agents. CONCLUSIONS: The model suggests first-line monotherapy with glipizide GITS should result in desirable short-term economic benefits for managed care. Because the model incorporates recommended glycemic goals and performed well in sensitivity analyses, it should be applicable to a variety of clinical practices and useful for economic assessments of new therapies. Results of this model should be verified prospectively in typical care settings. ----P Journal_Article ----M M_Acarbose_MeSH M_Decision_Trees_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH M_Drug_Costs_MeSH S_statistics_&_numerical_data_MeSH Drug_Costs_statistics_&_numerical_data_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_economics_MeSH Glipizide_economics_MeSH M_Health_Care_Costs_MeSH S_statistics_&_numerical_data_MeSH Health_Care_Costs_statistics_&_numerical_data_MeSH M_Health_Resources_MeSH S_economics_MeSH Health_Resources_economics_MeSH S_utilization_MeSH Health_Resources_utilization_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_economics_MeSH Hypoglycemic_Agents_economics_MeSH M_Managed_Care_Programs_MeSH S_economics_MeSH Managed_Care_Programs_economics_MeSH M_Markov_Chains_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_economics_MeSH Metformin_economics_MeSH M_Monte_Carlo_Method_MeSH M_Office_Visits_MeSH S_economics_MeSH Office_Visits_economics_MeSH S_statistics_&_numerical_data_MeSH Office_Visits_statistics_&_numerical_data_MeSH M_Support__Non-U_S__Gov't_MeSH M_Trisaccharides_MeSH S_administration_&_dosage_MeSH Trisaccharides_administration_&_dosage_MeSH S_economics_MeSH Trisaccharides_economics_MeSH M_United_States_MeSH ****** 10520444 ----K E ----T Recent advances in pharmacological treatment of type 2 diabetes mellitus. ----A Several new pharmacological agents attempt to correct abnormalities in the pathogenesis of type 2 diabetes mellitus. The availability of agents with different mechanisms of action and side-effect profiles permits the design of individualized regimens that address the various pathophysiologic abnormalities. ----P Journal_Article Review Review__Tutorial ----M M_Blood_Glucose_MeSH M_Combined_Modality_Therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diagnosis_MeSH Diabetes_Mellitus__Type_II_diagnosis_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Administration_Schedule_MeSH P_Exercise_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Prognosis_MeSH M_Weight_Loss_MeSH ****** 10526729 ----K E ----T Interaction of sulfonylureas and exercise on glucose homeostasis in type 2 diabetic patients. ----A OBJECTIVE: To determine whether the plasma glucose-lowering effects of sulfonylureas and acute submaximal exercise are additive and, accordingly, to determine whether they may increase the risk of hypoglycemia when combined in fasting patients. RESEARCH DESIGN AND METHODS: Eight postabsorptive type 2 diabetic patients were examined at three occasions: after oral sulfonylurea (7 mg glibenclamide), during 60 min of ergometer cycle exercise at 57 +/- 3% of VO2max, and during exercise after glibenclamide. RESULTS: Heart rate, VO2, and lactate responses to exercise were comparable (P > 0.05) on days with and without glibenclamide. Plasma insulin concentrations were always increased by glibenclamide, and they were lowered identically by exercise with and without glibenclamide. However, throughout exercise, absolute concentrations of insulin were lower on days without glibenclamide compared with days with glibenclamide (34.5 +/- 4.7 vs. 47.4 +/- 5.5 pmol/l; P < 0.05). At the start of exercise, glucose concentrations were similar between experiments (P > 0.05). The rate of decrease in glucose during exercise was higher (P < 0.05) on days with both glibenclamide and exercise, compared with days with glibenclamide alone and days with exercise alone (-0.035 +/- 0.009 vs. -0.016 +/- 0.002 and -0.022 +/- 0.005 mmol.l-1.min-1, respectively). Consequently, the glucose nadir was lower on days with glibenclamide and exercise than on days with glibenclamide or exercise alone (6.7 +/- 1.1 vs. 8.1 +/- 0.9 and 7.6 +/- 1.0 mmol/l, respectively; P < 0.05). During exercise, the rate of appearance of plasma glucose determined by 3-[3H]glucose infusion was lower on days with glibenclamide than on days without glibenclamide (2.3 +/- 0.1 vs. 2.9 +/- 0.1 mg.min-1.kg-1; P < 0.05). In contrast, glucose clearance was identical (P > 0.05). CONCLUSIONS: In postabsorptive type 2 diabetic patients, the hypoglycemic action of glibenclamide and exercise is enhanced when the treatments are combined. The interaction reflects an increased inhibition by glibenclamide-enhanced insulin levels of hepatic glucose production when hepatic glucose production is accelerated by exercise. ----P Journal_Article ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Epinephrine_MeSH S_blood_MeSH Epinephrine_blood_MeSH M_Exercise_MeSH S_physiology_MeSH Exercise_physiology_MeSH M_Exercise_Test_MeSH M_Exertion_MeSH S_physiology_MeSH Exertion_physiology_MeSH M_Glucagon_MeSH S_blood_MeSH Glucagon_blood_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Homeostasis_MeSH M_Human_MeSH M_Human_Growth_Hormone_MeSH S_blood_MeSH Human_Growth_Hormone_blood_MeSH M_Hydrocortisone_MeSH S_blood_MeSH Hydrocortisone_blood_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Middle_Aged_MeSH M_Norepinephrine_MeSH S_blood_MeSH Norepinephrine_blood_MeSH M_Oxygen_Consumption_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Time_Factors_MeSH ****** 11421558 ----K E ----T Tissue triglyceride levels in type 2 diabetes and the role of thiazolidinediones in reversing the effects of tissue hypertriglyceridemia: review of the evidence in animals and humans. ----A ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Human_MeSH M_Hypertriglyceridemia_MeSH S_drug_therapy_MeSH Hypertriglyceridemia_drug_therapy_MeSH S_metabolism_MeSH Hypertriglyceridemia_metabolism_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH S_metabolism_MeSH Triglycerides_metabolism_MeSH ****** 12099312 ----K E ----T Oral hypoglycemic agents and the pregnant diabetic: "from bench to bedside". ----A Today, the criteria for diagnosis and treatment have evolved into an evidence-based medicine approach. The need for evidence-based information is especially critical in the management of gestational diabetes, in general, and especially in the use of oral hypoglycemic agents. These agents have been categorically contraindicated for decades in the United States based on anecdotal and/or weak evidence for these recommendations. In this article, the similarities between gestational and type 2 diabetes are described and the rationale for the use of oral hypoglycemic agents for the treatment of both are discussed. The author will show how research from basic sciences (placental transfers) to clinical studies (perinatal outcome) can lead to significant evidence on which to base management recommendations. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetes__Gestational_MeSH S_drug_therapy_MeSH Diabetes__Gestational_drug_therapy_MeSH M_Evidence-Based_Medicine_MeSH S_methods_MeSH Evidence-Based_Medicine_methods_MeSH M_Female_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Pregnancy_MeSH M_Pregnancy_in_Diabetics_MeSH S_drug_therapy_MeSH Pregnancy_in_Diabetics_drug_therapy_MeSH M_Sulfonylurea_Compounds_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 12099966 ----K E ----T Changes in treatment after the start of oral hypoglycaemic therapy in Type 2 diabetes: a population-based study. ----A AIMS: To determine the changes in oral hypoglycaemic therapy and the time to incidence of insulin therapy in people with Type 2 diabetes. METHODS: A retrospective incidence cohort was constructed of 1305 subjects with Type 2 diabetes, who obtained a first prescription for oral hypoglycaemic medication between 1 July 1993 and 31 December 1994 in Tayside, Scotland. The primary endpoint of changes in oral hypoglycaemic therapy and time to insulin was determined up to the end of the follow-up, on 31 December 1995. RESULTS: Overall, 9.4% of subjects switched to insulin, while 11% of those initially on sulphonylurea, and 6% of those initially on metformin switched to insulin therapy. Approximately three-quarters (72%) remained on the same class of drug throughout the study period (median follow-up 588 days). Only 9% died during the follow-up and this did not differ appreciably by drug group. Males were more likely to switch to insulin compared with females (10.3% vs. 8.5%), and those who switched were slightly younger with a mean age of 58 years compared with a mean age of 60 years of those who did not switch. The median time of switching to insulin was 186 days or approximately 6 months for this cohort, giving a rate of switching to insulin of 5.84% per year. Poorer glycaemic control (HBA1c) and low body mass index (BMI) were associated with switching to insulin. CONCLUSIONS: Following initial therapy with oral hypoglycaemic medication in the population, switching to insulin occurred at a rate of 5.84% per year. Switching to insulin was associated with being younger, male, having low BMI and higher HbA1c. ----P Journal_Article ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Body_Mass_Index_MeSH M_Cohort_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Patient_Compliance_MeSH M_Retrospective_Studies_MeSH M_Scotland_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12147149 ----K I ----T Improved glycaemic control with metformin-glibenclamide combined tablet therapy (Glucovance) in Type 2 diabetic patients inadequately controlled on metformin. ----A AIMS: To evaluate the efficacy and safety of two dosage strengths of a single-tablet metformin-glibenclamide (glyburide) combination, compared with the respective monotherapies, in patients with Type 2 diabetes mellitus (DM) inadequately controlled by metformin monotherapy. METHODS: In this 16-week, double-blind, multicentre, parallel-group trial, 411 patients were randomized to receive metformin 500 mg, glibenclamide 5 mg, metformin-glibenclamide 500 mg/2.5 mg or metformin-glibenclamide 500 mg/5 mg, titrated with the intention to achieve fasting plasma glucose (FPG) < or = 7 mmol/l. RESULTS: Decreases in glycated haemoglobin (HbA1c) and FPG were greater (P < 0.05) for metformin-glibenclamide 500 mg/2.5 mg (-1.20% and -2.62 mmol/l) and 500 mg/5 mg (-0.91% and -2.34 mmol/l), compared with metformin (-0.19% and -0.57 mmol/l) or glibenclamide (-0.33% and -0.73 mmol/l). HbA1c < 7% was achieved by 75% and 64% of patients receiving metformin-glibenclamide 500 mg/2.5 mg and 500 mg/5 mg, respectively, compared with 42% for glibenclamide and 38% for metformin (P = 0.001). These benefits were achieved at lower mean doses of metformin or glibenclamide with metformin-glibenclamide 500 mg/2.5 mg and 500 mg/5 mg (1225 mg/6.1 mg and 1170 mg/11.7 mg) than with glibenclamide (13.4 mg) or metformin (1660 mg). Treatment-related serious adverse events occurred in two patients receiving glibenclamide. Plasma lipid profiles were unaffected and mean changes in body weight were < or = 1.0 kg. CONCLUSIONS: Intensive management of Type 2 DM with a new metformin-glibenclamide combination tablet improved glycaemic control and facilitated the attainment of glycaemic targets at lower doses of metformin or glibenclamide compared with the respective monotherapies, without compromising tolerability. ----P Clinical_Trial Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Weight_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Drug_Combinations_MeSH M_Female_MeSH M_Fructosamine_MeSH S_blood_MeSH Fructosamine_blood_MeSH M_Gastrointestinal_Diseases_MeSH S_chemically_induced_MeSH Gastrointestinal_Diseases_chemically_induced_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analogs_&_derivatives_MeSH Hemoglobin_A__Glycosylated_analogs_&_derivatives_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_blood_MeSH Hyperglycemia_blood_MeSH S_prevention_&_control_MeSH Hyperglycemia_prevention_&_control_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Tablets_MeSH M_Treatment_Outcome_MeSH ****** 12196422 ----K E ----T Combination therapy with nateglinide and a thiazolidinedione improves glycemic control in type 2 diabetes. ----A OBJECTIVE: To compare the effects of monotherapy using nateglinide and the thiazolidinedione troglitazone with initial combination of the two agents on glycated hemoglobin (HbA(1c)) in patients with type 2 diabetes inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS: This study consisted of a 28-week, double-blind, randomized, multicenter study that included a 4-week, single-blind, placebo, run-in period and a 24-week (shortened to 16 weeks), double-blind, active treatment period. RESULTS: At the 16-week end point, nateglinide 120 mg, troglitazone 600 mg, and the combination of the agents achieved statistically significant decreases in HbA(1c) in comparison with placebo and a baseline HbA(1c) of 8.1-8.4% (P < 0.001). The reductions in HbA(1c) were similar in the nateglinide (0.6%) and troglitazone (0.8%) monotherapy groups. The reduction in HbA(1c) (1.7%) was greatest in the combination group; 79% of patients in the combination group achieved HbA(1c) levels of <7%. The combination group had a higher number of adverse events, primarily due to an increased incidence of mild hypoglycemia in this treatment group. CONCLUSIONS: Nateglinide and troglitazone are equally effective in decreasing HbA(1c) levels. However, these reductions from baseline HbA(1c) values of >8% are not adequate to achieve HbA(1c) levels of <7%. In contrast, the combination of nateglinide and of a thiazolidinedione shows an additive effect that is highly effective in reducing HbA(1c) levels to the target of <7% in 66% of patients, from a baseline HbA(1c) that is just above 8%. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Cyclohexanes_MeSH S_administration_&_dosage_MeSH Cyclohexanes_administration_&_dosage_MeSH S_adverse_effects_MeSH Cyclohexanes_adverse_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_administration_&_dosage_MeSH Phenylalanine_administration_&_dosage_MeSH S_adverse_effects_MeSH Phenylalanine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH P_Thiazolidinediones_MeSH M_Treatment_Outcome_MeSH ****** 12196435 ----K E ----T Glimepiride improves both first and second phases of insulin secretion in type 2 diabetes. ----A OBJECTIVE: The purpose of this study was to assess the effect of glimepiride on insulin sensitivity and secretion in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: After a 2-week washout from prior sulfonylurea therapy, 11 obese subjects with type 2 diabetes underwent euglycemic and hyperglycemic clamp studies before and during glimepiride therapy. RESULTS: Glimepiride resulted in a 2.4-mmol/l decrease in fasting plasma glucose (P = 0.04) that was correlated with reductions in postabsorptive endogenous glucose production (EGP) (16.4 +/- 0.6 vs. 13.5 +/- 0.5 micro mol. kg(-1). min(-1), P = 0.01) (r = 0.21, P = 0.01). Postabsorptive EGP on glimepiride was similar to that of control subjects (12.8 +/- 0.9 micro mol. kg(-1). min(-1), NS). Fasting plasma insulin (66 +/- 18 vs. 84 +/- 48 pmol/l, P = 0.05), and first-phase (19 +/- 8 vs. 32 +/- 11 pmol/l, P = 0.04) and second-phase incremental insulin responses to glucose (48 +/- 23 vs. 72 +/- 32 pmol/l, P = 0.02) improved with glimepiride therapy. Insulin sensitivity did not change with treatment (4.6 +/- 0.7 vs. 4.3 +/- 0.7 micro mol. kg(-1). min(-1). pmol(-1)) and remained below that of control subjects (8.1 +/- 1.8 micro mol. kg(-1). min(-1). pmol(-1), P = 0.04). CONCLUSIONS: The current study demonstrates that glimepiride improves both first and second phases of insulin secretion, but not insulin sensitivity, in individuals with type 2 diabetes. ----P Clinical_Trial Journal_Article ----M M_Aged_MeSH M_Blood_Glucose_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Fasting_MeSH M_Female_MeSH M_Glucose_Clamp_Technique_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH S_metabolism_MeSH Hyperglycemia_metabolism_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Insulin_Resistance_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 12207812 ----K E ----T Gliclazide improves anti-oxidant status and nitric oxide-mediated vasodilation in Type 2 diabetes. ----A AIMS: To evaluate the effects of gliclazide on oxidative status and vascular response to systemic administration of L-arginine, the natural precursor of nitric oxide (NO), in Type 2 diabetic patients. METHODS: Thirty Type 2 diabetic patients received glibenclamide (n = 15) or gliclazide (n = 15) in a 12-week, randomized, observer-blinded, parallel study. Plasma lipid peroxides, total radical-trapping anti-oxidant parameter (TRAP), and blood pressure responses to an intravenous bolus of L-arginine were measured pre- and post-treatment. RESULTS: At 12 weeks, gliclazide patients had lower plasma lipid peroxides (13.3 +/- 3.8 micro mol/l vs. 19.2 +/- 4.3 micro mol/l; P = 0.0001) and higher plasma TRAP (1155.6 +/- 143.0 micro mol/l vs. 957.7 +/- 104.3 micro mol/l; P = 0.0001) than the glibenclamide patients. Gliclazide but not glibenclamide significantly reduced systolic and diastolic blood pressure (P = 0.0199 and P = 0.00199, respectively, two-way repeated measures analysis of variance) in response to intravenous L-arginine. CONCLUSIONS: Gliclazide reduces oxidative stress in Type 2 diabetic patients by improving plasma anti-oxidant status. This effect is associated with enhanced NO-mediated vasodilation. ----P Clinical_Trial Evaluation_Studies Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Antioxidants_MeSH S_analysis_MeSH Antioxidants_analysis_MeSH M_Arginine_MeSH S_pharmacology_MeSH Arginine_pharmacology_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Free_Radicals_MeSH S_blood_MeSH Free_Radicals_blood_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Injections__Intravenous_MeSH M_Lipid_Peroxides_MeSH S_blood_MeSH Lipid_Peroxides_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Nitric_Oxide_MeSH S_metabolism_MeSH Nitric_Oxide_metabolism_MeSH M_Oxidative_Stress_MeSH S_drug_effects_MeSH Oxidative_Stress_drug_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Vasodilation_MeSH S_drug_effects_MeSH Vasodilation_drug_effects_MeSH ****** 12351462 ----K I ----T Repaglinide versus metformin in combination with bedtime NPH insulin in patients with type 2 diabetes established on insulin/metformin combination therapy. ----A OBJECTIVE: To compare the effect on glycemic control and weight gain of repaglinide versus metformin combined with bedtime NPH insulin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 80 subjects treated with 850 or 1,000 mg t.i.d. metformin combined with bedtime NPH insulin were randomized to 13 weeks of open-label treatment with 4 mg t.i.d. repaglinide (n = 39) or metformin (dose unchanged) (n = 41). Insulin dose was titrated at the clinician's discretion, aiming for a fasting blood glucose (FBG) < or =6.0 mmol/l. RESULTS: Baseline age, diabetes duration, insulin requirement, weight, BMI, FBG, and HbA(1c) (Diabetes Control and Complications Trial-aligned assay, normal range 4.6-6.2%) were similar. Glycemic control improved (nonsignificantly) with insulin/metformin by (mean) 0.4%, from 8.4 to 8.1% (P = 0.09) but deteriorated with insulin/repaglinide by (mean) 0.4%, from 8.1 to 8.6% (P = 0.03; P = 0.005 between groups). Weight gain was less with insulin/metformin: 0.9 +/- 0.4 kg (means +/- SE) (P = 0.01) versus 2.7 +/- 0.4 kg (P < 0.0001) (P = 0.002 between groups). The Diabetes Treatment Satisfaction Questionnaire score (potential range 0 [minimum] to 36 [maximum]) increased from 32.4 +/- 0.8 to 34.1 +/- 0.5 (P = 0.01) with insulin/metformin but decreased from 32.5 +/- 0.9 to 29.1 +/- 1.3 (P < 0.002) with insulin/repaglinide. CONCLUSIONS: Combined with bedtime NPH insulin, metformin provides superior glycemic control to repaglinide with less weight gain and improved diabetes treatment satisfaction. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Carbamates_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Creatinine_MeSH S_blood_MeSH Creatinine_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Insulin__Isophane_MeSH S_administration_&_dosage_MeSH Insulin__Isophane_administration_&_dosage_MeSH S_adverse_effects_MeSH Insulin__Isophane_adverse_effects_MeSH S_therapeutic_use_MeSH Insulin__Isophane_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 12351470 ----K 2 ----T A diabetes outcome progression trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. ----A OBJECTIVE: Therapies with metformin, sulfonylureas, or insulin improve glycemic control in the short term but do not prevent progressive islet beta-cell failure or long-term deterioration in glycemia. Our goal was to evaluate, in patients recently diagnosed with type 2 diabetes (<3 years), the long-term efficacy of monotherapy with rosiglitazone on glycemic control and on the progression of pathophysiological abnormalities associated with type 2 diabetes as compared with metformin or glyburide monotherapy. RESEARCH DESIGN AND METHODS: A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind, parallel-group study consisting of a screening visit, a 4-week placebo run-in, a 4-year treatment period, and an observational follow-up of approximately 3,600 drug-naive patients with type 2 diabetes diagnosed within the previous 3 years. After run-in, patients will be randomized to rosiglitazone, glyburide, or metformin titrated to the maximum effective daily doses (8 mg rosiglitazone, 15 mg glyburide, or 2 g metformin). The primary outcome is time to monotherapy failure, defined as the time following titration to the maximal effective or tolerated dose when fasting plasma glucose exceeds 180 mg/dl (10 mmol/l). Secondary outcomes include measures of islet beta-cell function, insulin sensitivity, dyslipidemia, changes in urinary albumin excretion, plasminogen activator inhibitor-1 antigen, fibrinogen, and C-reactive protein. Safety and tolerability will also be evaluated. Patient-reported outcomes and resource utilization data will be collected and analyzed. CONCLUSIONS: ADOPT will provide data on the effect of mechanistically differing treatment options on metabolic control, beta-cell function, and markers of macrovascular disease risk in type 2 diabetes. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Albuminuria_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Disease_Progression_MeSH M_Double-Blind_Method_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Research_Design_MeSH M_Safety_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Time_Factors_MeSH M_Treatment_Failure_MeSH M_Treatment_Outcome_MeSH ****** 12380632 ----K E ----T Durability of efficacy and long-term safety profile of glyburide/metformin tablets in patients with type 2 diabetes mellitus: an open-label extension study. ----A BACKGROUND: Intensive glycemic control substantially reduces the microvascular and macrovascular complications of type 2 diabetes mellitus, although less than half of patients with diabetes achieve the target glycosylated hemoglobin (HbA1c) value recommended by the American Diabetes Association. Because monotherapy with an oral agent does not address the multiple pathophysiologic defects of diabetes, use of combination therapy appears to be warranted. A previous 32-week, randomized, double-blind, placebo-controlled trial found that treatment with glyburide/metformin tablets was associated with greater reductions in HbA1c values compared with glyburide monotherapy, metformin monotherapy, and placebo. OBJECTIVES: This study evaluated the durability of efficacy and long-term safety profile of therapy with glyburide/metformin tablets over 52 weeks. METHODS: Patients enrolled in this open-label extension study were drawn from 3 groups: those who completed the 32-week double-blind study, those who were discontinued from the double-blind study, and those who were ineligible for the double-blind study and were enrolled directly in the open-label extension study. Patients with an HbA1c of < 9% received glyburide/metformin 1.25 mg/250 mg tablets BID, and those with an HbA1c of > or = 9% received glyburide/metformin 2.5 mg/500 mg tablets BID. Primary efficacy variables included changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight at week 52. Safety was assessed based on adverse-event data and the results of physical examinations and laboratory tests. RESULTS: A total of 828 patients were enrolled in the study: 515 who completed the 32-week double-blind study, 138 who were discontinued from the double-blind study, and 175 who were directly enrolled. At week 52, the mean HbA1c value for the entire population had decreased from a baseline value of 8.73% to 7.04% (95% CI, -1.81 to -1.58). Patients who were enrolled directly had the poorest glycemic control at baseline and experienced the greatest reduction in HbA1c (-3.35%; 95% CI, -3.61 to -3.10). A reduction in mean FPG for the total population was observed as early as week 2, from 201 to 141 mg/dL (95% CI, -63.0 to -55.7). Symptoms of hypoglycemia occurred in 19.9% (165/828) of patients, although only one third of these patients had a documented finger-stick blood glucose value of > or = 50 mg/dL. CONCLUSIONS: In this 52-week, open-label extension study, glyburide/metformin tablets were well tolerated and effective in patients with type 2 diabetes. They provided rapid and sustainable reductions in HbA1c values and FPG concentrations. ----P Journal_Article ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Body_Weight_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH S_blood_MeSH Fasting_blood_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Longitudinal_Studies_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Tablets_MeSH ****** 12380634 ----K E ----T Lipid effects of glyburide/metformin tablets in patients with type 2 diabetes mellitus with poor glycemic control and dyslipidemia in an open-label extension study. ----A BACKGROUND: Because both type 2 diabetes and elevated plasma lipid levels are important independent risk factors for cardiovascular disease and coronary heart disease, the choice of an antihyperglycemic agent for patients with type 2 diabetes--in whom abnormal plasma lipid levels are often seen-should take into account effects on lipids as well as on markers of glycemic control. OBJECTIVE: This study assessed the effects on lipid levels of glyburide/metformin tablets in the treatment of type 2 diabetes, particularly in a group of patients who had poor glycemic control and dyslipidemia at baseline. METHODS: This 52-week, open-label study was an extension of a 32-week, double-blind, placebo-controlled study. The patient population was drawn from 3 groups: those who completed the double-blind study, those who were discontinued from the double-blind study, and those who were ineligible for the double-blind study based on predefined measures of glycemic control (screening fasting plasma glucose > 240 mg/dL and glycosylated hemoglobin [HbA1c] < or = 12%, or HbA1c 11%-12%) and were directly enrolled in the open-label extension study. Patients with an HbA1c of < 9% received glyburide/ metformin tablets 1.25 mg/250 mg BID; those with an HbA1c > or = 9% received glyburide/ metformin tablets 2.5 mg/500 mg BID. Changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were assessed for 52 weeks. RESULTS: The study population included 828 patients: 515 who completed the double-blind study, 138 who were discontinued from the double-blind study, and 175 who were enrolled directly. Direct enrollees had poor glycemic control and dyslipidemia at baseline. Improvements in plasma lipid levels were seen as early as week 13. At week 52, the mean change in TC from baseline was -8.0 mg/dL for the total population (95% CI, -10.9 to -5.2; P < 0.05) and -23.2 mg/dL for direct enrollees (95% CI, -30.1 to -16.4; P < 0.05). The mean decrease in LDL-C from baseline for the total population was 2.86 mg/dL (95% CI, -5.3 to -0.4; P < 0.05), compared with a reduction of 13.3 mg/dL for direct enrollees (95% CI, -18.5 to -8.1; P < 0.05). Mean HDL-C levels were minimally affected. Mean TG levels decreased by 27.8 mg/dL for the entire population (95% CI, -42.9 to -12.8; P < 0.05) and by 99.7 mg/dL for direct enrollees (95% CI, -152.5 to -46.8; P < 0.05). CONCLUSION: In this open-label extension study, treatment with glyburide/ metformin tablets for type 2 diabetes had a durable, favorable effect on lipid levels, particularly in those with poor glycemic control and dyslipidemia at baseline. ----P Journal_Article ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Cardiovascular_Diseases_MeSH S_blood_MeSH Cardiovascular_Diseases_blood_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH S_blood_MeSH Fasting_blood_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_drug_therapy_MeSH Hyperlipidemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipoproteins__HDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__HDL_Cholesterol_blood_MeSH M_Lipoproteins__LDL_Cholesterol_MeSH S_blood_MeSH Lipoproteins__LDL_Cholesterol_blood_MeSH M_Longitudinal_Studies_MeSH M_Male_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Risk_Factors_MeSH M_Triglycerides_MeSH S_blood_MeSH Triglycerides_blood_MeSH ****** 12389879 ----K E ----T A retrospective cohort analysis of the clinical effectiveness of a physician-pharmacist collaborative drug therapy management diabetes clinic. ----A The glycemic control of patients with diabetes in a physician-supervised, pharmacist-managed primary care clinic was compared with that of patients receiving standard care in the same health care system. We retrospectively analyzed the glycemic control of 87 men with type 1 or type 2 diabetes whose diabetes-related drug therapy was managed by clinical pharmacists compared with a control group of 85 similar patients whose care was not augmented by clinical pharmacists. Primary outcomes were differences in fasting blood glucose (FBG) and glycosylated hemoglobin (A1C) levels between groups. Secondary outcomes were relative risk (RR) for achieving an A1C of 7% or below, frequency of diabetes-related scheduled and unscheduled clinic visits, and frequency of hypoglycemic events. The study group had 864 clinic visits and the control group had 712 between October 1997 and June 2000. No statistical differences were noted in FBG or A1C between groups. The RR of achieving an A1C of 7% or below was significantly higher in the study cohort (RR 5.19, 95% confidence interval [CI] 2.62-10.26). The frequency of hypoglycemic events did not differ between groups. The mean +/- SD frequency of unscheduled diabetes-related clinic visits/patient/year was higher in the control group (1.33 +/- 3.74) than in the study group (0.11 +/- 0.46, p = 0.003). Pharmacist-managed diabetes care was effective in improving glycemic control and was not associated with an increased risk for hypoglycemic events or unscheduled diabetes-related clinic visits. ----P Journal_Article ----M M_Adult_MeSH M_Ambulatory_Care_Facilities_MeSH M_Blood_Glucose_Self-Monitoring_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Disease_Management_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Outcome_Assessment_(Health_Care)_MeSH P_Patient_Care_Team_MeSH M_Patient_Education_MeSH P_Pharmacists_MeSH P_Physicians_MeSH M_Retrospective_Studies_MeSH ****** 12390047 ----K E ----T Oral antihyperglycemic agents during pregnancy and lactation: a review. ----A The treatment approach of diabetes mellitus during pregnancy requires a combination of diet, exercise, multiple home glucose determinations and intensive insulin regimens. During the last decade there was an increased interest in the use of oral antihyperglycemic agents (OAHAs) as an alternative to insulin in achieving good glycemic control. OAHAs are divided into four groups: derivatives of sulfonylurea, biguanides, glucosidase inhibitors and thiazolidinediones. This review describes the possible teratogenic effects of the use of OAHAs during pregnancy and the effects of these drugs during lactation. Animal and human studies assessing the teratogenic effects of OAHAs have yielded conflicting data because the risk of major malformations in infants of mothers with diabetes appears to be related to maternal glycemic control rather than the antidiabetic therapy. A major concern with the use of OAHAs during pregnancy is neonatal hypoglycemia, which may be severe and persist for days. Therefore, insulin is still the drug of choice because it has not been implicated as a teratogen in human pregnancies. In addition, because of the lack of data regarding the use of OAHAs in pregnancy, we cannot draw firm conclusions about all of the available drugs. However, OAHAs, especially glibenclamide (glyburide), may be beneficial in a situation where the proper use of insulin is problematic. Because there are very limited clinical data on the exposure of OAHAs to the infant via breast milk, and the potentially serious effect of neonatal hypoglycemia, the safest recommendation is not to breast feed while taking OAHAs. Well-conducted, prospective, controlled studies regarding the feasibility of OAHAs in pregnant women with diabetes and during lactation are needed. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Biguanides_MeSH S_adverse_effects_MeSH Biguanides_adverse_effects_MeSH S_pharmacokinetics_MeSH Biguanides_pharmacokinetics_MeSH S_therapeutic_use_MeSH Biguanides_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetes__Gestational_MeSH S_drug_therapy_MeSH Diabetes__Gestational_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lactation_MeSH M_Milk__Human_MeSH S_metabolism_MeSH Milk__Human_metabolism_MeSH M_Pregnancy_MeSH M_Pregnancy_Outcome_MeSH M_Pregnancy_in_Diabetics_MeSH S_drug_therapy_MeSH Pregnancy_in_Diabetics_drug_therapy_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_pharmacokinetics_MeSH Thiazoles_pharmacokinetics_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH ****** 12393300 ----K E ----T Troglitazone: the discovery and development of a novel therapy for the treatment of Type 2 diabetes mellitus. ----A Prior to the introduction of troglitazone, it had been more than 30 years since the last significant improvement in antidiabetic therapy. In view of the pressing need for more effective oral agents for the treatment of Type 2 diabetes mellitus, troglitazone was granted priority review by the FDA and was launched in the USA in 1997. The first of the thiazolidinedione insulin sensitizing agents, troglitazone was quickly followed by rosiglitazone and pioglitazone. The glitazones proved to be effective not only in lowering blood glucose, but also to have beneficial effects on cardiovascular risk. Troglitazone was subsequently withdrawn because of concerns about hepatotoxicity, which appears to be less of a problem with rosiglitazone and pioglitazone. Recent insights into the molecular mechanism of action of the glitazones, which are ligands for the peroxisome proliferator-activated receptors, open the prospect of designing more effective, selective and safer antidiabetic agents. This document will review the history of troglitazone from discovery through clinical development. ----P Journal_Article Review Review__Tutorial ----M M_Chromans_MeSH S_adverse_effects_MeSH Chromans_adverse_effects_MeSH S_pharmacokinetics_MeSH Chromans_pharmacokinetics_MeSH S_pharmacology_MeSH Chromans_pharmacology_MeSH S_therapeutic_use_MeSH Chromans_therapeutic_use_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_pharmacokinetics_MeSH Thiazoles_pharmacokinetics_MeSH S_pharmacology_MeSH Thiazoles_pharmacology_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 12401757 ----K 3 ----T A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. ----A OBJECTIVE: This open-label, active-controlled study investigated the cardiac safety and antihyperglycemic effect of rosiglitazone (RSG) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Of the 203 patients randomly assigned to RSG (4 mg b.i.d.) or glyburide (GLB) (titrated to achieve optimal glycemic control for the first 8 weeks only to limit the risk of hypoglycemia; mean 10.5 mg/day), 118 had an echocardiogram performed at week 52. Left ventricular (LV) mass index, ejection fraction, and left ventricular end-diastolic volume were assessed by M-mode echocardiography at baseline and weeks 12, 28, and 52; 24-h ambulatory blood pressure was assessed at baseline and at weeks 28 and 52. Glycemic control was assessed by measuring fasting plasma glucose (FPG) and HbA(1c). RESULTS: Neither treatment produced an increase in LV mass index that exceeded 1 SD. Ejection fraction did not change in either group. Both groups had clinically insignificant increases in LV end-diastolic volume. RSG, but not GLB, caused a statistically significant reduction in ambulatory diastolic blood pressure. Both treatments reduced HbA(1c) and FPG. CONCLUSIONS: A total of 52 weeks of therapy with RSG (4 mg b.i.d.) did not adversely affect cardiac structure or function in patients with type 2 diabetes and produced significant and sustained reductions in hyperglycemia. Decreases in ambulatory diastolic blood pressure with RSG were superior to those with GLB. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Body_Mass_Index_MeSH M_Cardiovascular_Physiology_MeSH M_Cardiovascular_System_MeSH S_drug_effects_MeSH Cardiovascular_System_drug_effects_MeSH M_Comparative_Study_MeSH M_Continental_Population_Groups_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemodynamic_Processes_MeSH S_drug_effects_MeSH Hemodynamic_Processes_drug_effects_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Placebos_MeSH M_Safety_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_Time_Factors_MeSH M_Ventricular_Function__Left_MeSH S_drug_effects_MeSH Ventricular_Function__Left_drug_effects_MeSH S_physiology_MeSH Ventricular_Function__Left_physiology_MeSH ****** 12406033 ----K E ----T Glyburide/metformin combination product is safe and efficacious in patients with type 2 diabetes failing sulphonylurea therapy. ----A AIM: To compare the efficacy, safety and tolerability of a fixed combination glyburide/metformin preparation with those of glyburide or metformin alone in patients with type 2 diabetes inadequately controlled by sulphonylurea, diet and exercise. METHODS: In this 16-week, randomized, double-blind, parallel group study, 639 patients with inadequate glycaemic control on at least half-maximal dose of sulphonylurea were randomly assigned to: glyburide 10 mg b.i.d. (n = 164); metformin 500 mg (n = 153); glyburide/metformin 2.5 mg/500 mg (n = 160); or glyburide/metformin 5 mg/500 mg (n = 162). Titration was allowed to maximum doses of 2000 mg for metformin or 10 mg/2000 mg and 20 mg/2000 mg for glyburide/metformin 2.5 mg/500 mg and 5 mg/500 mg respectively. The primary outcome measure was HbA1c level after 16 weeks; secondary end-points included fasting and 2-h post-prandial plasma glucose. Adverse events (AEs) were recorded and summarized by treatment group. RESULTS: Both strengths of glyburide/metformin equally reduced mean HbA1c by 1.7% more than did glyburide alone (p < 0.001), and by 1.9% more than did metformin alone (p < 0.001). Final mean fasting plasma glucose concentrations were also lower in both glyburide/metformin groups than in the glyburide (-2.8 mmol/l, -51.3 mg/dl; p < 0.001) and metformin groups (-3.6 mmol/l, -64.2 mg/dl; p < 0.001). Safety and tolerability were similar across all treatment groups, except for a higher incidence of gastrointestinal AEs in the metformin monotherapy group, and more patients reporting mild or moderate symptoms of hypoglycaemia while taking glyburide/metformin. CONCLUSIONS: Both glyburide/metformin tablet strengths produced, with equal efficacy, significantly better glycaemic control than monotherapy with either agent. These data also confirm that glycaemic efficacy does not require maximal sulphonylurea doses in combination with metformin. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Combinations_MeSH M_Female_MeSH M_Glyburide_MeSH S_adverse_effects_MeSH Glyburide_adverse_effects_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Failure_MeSH ****** 12412817 ----K E ----T Plasminogen activator inhibitor-1: physiologic role, regulation, and the influence of common pharmacologic agents. ----A Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of endogenous thrombolysis, thereby promoting thrombosis. PAI-1 is also a primary contributor to the development and recurrence of acute myocardial infarction. The renin angiotensin system, hypertriglyceridemia, hyperglycemia and hyperinsulinemia, and estrogen all influence the fibrinolytic system and PAI-1 in particular. Available data strongly suggest that angiotensin-converting enzyme (ACE) inhibitors and hormone replacement therapy with estrogen beneficially reduce PAI-1 production. Metformin, an agent commonly used for non-insulin-dependent diabetes mellitus (NIDDM), appears to favorably decrease PAI-1 production in NIDDM patients but not nondiabetic patients. Among the cholesterol-lowering statins, clinical literature evaluating pravastatin provides the most compelling data to support this agent's favorable effect on PAI-1. Other available statins either have not displayed an effect on PAI-1 or do not have clear data to conclusively define their effects on the fibrinolytic system. ----P Journal_Article Review Review__Tutorial ----M M_Angiotensin-Converting_Enzyme_Inhibitors_MeSH S_pharmacology_MeSH Angiotensin-Converting_Enzyme_Inhibitors_pharmacology_MeSH M_Clinical_Trials_MeSH M_Coronary_Thrombosis_MeSH S_blood_MeSH Coronary_Thrombosis_blood_MeSH S_etiology_MeSH Coronary_Thrombosis_etiology_MeSH S_prevention_&_control_MeSH Coronary_Thrombosis_prevention_&_control_MeSH M_Estrogen_Replacement_Therapy_MeSH M_Fibrinolysis_MeSH S_physiology_MeSH Fibrinolysis_physiology_MeSH M_Human_MeSH M_Hydroxymethylglutaryl-CoA_Reductase_Inhibitors_MeSH S_pharmacology_MeSH Hydroxymethylglutaryl-CoA_Reductase_Inhibitors_pharmacology_MeSH M_Hyperglycemia_MeSH S_complications_MeSH Hyperglycemia_complications_MeSH M_Hyperinsulinism_MeSH S_complications_MeSH Hyperinsulinism_complications_MeSH M_Hyperlipidemia_MeSH S_complications_MeSH Hyperlipidemia_complications_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Myocardial_Infarction_MeSH S_blood_MeSH Myocardial_Infarction_blood_MeSH S_etiology_MeSH Myocardial_Infarction_etiology_MeSH S_prevention_&_control_MeSH Myocardial_Infarction_prevention_&_control_MeSH M_Plasminogen_Activator_Inhibitor_1_MeSH S_biosynthesis_MeSH Plasminogen_Activator_Inhibitor_1_biosynthesis_MeSH S_physiology_MeSH Plasminogen_Activator_Inhibitor_1_physiology_MeSH M_Receptors__Angiotensin_MeSH S_antagonists_&_inhibitors_MeSH Receptors__Angiotensin_antagonists_&_inhibitors_MeSH M_Renin-Angiotensin_System_MeSH S_physiology_MeSH Renin-Angiotensin_System_physiology_MeSH ****** 12437315 ----K E ----T Therapeutic options for the management of type 2 diabetes mellitus. ----A The incidence of diabetes mellitus is steadily increasing in the United States. Currently the United States spends approximately $100 billion in healthcare costs annually for the management of diabetes. Most of the costs are attributed to hospitalizations and treatment of diabetes complications. Preventing these complications with tight glycemic control is the key to reducing morbidity, mortality, and healthcare costs secondary to diabetes mellitus. Recently, the American College of Endocrinology also stressed earlier screening for diabetes and endorsed lowering the goal percent of hemoglobin glycosylation to 6.5%. These strategies help identify patients with diabetes at an earlier stage and in turn prevent more complications. Better control of diabetes is now feasible with the recent approval of 8 new antidiabetic products. Pioglitazone and rosiglitazone are agents with a novel mechanism of action. Metformin XR, insulin aspart, and miglitol are agents that are similar to previously marketed products, but have different pharmacokinetic or pharmacodynamic properties. Metformin/glyburide is the first combination product for the treatment of diabetes. Nateglinide represents the first agent in a new class of antidiabetic agents and insulin glargine is a novel insulin preparation. All of the agents have unique characteristics that may render them useful in specific patient populations. ----P Journal_Article Review Review__Tutorial ----M M_Adult_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH P_Disease_Management_MeSH M_Education__Medical__Continuing_MeSH M_Education__Pharmacy__Continuing_MeSH M_Glucosamine_MeSH S_administration_&_dosage_MeSH Glucosamine_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Glucosamine_analogs_&_derivatives_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_classification_MeSH Hypoglycemic_Agents_classification_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH P_Managed_Care_Programs_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH M_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH P_Thiazolidinediones_MeSH M_United_States_MeSH S_epidemiology_MeSH United_States_epidemiology_MeSH ****** 12437490 ----K E ----T The contentious nature of gestational diabetes: diet, insulin, glyburide and metformin. ----A Gestational diabetes (GD) develops because pregnancy increases requirements for insulin secretion while increasing insulin resistance. Women with GD often have impaired pancreatic beta-cell compensation for insulin resistance. The nature of GD is currently contentious, with debate about its existence, diagnosis and ramifications for both mother and offspring from pregnancy into later life. Also contentious are the outcomes of intervention with diet, insulin, glyburide (Glynase trade mark, Pharmacia Upjohn) and metformin (Glucophage trade mark, Bristol-Myers Squibb). There is consensus that women with unequivocal GD have a significant risk of adverse perinatal outcomes and increased risk of later type 2 diabetes mellitus. Foetuses from pregnancies with GD have a higher risk of macrosomia (associated with higher rate of birth injuries), asphyxia, and neonatal hypoglycaemia and hyperinsulinaemia. Uncontrolled GD predisposes foetuses to accelerated, excessive fat accumulation, insulin resistance, pancreatic exhaustion secondary to prenatal hyperglycaemia and possible higher risk of child and adult obesity and type 2 diabetes mellitus later in adult life. However, there is no consensus as to whether glucose intolerance of a severity below unequivocal GD is related to adverse maternal, fetal or perinatal outcomes, and whether this relationship is a continuous one. If dietary intervention is not sufficient in the treatment of GD, then, historically, insulin has been added. Recent studies suggest that glyburide may be efficaciously substituted for insulin. Preliminary studies suggest that metformin may have the unique potential to prevent the development of GD. ----P Journal_Article Review Review__Tutorial ----M M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Diabetes__Gestational_MeSH S_diet_therapy_MeSH Diabetes__Gestational_diet_therapy_MeSH S_epidemiology_MeSH Diabetes__Gestational_epidemiology_MeSH S_etiology_MeSH Diabetes__Gestational_etiology_MeSH S_therapy_MeSH Diabetes__Gestational_therapy_MeSH M_Female_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Polycystic_Ovary_Syndrome_MeSH S_complications_MeSH Polycystic_Ovary_Syndrome_complications_MeSH S_drug_therapy_MeSH Polycystic_Ovary_Syndrome_drug_therapy_MeSH M_Pregnancy_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12452739 ----K E ----T Pharmacokinetics and pharmacodynamics of glyburide/metformin tablets (Glucovance) versus equivalent doses of glyburide and metformin in patients with type 2 diabetes. ----A OBJECTIVE: To compare the effects of two different formulations of glibenclamide (glyburide) combined with metformin on postprandial glucose excursions, and to assess their pharmacokinetics. The formulations were a combination glibenclamide/metformin tablet (Glucovance; controlled-particle-size glibenclamide and metformin) versus glibenclamide (Micronase) and metformin (Glucophage) coadministered separately. DESIGN: A randomised, double-blind, two-way crossover study in which patients with type 2 diabetes received either glibenclamide/metformin 2.5/500mg tablets or glibenclamide 2.5mg with metformin 500mg twice daily for 14 days. After a 2-week washout, patients were crossed over to the other treatment for 14 days. Patients consumed standardised meals on the days when pharmacokinetic and pharmacodynamic evaluations were performed. PARTICIPANTS: Forty patients with type 2 diabetes were enrolled; 37 were randomised (18 men, 19 women) and 35 completed the study. Mean age was 58 years; mean body mass index was 31 kg/m(2). The baseline glycated haemoglobin (HbA(1c)) was 9.3% for both treatment groups. MAIN OUTCOME MEASURE: Two-hour postprandial glucose excursion (PPGE) was used to assess postprandial glucose dynamics. RESULTS: Treatment with glibenclamide/metformin resulted in a significantly smaller mean PPGE than was attained by treatment with glibenclamide plus metformin, according to measurements taken after the day 14 afternoon standardised meal (89.5 vs 117.4 mg/dl, p = 0.011). The mean glibenclamide peak concentration (C(max)) was significantly greater (approximately 16%) after glibenclamide/metformin treatment on both days 1 and 14. Glibenclamide/metformin treatment was associated with a 2-fold greater area under the concentration-time curve to 3 hours for glibenclamide (AUC(3)) [p < 0.001], although the AUC over the administration interval was equivalent for both formulations. CONCLUSION: In patients with type 2 diabetes, glibenclamide/metformin resulted in lower PPGE, suggesting that the higher glibenclamide AUC(3) observed with this formulation may contribute to better postprandial glycaemic control than is attained by glibenclamide plus metformin separately. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Combinations_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Glyburide_pharmacokinetics_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Half-Life_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Support__Non-U_S__Gov't_MeSH M_Tablets_MeSH ****** 12453948 ----K E ----T Effect of combination glipizide GITS/metformin on fibrinolytic and metabolic parameters in poorly controlled type 2 diabetic subjects. ----A OBJECTIVE: Epidemiological studies have implicated increased plasminogen-activated inhibitor 1 (PAI-1) as a marker or predictor of accelerated coronary atherosclerotic disease in type 2 diabetes. We sought to determine whether metabolic control, independent of its oral mode of implementation, affects PAI-1 in patients with marked hyperglycemia. RESEARCH DESIGN AND METHODS: A total of 91 subjects were screened, subjected to a 4-week drug washout, and randomized to daily treatment with glipizide GITS (maximum 20 mg, n = 46) or metformin (maximum 2,550 mg, n = 45) as monotherapy. After monotherapy, combination therapy was initiated by adding the second agent to the regimen. Plasma glucose (fasting and postprandial), HbA(1c), fructosamine, and PAI-1 were assayed before and after randomization and sequentially thereafter in all subjects; hepatic glucose output (HGO) and abdominal fat distribution were each measured in a subset of subjects. RESULTS: Glycemic control was markedly impaired at baseline (mean HbA(1c) 10.4 +/- 0.2% glipizide GITS; 10.0 +/- 0.2% metformin) but improved comparably with each agent as monotherapy and in combination (P < 0.0001 vs. baseline), as assessed with meal tolerance studies, fructosamine values, and HGO. Body weight and abdominal fat distribution did not change significantly in either group. PAI-1 concentrations were extraordinarily high (5- to 10-fold more than normal) at baseline (202 +/- 12 ng/ml glipizide GITS; 201 +/- 13 ng/ml metformin) but declined comparably, and significantly, after treatment with either agent as monotherapy and decreased further with combination therapy. CONCLUSIONS: When hyperglycemia is profound, increases in PAI-1 are also profound. Control of hyperglycemia with either glipizide GITS, an insulin secretagogue, or metformin as monotherapy comparably ameliorates elevated PAI-1. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Fibrinolysis_MeSH S_drug_effects_MeSH Fibrinolysis_drug_effects_MeSH M_Glipizide_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glucose_Tolerance_Test_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Research_Design_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12453951 ----K 4 ----T Nateglinide improves early insulin secretion and controls postprandial glucose excursions in a prediabetic population. ----A OBJECTIVE: The purpose of this study was to evaluate the metabolic effectiveness, safety, and tolerability of nateglinide in subjects with impaired glucose tolerance (IGT) and to identify a dose appropriate for use in a diabetes prevention study. RESEARCH DESIGN AND METHODS: This multicenter, double-blind, randomized, parallel-group, fixed-dose study of 8 weeks' duration was performed in a total of 288 subjects with IGT using a 2:2:2:1 randomization. Subjects received nateglinide (30, 60, and 120 mg) or placebo before each main meal. Metabolic effectiveness was assessed during a standardized meal challenge performed before and after the 8-week treatment. All adverse events (AEs) were recorded, and confirmed hypoglycemia was defined as symptoms accompanied by a self-monitoring of blood glucose measurement < or =3.3 mmol/l (plasma glucose < or =3.7 mmol/l). RESULTS: Nateglinide elicited a dose-related increase of insulin and a decrease of glucose during standardized meal challenges, with the predominant effect on early insulin release, leading to a substantial reduction in peak plasma glucose levels. Nateglinide was well tolerated, and symptoms of hypoglycemia were the only treatment-emergent AEs. Confirmed hypoglycemia occurred in 28 subjects receiving nateglinide (30 mg, 0 [0%]; 60 mg, 5 [6.6%]; 120 mg, 23 [26.7%]) and in 1 (2.3%) subject receiving placebo. CONCLUSIONS: Nateglinide was safe and effective in reducing postprandial hyperglycemia in subjects with IGT. Preprandial doses of 30 or 60 mg nateglinide would be appropriate to use for longer-term studies to determine whether a rapid-onset, rapidly reversible, insulinotropic agent can delay or prevent the development of type 2 diabetes. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Cyclohexanes_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Glucose_Tolerance_Test_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH S_secretion_MeSH Insulin_secretion_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Postprandial_Period_MeSH M_Prediabetic_State_MeSH S_blood_MeSH Prediabetic_State_blood_MeSH S_drug_therapy_MeSH Prediabetic_State_drug_therapy_MeSH ****** 12461471 ----K E ----T Oral anti diabetic polychemotherapy in type 2 diabetes mellitus. ----A The therapeutic guidelines of the seventies for type 2 diabetic patients was a monotherapy which choice was based on the BMI of the patient and a bitherapy in case of a blood glucose increase. The pathophysiologic knowledge on type 2 diabetes has moved and the disease is nowadays more complex with a loss of the beta cell mass and an insulin resistance state of the liver, muscle and adipocyte tissue associated with a defect in gastro-intestinal hormones in the postprandial state. The pathophysiologic knowledge and the existence of new therapeutic agents led us to discuss oral antidiabetic polychemotherapy at the first drug prescription. This intuitive proposition has no evidence-based arguments with prospective long-term studies that would demonstrate the benefit of such a proposition. Moreover, if nowadays we can imagine a tritherapy proposition, progress in chemistry research will conduct to a quadri- and penta-therapy with expected difficulties in therapeutic compliance of the patient. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_Resistance_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 12467917 ----K 5 ----T High-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography-tandem mass spectrometry. ----A A method has been developed for the high-throughput inhibition screening of the major human cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro substrate cocktail and liquid chromatography-tandem mass spectrometry (LC-MS-MS). A cocktail consisting of the selective substrates phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), bufuralol (CYP2D6), and midazolam (CYP3A4) was incubated with human liver microsomes. The metabolic reactions were terminated with methanol containing dextrorphan as an internal standard. Following centrifugation, the supernatant was analyzed by LC-MS-MS employing a fast gradient. The concentrations of the substrate metabolites-paracetamol, 4-hydroxytolbutamide, 5-hydroxyomeprazole, 1'-hydroxybufuralol, and 1'-hydroxymidazolam-in each sample were determined by LC-MS-MS in a single assay. The method was validated by incubating known CYP inhibitors (furafylline, CYP1A2; sulfaphenazole, CYP2C9; s-mephenytoin, CYP2C19; quinidine, CYP2D6; and troleandomycin, CYP3A4) with the individual substrates they were known to inhibit and with the substrate cocktail. IC50s (microM) determined using the substrate cocktail were in good agreement with those obtained with individual substrates (furafylline, 2.9 vs. 2.0; sulfaphenazole, 0.75 vs. 0.72; s-mephenytoin, 170 vs. 180; quinidine, 0.17 vs. 0.24; troleandomycin, 2.6 vs. 3.2) and with previously reported values in the literature. ----P Journal_Article ----M M_Cytochrome_P-450_Enzyme_System_MeSH S_analysis_MeSH Cytochrome_P-450_Enzyme_System_analysis_MeSH M_Human_MeSH M_Mass_Fragmentography_MeSH S_methods_MeSH Mass_Fragmentography_methods_MeSH M_Microsomes__Liver_MeSH S_enzymology_MeSH Microsomes__Liver_enzymology_MeSH M_Pharmaceutical_Preparations_MeSH S_analysis_MeSH Pharmaceutical_Preparations_analysis_MeSH S_chemistry_MeSH Pharmaceutical_Preparations_chemistry_MeSH M_Reproducibility_of_Results_MeSH M_Substrate_Specificity_MeSH S_physiology_MeSH Substrate_Specificity_physiology_MeSH ****** 12472202 ----K E ----T Does type 2 diabetes mellitus delay renal failure in autosomal dominant polycystic kidney disease? ----A Autosomal dominant polycystic kidney disease (ADPKD) is a common renal disease without an effective therapeutic intervention to delay renal failure. Within kindreds, renal dysfunction often develops at a similar age in affected individuals, although there are known modifying factors. Two kindreds with ADPKD have shown a striking pattern of delayed onset of renal insufficiency in those individuals also suffering from type 2 diabetes mellitus. Eight nondiabetic patients with ADPKD had onset of dialysis or renal death at ages 38-52 years, (mean +/- SEM 46 +/- 1.9, n = 7) as compared with four diabetics who started dialysis or are still off dialysis at the age of 61 +/- 2.8 years (p < 0.01). Two of the four diabetics still have reasonable renal function at age 61 and 66. The diabetes was diagnosed at age 32 +/- 2 years and was treated with oral hypoglycemics for 19 +/- 2 years before institution of insulin. Cardiovascular disease dominated the clinical picture in the diabetics. In conclusion, onset of renal failure in ADPKD was delayed for over 15 years in individuals who also suffered from type 2 diabetes mellitus, in two ADPKD kindreds. Possible mechanisms are discussed, including glibenclamide inhibition of the cystic fibrosis transmembrane conductance regulator. The striking delay associated with type 2 diabetes mellitus in ADPKD induced renal failure should be evaluated further. ----P Case_Reports Journal_Article ----M M_Adult_MeSH M_Age_of_Onset_MeSH M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_genetics_MeSH Diabetes_Mellitus__Type_II_genetics_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Disease_Progression_MeSH M_Female_MeSH M_Human_MeSH M_Kidney_Failure_MeSH S_etiology_MeSH Kidney_Failure_etiology_MeSH S_genetics_MeSH Kidney_Failure_genetics_MeSH S_physiopathology_MeSH Kidney_Failure_physiopathology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Pedigree_MeSH M_Polycystic_Kidney__Autosomal_Dominant_MeSH S_complications_MeSH Polycystic_Kidney__Autosomal_Dominant_complications_MeSH S_genetics_MeSH Polycystic_Kidney__Autosomal_Dominant_genetics_MeSH S_physiopathology_MeSH Polycystic_Kidney__Autosomal_Dominant_physiopathology_MeSH M_Time_Factors_MeSH ****** 12473527 ----K E ----T [Aspects of antihyperglycemic oral bitherapy in 76 cases of non insulindependent diabetes in Dakar] ----A Some reasons justify the introduction of the association of sulfonylurea and metformine when monotherapy is ineffective. Hereafter a period of monotherapy by sulfonylurea or metformine only bitherapy has been instituted. Socio-demography, number of consultations, type of monotherapy and of association, duration of treatment, body mass index, fasting blood glycemia and post-prandial glycemia, blood pressure and type of complication were studied. There were 2.5 times more women than men with lower mean age for women. The majority of patients were from Dakar (81.6%). More than half of patients were women at home (60.5%). Present obesity (plethoric diabetes) or past obesity (metaplethoric diabetes) concerned 90.3% of patients. Patients have done 9.14 4.39 consultations under bitherapy. The gliclazide-metformin association was observed 37 times and the glibenclamide-metformin association 67 times. The duration of monotherapy was 45.9 39.7 months and that of bitherapy 92.5 43.7 months. The variations of body mass index showed a diminution of 1.26 kg/m2 and for fasting blood glycemia and augmentation of 0.011 g/L and post-prandial a diminution of 0.05 g/L. The body mass index variations in diabetic patients showed a diminution of weight more in plethoric patients in bitherapy compared to monotherapy. This study is retrospective and cannot show the optimal efficacy of bitherapy. But the combination of enhancement of glucose captation and lowering of hepatic glucose production has been shown during this bitherapeutic association. Addition of metformine and treatment with sulfonylurea make a combination that significatively improves glycemic control but also cholesterol level and allows obtation of better weight in type 2 non insulin-dependent diabetes with insulinoresistance. ----P Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH M_Body_Weight_MeSH M_Cholesterol_MeSH S_blood_MeSH Cholesterol_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Female_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_MeSH S_complications_MeSH Obesity_complications_MeSH M_Senegal_MeSH ****** 12519086 ----K E ----T Effects of inhibition of ATP-sensitive potassium channels on metabolic vasodilation in the human forearm. ----A Experimental data suggest that vascular ATP-sensitive potassium (K(ATP)) channels may be an important determinant of functional hyperaemia, but the contribution of K(ATP) channels to exercise-induced hyperaemia in humans is unknown. Forearm blood flow was assessed in 39 healthy subjects (23 males/16 females; age 22+/-4 years) using the technique of venous occlusion plethysmography. Resting forearm blood flow and functional hyperaemic blood flow (FHBF) were measured before and after brachial artery infusion of the K(ATP) channel inhibitors glibenclamide (at two different doses: 15 and 100 microg/min) and gliclazide (at 300 microg/min). FHBF was induced by 2 min of non-ischaemic wrist flexion-extension exercise at 45 cycles/min. Compared with vehicle (isotonic saline), glibenclamide at either 15 microg/min or 100 microg/min did not significantly alter resting forearm blood flow or peak FHBF. The blood volume repaid at 1 and 5 min after exercise was not diminished by glibenclamide. Serum glucose was unchanged after glibenclamide, but plasma insulin rose by 36% (from 7.2+/-0.8 to 9.8+/-1.3 m-units/l; P =0.02) and 150% (from 9.1+/-1.3 to 22.9+/-3.5 m-units/l; P =0.002) after the 15 and 100 microg/min infusions respectively. Gliclazide also did not affect resting forearm blood flow, peak FHBF, or the blood volume repaid at 1 and 5 min after exercise, compared with vehicle (isotonic glucose). Gliclazide induced a 12% fall in serum glucose (P =0.009) and a 38% increase in plasma insulin (P =0.001). Thus inhibition of vascular K(ATP) channels with glibenclamide or gliclazide does not appear to affect resting forearm blood flow or FHBF in healthy humans. These findings suggest that vascular K(ATP) channels may not play an important role in regulating basal vascular tone or skeletal muscle metabolic vasodilation in the forearm of healthy human subjects. ----P Journal_Article ----M M_Adenosine_Triphosphate_MeSH S_physiology_MeSH Adenosine_Triphosphate_physiology_MeSH M_Adult_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Female_MeSH M_Forearm_MeSH S_blood_supply_MeSH Forearm_blood_supply_MeSH M_Gliclazide_MeSH S_pharmacology_MeSH Gliclazide_pharmacology_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hyperemia_MeSH S_physiopathology_MeSH Hyperemia_physiopathology_MeSH M_Male_MeSH M_Muscle__Skeletal_MeSH S_blood_supply_MeSH Muscle__Skeletal_blood_supply_MeSH M_Plethysmography_MeSH M_Potassium_Channel_Blockers_MeSH S_pharmacology_MeSH Potassium_Channel_Blockers_pharmacology_MeSH M_Potassium_Channels_MeSH S_physiology_MeSH Potassium_Channels_physiology_MeSH M_Regional_Blood_Flow_MeSH S_drug_effects_MeSH Regional_Blood_Flow_drug_effects_MeSH S_physiology_MeSH Regional_Blood_Flow_physiology_MeSH M_Support__Non-U_S__Gov't_MeSH M_Vasodilation_MeSH S_drug_effects_MeSH Vasodilation_drug_effects_MeSH S_physiology_MeSH Vasodilation_physiology_MeSH ****** 12520624 ----K 3 ----T Pharmacokinetics of repaglinide in healthy caucasian and Japanese subjects. ----A The objective of this study was to investigate the pharmacokinetics of three different single doses (0.5, 1.0, and 2.0 mg) of repaglinide in healthy Caucasian and Japanese subjects. In this single-center, open-label, randomized, three-period crossover study, 27 healthy male subjects (15 Caucasian and 12 Japanese) each received three different single doses of repaglinide (0.5, 1.0, and 2.0 mg) at consecutive 24-hour intervals. Pharmacokinetic profiles, including area under the curve (AUC0-t), maximum serum concentration (Cmax), time to Cmax (tmax), and half-life (t1/2), were determined for each dose of repaglinide. The relative change in blood glucose level (RC1h) and area under the blood glucose curve (AUGC0-1) at 1 hour after dose were also measured. After oral dosing, both Cmax and AUC0-t increased linearly with dose within the 0.5- to 2.0-mg dose range, regardless of ethnic group. Both Cmax and AUC0-t were significantly higher in Japanese subjects than in Caucasian subjects. At each dose of repaglinide, Cmax and AUC were statistically significantly higher in Japanese than in Caucasian subjects (p = 0.0038 and 0.023, respectively). Discrepancies in body weight and body mass index (BMI) between Caucasian and Japanese subjects could not explain the between-group differences in Cmax or AUC0-t. Statistically significant differences in pharmacodynamic parameters (RC1h and AUGC0-1) were found between ethnic groups (p < 0.0001), the difference being more pronounced for RC1h than AUGC0-1. At a dose of 2.0 mg, the mean decrease in RC1h was 41% for Japanese subjects and 24% for Caucasian subjects. Hypoglycemic reactions were more common at the highest dose (2.0 mg), where they were observed more frequently in Japanese (7 cases) than in Caucasian subjects (4 cases). It was concluded that higher serum levels of repaglinide and greater reductions in blood glucose levels are found in Japanese than in Caucasian subjects following a single oral dose of repaglinide within the 0.5- to 2.0-mg dose range. Repaglinide is well tolerated in both ethnic groups. The results indicate that glycemic control targets may be achieved at lower doses within the recommended range (0.5-4.0 mg/meal) when repaglinide is used to treat Japanese patients in comparison to Caucasian patients. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adolescent_MeSH M_Adult_MeSH P_Asian_Continental_Ancestry_Group_MeSH M_Carbamates_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Dose-Response_Relationship__Drug_MeSH M_European_Continental_Ancestry_Group_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12520632 ----K E ----T Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans. ----A The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9-mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losartan, respectively (r2 = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0- to 12-hour urinary amount of 4'-hydroxytolbutamide and carboxytolbutamide (r = 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0- to 12-hour amount of 4'-hydroxytolbutamide and carboxytolbutamide is the best urinary measure of its metabolism. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aryl_Hydrocarbon_Hydroxylases_MeSH S_genetics_MeSH Aryl_Hydrocarbon_Hydroxylases_genetics_MeSH S_metabolism_MeSH Aryl_Hydrocarbon_Hydroxylases_metabolism_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Female_MeSH M_Flurbiprofen_MeSH S_pharmacokinetics_MeSH Flurbiprofen_pharmacokinetics_MeSH S_urine_MeSH Flurbiprofen_urine_MeSH M_Genotype_MeSH M_Human_MeSH M_Losartan_MeSH S_pharmacokinetics_MeSH Losartan_pharmacokinetics_MeSH S_urine_MeSH Losartan_urine_MeSH M_Male_MeSH M_Phenotype_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Tolbutamide_MeSH S_pharmacokinetics_MeSH Tolbutamide_pharmacokinetics_MeSH S_urine_MeSH Tolbutamide_urine_MeSH ****** 12523675 ----K E ----T The angiotensin-receptor blockers: from antihypertensives to cardiovascular all-round medications in 10 years? ----A Angiotensin-receptor blockers have been part of the antihypertensive treatment armamentarium since the mid-1990s. During this period, the number of agents has increased greatly, as has the number of indications for which these drugs are being tested in randomized controlled clinical trials. Beginning as efficacious and very well tolerated antihypertensives, angiotensin-receptor blockers have been shown to have benefits in patients with diabetes and heart failure that are not only attributable to the reduced blood pressure, as supported by recently concluded trials. The expanding treatment areas with these agents widen the interest in their applicability across the entire cardiovascular continuum. A number of large-scale studies set to report within the next few years will further determine the effects of angiotensin-receptor blockers in a range of cardiovascular indications beyond hypertension. ----P Journal_Article Review Review__Academic ----M M_Angiotensin-Converting_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Angiotensin-Converting_Enzyme_Inhibitors_therapeutic_use_MeSH M_Animals_MeSH M_Antihypertensive_Agents_MeSH S_therapeutic_use_MeSH Antihypertensive_Agents_therapeutic_use_MeSH M_Cardiovascular_Agents_MeSH S_therapeutic_use_MeSH Cardiovascular_Agents_therapeutic_use_MeSH M_Cardiovascular_Diseases_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Heart_Failure__Congestive_MeSH S_epidemiology_MeSH Heart_Failure__Congestive_epidemiology_MeSH S_prevention_&_control_MeSH Heart_Failure__Congestive_prevention_&_control_MeSH M_Human_MeSH M_Myocardial_Infarction_MeSH S_drug_therapy_MeSH Myocardial_Infarction_drug_therapy_MeSH M_Receptors__Angiotensin_MeSH S_antagonists_&_inhibitors_MeSH Receptors__Angiotensin_antagonists_&_inhibitors_MeSH M_Renin-Angiotensin_System_MeSH S_drug_effects_MeSH Renin-Angiotensin_System_drug_effects_MeSH S_physiology_MeSH Renin-Angiotensin_System_physiology_MeSH ****** 12524280 ----K 5 ----T Molecular basis for Kir6.2 channel inhibition by adenine nucleotides. ----A K(ATP) channels are comprised of a pore-forming protein, Kir6.x, and the sulfonylurea receptor, SURx. Interaction of adenine nucleotides with Kir6.2 positively charged amino acids such as K185 and R201 on the C-terminus causes channel closure. Substitution of these amino acids with other positively charged residues had small effects on inhibition by adenine nucleotide, while substitution with neutral or negative residues had major effects, suggesting electrostatic interactions between Kir6.2 positive charges and adenine nucleotide negative phosphate groups. Furthermore, R201 mutation decreased channel sensitivity to ATP, ADP, and AMP to a similar extent, but K185 mutation decreased primarily ATP and ADP sensitivity, leaving the AMP sensitivity relatively unaffected. Thus, channel inhibition by ATP may involve interaction of the alpha-phosphate with R201 and interaction of the beta-phosphate with K185. In addition, decreased open probability due to rundown or sulfonylureas caused an increase in ATP sensitivity in the K185 mutant, but not in the R201 mutant. Thus, the beta-phosphate may bind in a state-independent fashion to K185 to destabilize channel openings, while R201 interacts with the alpha-phosphate to stabilize a channel closed configuration. Substitution of R192 on the C-terminus and R50 on the N-terminus with different charged residues also affected ATP sensitivity. Based on these results a structural scheme is proposed, which includes features of other recently published models. ----P Journal_Article ----M M_Adenine_Nucleotides_MeSH S_chemistry_MeSH Adenine_Nucleotides_chemistry_MeSH S_pharmacology_MeSH Adenine_Nucleotides_pharmacology_MeSH S_physiology_MeSH Adenine_Nucleotides_physiology_MeSH M_Adenosine_Triphosphate_MeSH S_chemistry_MeSH Adenosine_Triphosphate_chemistry_MeSH S_pharmacology_MeSH Adenosine_Triphosphate_pharmacology_MeSH S_physiology_MeSH Adenosine_Triphosphate_physiology_MeSH M_Amino_Acids_MeSH S_chemistry_MeSH Amino_Acids_chemistry_MeSH S_pharmacology_MeSH Amino_Acids_pharmacology_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Ion_Channel_Gating_MeSH S_drug_effects_MeSH Ion_Channel_Gating_drug_effects_MeSH S_physiology_MeSH Ion_Channel_Gating_physiology_MeSH M_Kidney_MeSH S_chemistry_MeSH Kidney_chemistry_MeSH S_drug_effects_MeSH Kidney_drug_effects_MeSH S_physiology_MeSH Kidney_physiology_MeSH M_Potassium_Channels__Inwardly_Rectifying_MeSH S_antagonists_&_inhibitors_MeSH Potassium_Channels__Inwardly_Rectifying_antagonists_&_inhibitors_MeSH S_chemistry_MeSH Potassium_Channels__Inwardly_Rectifying_chemistry_MeSH S_physiology_MeSH Potassium_Channels__Inwardly_Rectifying_physiology_MeSH M_Recombinant_Proteins_MeSH S_chemistry_MeSH Recombinant_Proteins_chemistry_MeSH S_metabolism_MeSH Recombinant_Proteins_metabolism_MeSH M_Sensitivity_and_Specificity_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__P_H_S__MeSH M_Transfection_MeSH ****** 12542723 ----K E ----T Influence of treatment with acarbose or glibenclamide on insulin sensitivity in type 2 diabetic patients. ----A AIM: The aim of our double-blind, placebo-controlled study was to compare the effect of acarbose and glibenclamide on the insulin sensitivity in type 2 diabetes. METHODS: We investigated 77 patients (mean age 58.7 years, mean BMI 27.3 kg/m2), treated by diet alone for at least 4 weeks. The subjects were randomized into three treatment groups for 16 weeks: 100 mg t.i.d. acarbose (n = 25) or 1 mg t.i.d. glibenclamide (n = 27) or one t.i.d. placebo (n = 25). Before and after therapy, the levels of fasting plasma glucose, glycosylated haemoglobin, fasting insulin, plasma glucose and insulin 1 h after a standardized breakfast were measured and insulin sensitivity determined by euglycaemic hyperinsulinaemic clamp test. RESULTS: After the treatment period, BMI in the acarbose and placebo group decreased significantly, whereas in the glibenclamide group a significant increase was observed. Fasting plasma glucose was only significant reduced under glibenclamide. The postprandial glucose decreased significantly after acarbose (13.8 vs. 11.4 mmol/l, p < 0.05) and glibenclamide treatment (14.6 vs. 11.4 mmol/l, p < 0.05) and was unchanged under placebo (13.8 vs. 13.7 mmol/l). The fasting insulin levels remained unchanged in all three groups, whereas postprandial insulin values increased significantly under glibenclamide. Neither acarbose nor glibenclamide significantly changed insulin sensitivity [acarbose: glucose disposal rate before treatment 2.3 mg/kg body weight/min/insulin, after treatment 3.2; glibenclamide 2.2 vs. 2.1; placebo 2.6 vs. 3.0]. CONCLUSIONS: Our results show a more substantial improvement of glucose control under glibenclamide than under acarbose which, however, was not associated with an increase of insulin sensitivity. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Acarbose_MeSH S_therapeutic_use_MeSH Acarbose_therapeutic_use_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Body_Mass_Index_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Glucose_Clamp_Technique_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH P_Insulin_Resistance_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH ****** 12547850 ----K 6 ----T Plasma adiponectin plays an important role in improving insulin resistance with glimepiride in elderly type 2 diabetic subjects. ----A OBJECTIVE: We investigated the effect of glimepiride, a third-generation sulfonylurea hypoglycemic agent, on insulin resistance in elderly patients with type 2 diabetes, in connection with plasma adiponectin and 8-epi-prostagrandin F2alpha (8-epi-PGF2alpha), an oxidative stress marker. RESEARCH DESIGN AND METHODS: A total of 17 elderly patients with type 2 diabetes received 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of beta-cell function, HbA(1c), C-peptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2alpha, tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinemic-euglycemic clamp. RESULTS: After 8 weeks of glimepiride treatment, significant reductions were observed in HbA(1c) (from 8.4 +/- 1.9 to 6.9 +/- 1.0%), HOMA-IR (from 2.54 +/- 2.25 to 1.69 +/- 0.95%), and plasma TNF-alpha concentrations (from 4.0 +/- 2.0 to 2.6 +/- 2.5 pg/ml). MCR-g was significantly increased from 3.92 +/- 1.09 to 5.73 +/- 1.47 mg. kg(-1). min(-1). Plasma adiponectin increased from 6.61 +/- 3.06 to 10.2 +/- 7.14 micro g/ml. In control subjects, who maintained conventional treatment, no significant changes were observed in any of these markers. CONCLUSIONS: Glimepiride remarkably improved insulin resistance, suggested by a significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA(1c) without changing extrapancreatic beta-cell function and urine CPR. Increased plasma adiponectin and decreased plasma TNF-alpha may underlie the improvement of insulin resistance with glimepiride. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Dinoprost_MeSH S_analogs_&_derivatives_MeSH Dinoprost_analogs_&_derivatives_MeSH S_blood_MeSH Dinoprost_blood_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH P_Insulin_Resistance_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Osmolar_Concentration_MeSH M_Plasminogen_Activator_Inhibitor_1_MeSH S_blood_MeSH Plasminogen_Activator_Inhibitor_1_blood_MeSH M_Proteins_MeSH S_analysis_MeSH Proteins_analysis_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Tumor_Necrosis_Factor_MeSH S_analysis_MeSH Tumor_Necrosis_Factor_analysis_MeSH ****** 12549986 ----K I ----T Pharmacotherapy of diabetes mellitus: implications for the prevention and treatment of cardiovascular disease. ----A Diabetes mellitus in adults is associated with an increased risk of premature vascular disease and a higher mortality rate. The presence of other risk factors, often seen in diabetic patients, such as systemic hypertension, augments the rate of vascular diseases. Evidence is growing that tight control of hyperglycemia using insulin and/or oral hypoglycemic agents will modify this risk. More aggressive control of concomitant hypertension and/or hyperlipidemia is also required. Diabetic patients who have myocardial infarctions do worse than nondiabetic patients. Various strategies to improve outcomes include the use of tight blood glucose control, and various coronary interventions are currently under clinical study. ----P Journal_Article Review Review__Academic ----M M_Cardiovascular_Diseases_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Drug_Therapy__Combination_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_drug_therapy_MeSH Hyperlipidemia_drug_therapy_MeSH M_Hypertension_MeSH S_drug_therapy_MeSH Hypertension_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Myocardial_Infarction_MeSH S_drug_therapy_MeSH Myocardial_Infarction_drug_therapy_MeSH M_Risk_Factors_MeSH M_Thrombophilia_MeSH S_drug_therapy_MeSH Thrombophilia_drug_therapy_MeSH ****** 12556541 ----K E ----T Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. ----A BACKGROUND: Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. METHODS: The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. RESULTS: The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79). CONCLUSIONS: A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Amputation_MeSH M_Angiotensin_II_MeSH S_antagonists_&_inhibitors_MeSH Angiotensin_II_antagonists_&_inhibitors_MeSH M_Angiotensin-Converting_Enzyme_Inhibitors_MeSH S_therapeutic_use_MeSH Angiotensin-Converting_Enzyme_Inhibitors_therapeutic_use_MeSH M_Antihypertensive_Agents_MeSH S_therapeutic_use_MeSH Antihypertensive_Agents_therapeutic_use_MeSH M_Antilipemic_Agents_MeSH S_therapeutic_use_MeSH Antilipemic_Agents_therapeutic_use_MeSH M_Cardiovascular_Diseases_MeSH S_mortality_MeSH Cardiovascular_Diseases_mortality_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Cerebrovascular_Accident_MeSH S_prevention_&_control_MeSH Cerebrovascular_Accident_prevention_&_control_MeSH M_Combined_Modality_Therapy_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Diet__Fat-Restricted_MeSH M_Exercise_MeSH M_Female_MeSH M_Human_MeSH M_Hyperlipidemia_MeSH S_complications_MeSH Hyperlipidemia_complications_MeSH S_therapy_MeSH Hyperlipidemia_therapy_MeSH M_Hypertension_MeSH S_complications_MeSH Hypertension_complications_MeSH S_drug_therapy_MeSH Hypertension_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Myocardial_Infarction_MeSH S_prevention_&_control_MeSH Myocardial_Infarction_prevention_&_control_MeSH M_Obesity_in_Diabetes_MeSH S_diet_therapy_MeSH Obesity_in_Diabetes_diet_therapy_MeSH M_Risk_Factors_MeSH M_Smoking_Cessation_MeSH M_Support__Non-U_S__Gov't_MeSH M_Vitamins_MeSH S_therapeutic_use_MeSH Vitamins_therapeutic_use_MeSH ****** 12558728 ----K E ----T Treatment of diabetes mellitus in older people: oral therapy options. ----A ----P Journal_Article ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH ****** 12571611 ----K E ----T Rosiglitazone reduces urinary albumin excretion in type II diabetes. ----A This study examines the effect of rosiglitazone on urinary albumin excretion (UAE) in patients with type II diabetes. Urinary albumin: creatinine ratio (ACR) was measured in a 52-week, open-label, cardiac safety study comparing rosiglitazone and glyburide. Patients were randomised to treatment with rosiglitazone 4 mg b.i.d. or glyburide. ACR was measured at baseline and after 28 and 52 weeks of treatment. Statistically significant reductions from baseline in ACR were observed in both treatment groups at week 28. By week 52, only the rosiglitazone group showed a significant reduction from baseline. Similar results were observed for the overall study population and for the subset of patients with baseline microalbuminuria. For patients with microalbuminuria at baseline, reductions in ACR did not correlate strongly with reductions in glycosylated haemoglobin, or fasting plasma glucose, but showed strong correlation with changes in mean 24-h systolic and diastolic blood pressure for rosiglitazone-treated patients (deltaACR vs deltamean 24-h systolic blood pressure, r=0.875; deltaACR vs deltamean 24-h diastolic blood pressure, r=0.755; P < 0.05 for both). No such correlation was observed for glyburide-treated patients. In conclusion, rosiglitazone treatment was associated with a decrease in urinary albumin excretion. These findings suggest a potential beneficial effect of rosiglitazone in the treatment or prevention of renal and vascular complications of type II diabetes. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Albuminuria_MeSH S_prevention_&_control_MeSH Albuminuria_prevention_&_control_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diagnosis_MeSH Diabetes_Mellitus__Type_II_diagnosis_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Angiopathies_MeSH S_prevention_&_control_MeSH Diabetic_Angiopathies_prevention_&_control_MeSH M_Diabetic_Nephropathies_MeSH S_prevention_&_control_MeSH Diabetic_Nephropathies_prevention_&_control_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Follow-Up_Studies_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH M_Kidney_Function_Tests_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Reference_Values_MeSH M_Sensitivity_and_Specificity_MeSH M_Thiazoles_MeSH S_administration_&_dosage_MeSH Thiazoles_administration_&_dosage_MeSH P_Thiazolidinediones_MeSH M_Treatment_Outcome_MeSH ****** 12580986 ----K E ----T Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-a-day modified release (MR) formulation. ----A AIMS: To study the relationship between the pharmacokinetics (PK) of gliclazide and its long-term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability. METHODS: A PKPD database of 634 Type 2 diabetic patients with a total of 5,258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease-progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR. RESULTS: Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half-life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l(-1) year(-1) (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1-year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control. CONCLUSIONS: This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long-term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control. ----P Clinical_Trial Clinical_Trial__Phase_II Clinical_Trial__Phase_III Journal_Article ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Disease_Progression_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Female_MeSH M_Gliclazide_MeSH S_administration_&_dosage_MeSH Gliclazide_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Gliclazide_pharmacokinetics_MeSH S_pharmacology_MeSH Gliclazide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Models__Biological_MeSH ****** 12589230 ----K E ----T Beneficial effects of a glyburide/metformin combination preparation in type 2 diabetes mellitus. ----A BACKGROUND: Type 2 diabetes mellitus is characterized by both insulin deficiency and insulin resistance. Effective treatment often requires therapy directed at both abnormalities. Patients on monotherapy might benefit from a combination agent such as glyburide/metformin, which increases insulin secretion and reduces insulin resistance. METHODS: All patients taking a glyburide/metformin preparation at the Carl T. Hayden VAMC were identified from pharmacy records. Patients with documented hemoglobin A values within 31 weeks prior and between 3 and 33 weeks after initiation of therapy (92 subjects) were examined. RESULTS: Glyburide/metformin combination therapy reduced hemoglobin A levels from 0.087 to 0.083 (P < 0.06). Significant reductions were seen in those patients with initial levels higher than 0.08 (0.094 to 0.087; P < 0.01). No significant reductions were seen in those patients with initial levels lower than 0.08. CONCLUSIONS: In patients on monotherapy or on dual oral therapy with inadequate control, changing to a glyburide/metformin combination preparation may improve glucose control. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Combinations_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A_MeSH S_metabolism_MeSH Hemoglobin_A_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH M_Insulin_Resistance_MeSH S_physiology_MeSH Insulin_Resistance_physiology_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH ****** 12602406 ----K I ----T Treatment of type 2 diabetes: inadequate assessment of oral antidiabetic combinations. ----A (1) Metformin and glibenclamide are the only oral antidiabetics with a proven impact on the complications of type 2 diabetes. (2) Treatment with one of these drugs often fails to achieve the recommended target in HbA1c level (below 7%). (3) Only one randomised trial has assessed the preventive efficacy of a combination of oral antidiabetics when hyperglycaemia persists despite treatment with a glucose-lowering sulphonylurea. The trial showed that combining metformin and a glucose-lowering sulphonylurea is associated with a higher mortality than therapy with a sulphonylurea alone. (4) Despite this result, most clinical guidelines recommend the metformin + glucose-lowering sulphonylurea combination when oral antidiabetic monotherapy fails. (5) In the absence of convincing data supporting any particular strategy, all options should be discussed with patients including continuing with oral antidiabetic monotherapy, or starting insulin. ----P Journal_Article ----M M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_mortality_MeSH Diabetes_Mellitus__Type_II_mortality_MeSH M_Drug_Therapy__Combination_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Randomized_Controlled_Trials_MeSH ****** 12602474 ----K 5 ----T Use of octreotide to treat prolonged sulfonylurea-induced hypoglycemia in a patient with chronic renal failure. ----A A diabetic patient with chronic renal failure who developed recurrent and prolonged episodes of hypoglycemia associated with use of sulfonylurea agent is presented here. This patient was hospitalized with neuroglycopenic symptoms of hypoglycemia that persisted in spite of large doses of parenteral glucose replacement. On administration of somatostatin analogue octreotide, hypoglycemia resolved and, blood glucose levels were maintained even after cessation of parenteral glucose. The patient received 2 subcutaneous doses of octreotide 12 hours apart, and made a complete recovery. Our experience suggests that use of octerotide to treat refractory or prolonged sulfonylurea-included hypoglycemia in renal failure patients is safe and effective; large prospective studies would be needed to validate these findings. ----P Case_Reports Journal_Article ----M M_Adult_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Gastrointestinal_Agents_MeSH S_therapeutic_use_MeSH Gastrointestinal_Agents_therapeutic_use_MeSH M_Glipizide_MeSH S_adverse_effects_MeSH Glipizide_adverse_effects_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH S_drug_therapy_MeSH Hypoglycemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Kidney_Failure__Chronic_MeSH S_complications_MeSH Kidney_Failure__Chronic_complications_MeSH M_Male_MeSH M_Octreotide_MeSH S_therapeutic_use_MeSH Octreotide_therapeutic_use_MeSH M_Seizures_MeSH S_etiology_MeSH Seizures_etiology_MeSH ****** 12610054 ----K I ----T Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. ----A OBJECTIVE: To evaluate the influence of renal impairment on the safety and efficacy of repaglinide in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: This multinational, open-label study comprised a 6-week run-in period, continuing prestudy antidiabetic medication, followed by a titration period (1-4 weeks) and a 3-month maintenance period. Patients with normal renal function (n = 151) and various degrees of renal impairment (n = 130) were treated with repaglinide (maximal dose of 4 mg, three times daily). Safety and efficacy assessments were performed at baseline (end of run-in) and at the end of study treatment. RESULTS: The type and severity of adverse events during repaglinide treatment were similar to the run-in period. The number of patients with adverse events was not significantly related to renal function during run-in or repaglinide treatment. Percentage of patients with hypoglycemic episodes increased significantly (P = 0.007) with increasing severity of renal impairment during run-in but not during repaglinide treatment (P = 0.074). Metabolic control (HbA(1c) and fasting blood glucose) with repaglinide was unchanged from that on previous antidiabetic medication. Final repaglinide dose tended to be lower for patients with severe and extreme renal impairment than for patients with less severe renal impairment or normal renal function (P = 0.032). CONCLUSIONS: Repaglinide has a good safety and efficacy profile in type 2 diabetic patients complicated by renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal impairment. ----P Clinical_Trial Journal_Article Multicenter_Study ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Carbamates_MeSH S_administration_&_dosage_MeSH Carbamates_administration_&_dosage_MeSH S_adverse_effects_MeSH Carbamates_adverse_effects_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Diabetic_Nephropathies_MeSH S_drug_therapy_MeSH Diabetic_Nephropathies_drug_therapy_MeSH S_etiology_MeSH Diabetic_Nephropathies_etiology_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_administration_&_dosage_MeSH Piperidines_administration_&_dosage_MeSH S_adverse_effects_MeSH Piperidines_adverse_effects_MeSH M_Severity_of_Illness_Index_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12616669 ----K E ----T Pharmacokinetics of nateglinide in renally impaired diabetic patients. ----A Treatment of hyperglycemia in patients with diabetes mellitus and renal insufficiency is complicated by altered pharmacokinetics of hypoglycemic agents. This study evaluated the pharmacokinetic profile and safety of nateglinide, an amino acid derivative that improves early phase insulin secretion and reduces mealtime glucose excursions. This open-label, single-dose, two-center study included patients (mean age = 57 +/- 10 years) with type 1 or 2 diabetes with impaired renal function (IRF) (n = 10) or with renal failure undergoing hemodialysis (n = 10). Both groups were compared with age-, sex-, height-, and weight-matched healthy controls (n = 20). All participants received a single 120-mg dose of nateglinide immediately before breakfast. Pharmacokinetic and safety evaluations were undertaken up to 48 hours postdose. All 40 subjects completed the study. Plasma nateglinide concentrations increased rapidly in patients undergoing dialysis and matched healthy subjects (tmax = 0.95 vs. 0.78 h, respectively) and was comparable with patients with IRF and matched healthy subjects (tmax = 0.80 vs. 0.65 h, respectively). There were no statistically significant differences for Cmax or AUC0-t between the groups. Nateglinide was eliminated rapidly in all groups (t1/2 = 1.9-2.8 h). There was no correlation between the level of renal function and systemic exposure. There was a low extent of renal excretion of nateglinide in healthy subjects (11%) and diabetic patients with IRF (3%). Nateglinide was well tolerated. These data suggest that nateglinide is suitable for use in diabetic patients with IRF or with renal failure undergoing dialysis. Given the comparable absorption and elimination profiles of nateglinide in renally impaired and healthy subjects, no dose adjustment appears necessary in the renally impaired. ----P Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Case-Control_Studies_MeSH M_Cyclohexanes_MeSH S_blood_MeSH Cyclohexanes_blood_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH S_pharmacology_MeSH Cyclohexanes_pharmacology_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_I_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Female_MeSH M_Half-Life_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Kidney_Failure__Chronic_MeSH S_metabolism_MeSH Kidney_Failure__Chronic_metabolism_MeSH M_Male_MeSH M_Metabolic_Clearance_Rate_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_blood_MeSH Phenylalanine_blood_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH S_pharmacology_MeSH Phenylalanine_pharmacology_MeSH M_Renal_Dialysis_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12637120 ----K I ----T Efficacy and safety profile of glimepiride in Mexican American Patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. ----A BACKGROUND: Mexican Americans, the fastest growing ethnic group in the United States, have a 2- to 3-fold higher prevalence of type 2 diabetes mellitus relative to the non-Hispanic white population. It is estimated that 10% of Mexican Americans >or=20 years of age have diabetes. OBJECTIVE: The goal of this study was to evaluate the efficacy and safety of glimepiride, a long-acting sulfonylurea, as an adjunct to diet/exercise in Mexican Americans with type 2 diabetes mellitus. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. Mexican Americans with uncontrolled type 2 diabetes, defined as a fasting plasma glucose (FPG) level between 120 mg/dL and 225 mg/dL and glycated hemoglobin (HbA(1c)) values between 8.0% and 10.5%, after >or=3 months of diet/exercise were enrolled. Patients were randomized in a 2:1 ratio (using the lowest available treatment assignment number when eligibility was established) to receive 14 weeks of glimepiride or matching placebo once daily with continued diet/exercise. The starting glimepiride dose was 1 mg, with titration to 2 mg and 4 mg for FPG levels >120 mg/dL. The primary efficacy variable was change in HbA(1c) from baseline to study end point. Secondary efficacy variables were HbA(1c) response (rated as excellent, good, or marginal) and changes in FPG, fasting insulin, fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) levels from baseline to study end point. The tolerability of glimepiride in this study population was determined by evaluating adverse events, hypoglycemic episodes, and physical examination as well as laboratory findings. All analyses were performed on an intent-to-treat basis. A per-protocol analysis also was conducted to support the primary efficacy analysis. RESULTS: Seventy patients were randomized to treatment with glimepiride (n = 48) or placebo ((n = 22). The glimepiride and placebo groups were similar with respect to mean (SE) age (48.4 [11.7] and 50.7 [10.0] years, respectively) and sex (56.3% [27/48] and 50.0% [11/22] were male, respectively). However, the glimepiride group had a higher mean body weight (83.3 [17.0] vs 76.3 [18.5] kg) and a significantly higher mean fasting insulin level (23.8 [17.7] vs 17.8 [19.7] microU/mL; P = 0.031). The mean (SE) HbA(1c) values at study end point were 7.8% (0.2%) and 9.9% (0.7%) in patients receiving glimepiride and placebo, respectively. The adjusted mean difference in HbA(1c) reduction from baseline to end point was statistically significant in favor of glimepiride (-1.8% [0.4%]; P < 0.001). More pronounced HbA(1c) impairment at baseline was associated with greater glimepiride-placebo differences in HbA(1c) reduction. Glimepiride-treated patients also achieved a significantly greater improvement in FPG, with an adjusted mean (SE) treatment difference of -46.7 (16.7) mg/dL (P = 0.007). Glimepiride did not appear to affect fibrinogen and PAI-1 levels but was associated with significantly greater mean increases in fasting insulin (10.2 vs -2.1 microU/mL; P = 0.002) and body weight (2.3 vs 2.1 kg; P < 0.001) compared with placebo. Glimepiride was well tolerated, with an adverse-event profile similar to that of placebo. CONCLUSIONS: These results indicate that once-daily glimepiride plus diet/exercise was effective in Mexican Americans with type 2 diabetes whose disease was inadequately controlled with diet/exercise alone. It appeared to be well tolerated in the population studied. More weight gain was seen with glimepiride compared with placebo. Given the high prevalence of type 2 diabetes among Mexican Americans, further clinical studies of glimepiride and other glucose-lowering therapies are needed in this ethnic subset. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diet_therapy_MeSH Diabetes_Mellitus__Type_II_diet_therapy_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_ethnology_MeSH Diabetes_Mellitus__Type_II_ethnology_MeSH M_Double-Blind_Method_MeSH M_Fasting_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH P_Mexican_Americans_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_United_States_MeSH S_epidemiology_MeSH United_States_epidemiology_MeSH ****** 12637977 ----K E ----T The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. ----A The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes. ----P Journal_Article Review Review__Tutorial ----M M_Adipose_Tissue_MeSH S_pathology_MeSH Adipose_Tissue_pathology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_diagnosis_MeSH Diabetes_Mellitus__Type_II_diagnosis_MeSH S_pathology_MeSH Diabetes_Mellitus__Type_II_pathology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH M_Human_MeSH M_Insulin_MeSH S_metabolism_MeSH Insulin_metabolism_MeSH P_Insulin_Resistance_MeSH M_Islets_of_Langerhans_MeSH S_physiopathology_MeSH Islets_of_Langerhans_physiopathology_MeSH M_Support__U_S__Gov't__Non-P_H_S__MeSH M_Support__U_S__Gov't__P_H_S__MeSH ****** 12648023 ----K E ----T Maternal-fetal transport of hypoglycaemic drugs. ----A Due to legal, ethical and monetary problems, drug studies in pregnancy are rare. Numerous pharmacokinetic and pharmacodynamic changes occur in pregnancy that can affect the efficacy and safety of drugs, and these are difficult to predict without appropriate studies. Drugs potentially useful and safe in pregnancy have to either not cross the placenta and/or be harmless to the fetus at clinically relevant concentrations. The first characteristic can be predicted using in vitro models such as the placenta perfusion model. In the case of glibenclamide (glyburide), in vitro experiments showed minimal maternal-fetal transfer, leading to completion of a successful clinical trial of this drug in gestational diabetes. Insulin, the main drug used in diabetes during pregnancy, has also been shown not to cross the placenta in vitro, as has insulin lispro. Animal insulin may cross the placenta when complexed with anti-insulin antibodies. Other sulphonylurea drugs (tolbutamide and chlorpropamide) have been shown to cross the placenta both in vitro and in vivo and to produce toxicity in the fetus. This review summarises the pharmacokinetic data available for hypoglycaemic drugs during pregnancy, as well as the potential role for the in vitro placenta perfusion model in the preclinical evaluation of drugs with potential usefulness in pregnancy. ----P Journal_Article Review Review__Tutorial ----M M_Abnormalities__Drug-Induced_MeSH S_etiology_MeSH Abnormalities__Drug-Induced_etiology_MeSH M_Biological_Transport_MeSH M_Clinical_Trials_MeSH M_Diabetes__Gestational_MeSH S_drug_therapy_MeSH Diabetes__Gestational_drug_therapy_MeSH S_metabolism_MeSH Diabetes__Gestational_metabolism_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_pharmacokinetics_MeSH Insulin_pharmacokinetics_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH P_Maternal-Fetal_Exchange_MeSH M_Placenta_MeSH S_metabolism_MeSH Placenta_metabolism_MeSH M_Pregnancy_MeSH M_Pregnancy_in_Diabetics_MeSH S_drug_therapy_MeSH Pregnancy_in_Diabetics_drug_therapy_MeSH S_metabolism_MeSH Pregnancy_in_Diabetics_metabolism_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12663588 ----K 3 ----T Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. ----A OBJECTIVE:To determine whether oral magnesium supplementation (as magnesium chloride [MgCl(2)] solution) improves both insulin sensitivity and metabolic control in type 2 diabetic subjects with decreased serum magnesium levels. RESEARCH DESIGN AND METHODS: This study was a clinical randomized double-blind placebo-controlled trial. A total of 63 subjects with type 2 diabetes and decreased serum magnesium (serum magnesium levels </=0.74 mmol/l) treated by glibenclamide received either 50 ml MgCl(2) solution (containing 50 g MgCl(2) per 1,000 ml solution) or placebo daily for 16 weeks. Chronic diarrhea, alcoholism, use of diuretic and/or calcium antagonist drugs, and reduced renal function were exclusion criteria. Homeostasis model assessment for insulin resistance (HOMA-IR) was used as the parameter of insulin sensitivity and glucose and HbA(1c) as parameters of metabolic control. RESULTS: At the end of the study, subjects who received magnesium supplementation showed significant higher serum magnesium concentration (0.74 +/- 0.10 vs. 0.65 +/- 0.07 mmol/l, P = 0.02) and lower HOMA-IR index (3.8 +/- 1.1 vs. 5.0 +/- 1.3, P = 0.005), fasting glucose levels (8.0 +/- 2.4 vs. 10.3 +/- 2.1 mmol/l, P = 0.01), and HbA(1c) (8.0 +/- 2.4 vs. 10.1 +/- 3.3%, P = 0.04) than control subjects. CONCLUSIONS: Oral supplementation with MgCl(2) solution restores serum magnesium levels, improving insulin sensitivity and metabolic control in type 2 diabetic patients with decreased serum magnesium levels. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Blood_Pressure_MeSH M_Body_Constitution_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH M_Dietary_Supplements_MeSH M_Double-Blind_Method_MeSH M_Follow-Up_Studies_MeSH M_Human_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Magnesium_Chloride_MeSH S_administration_&_dosage_MeSH Magnesium_Chloride_administration_&_dosage_MeSH S_therapeutic_use_MeSH Magnesium_Chloride_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Patient_Selection_MeSH M_Placebos_MeSH M_Support__Non-U_S__Gov't_MeSH M_Time_Factors_MeSH ****** 12674170 ----K E ----T Oral hypoglycaemic agent failure. ----A Type 2 diabetic patients initially respond satisfactorily to diet, exercise and oral hypoglycaemic agents (OHA), but a fraction of them acquires resistance to drugs, right from the beginning (primary OHA failure) or in due course of time (secondary OHA failure) and becomes insulin requiring ultimately. Poor diet compliance and deterioration of beta-cell function are major causes of OHA failure and annual incidence is 3 to 30%. Keeping in mind the benefit of organ salvage in diabetes, failure with OHA treatment should be detected earliest and necessary measures adopted as early as possible. Recognition, appraisal and assessment of total problem can help a diabetic to enjoy a normal life. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Treatment_Failure_MeSH ****** 12674176 ----K 3 ----T Efficacy and safety of nateglinide in the treatment of type II diabetes mellitus. ----A Nateglinide a new short-acting D-phenylalanine derivative represents a new chemical class of drugs for treating type 2 diabetes that is pharmacologically and therapeutically distinct from currently existing agents. Studies in normal patients and those with type 2 diabetes have shown that nateglinide reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. Nateglinide binds to and inhibits the K+(ATP) channel of the beta-cell, causing membrane depolarisation, with a subsequent influx of extracellular calcium that results in insulin secretion. A total of 105 patients in 5 centres with type II diabetes mellitus were taken according to the inclusion criteria and given drug treatment and were evaluated on their improvement in fasting and postprandial plasma glucose and glycosylated haemoglobin values for efficacy, besides physician's assessment of the overall safety and efficacy. Nateglinide in a dose of 60 mg before three main meals was given and increased to a maximum of 120 mg thrice daily over the first 3-4 weeks. Nateglinide had to be taken 10 minutes before meals. Duration of treatment was 12 weeks. The patients showed decrease in fasting plasma glucose from 2nd week onwards and reduction in glycosylated haemoglobin by 6th week onwards. Postprandial glucose reduction was also significant at the end of 12th week. The frequency of adverse effects was low and no serious adverse effects were encountered. ----P Clinical_Trial Evaluation_Studies Journal_Article Multicenter_Study ----M M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cyclohexanes_MeSH S_administration_&_dosage_MeSH Cyclohexanes_administration_&_dosage_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_administration_&_dosage_MeSH Phenylalanine_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Prospective_Studies_MeSH M_Treatment_Outcome_MeSH ****** 12679603 ----K E ----T Obesity and type-2 diabetes in the elderly. ----A Type-2 diabetes is common in the elderly and when compounded by obesity presents a major challenge for the physician. Obesity plays a central role in the aetiology and pathogenesis of type-2 diabetes. Body weight is determined by an interaction between genetic, environmental and psychosocial factors acting through the physiological mediators of energy intake and expenditure. Obesity is thought to predispose to type-2 diabetes primarily by causing insulin resistance. Education and changes in lifestyle remain the key issues in obesity management. Anti-obesity drugs may delay the onset of diabetes but there is limited experience of their use in elderly patients. Obesity should not be viewed as a cosmetic problem that affects a few individuals, but a major health hazard that is both preventable and amenable to treatment. ----P Journal_Article Review Review__Tutorial ----M M_Adult_MeSH M_Aged_MeSH M_Anthropometry_MeSH M_Continental_Population_Groups_MeSH S_genetics_MeSH Continental_Population_Groups_genetics_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_etiology_MeSH Diabetes_Mellitus__Type_II_etiology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_II_physiopathology_MeSH S_therapy_MeSH Diabetes_Mellitus__Type_II_therapy_MeSH M_Female_MeSH M_Genetic_Predisposition_to_Disease_MeSH M_Health_Behavior_MeSH M_Human_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Obesity_in_Diabetes_MeSH S_etiology_MeSH Obesity_in_Diabetes_etiology_MeSH S_physiopathology_MeSH Obesity_in_Diabetes_physiopathology_MeSH S_therapy_MeSH Obesity_in_Diabetes_therapy_MeSH M_Socioeconomic_Factors_MeSH ****** 12685875 ----K E ----T Slowly progressing type 1 diabetes: persistence of islet cell autoantibodies is related to glibenclamide treatment. ----A BACKGROUND: Several experimental studies in rats have demonstrated that sulfonylurea treatment increases autoantigen expression in B-cells. This phenomenon may be deleterious for the preservation of residual beta cell function in patients with slowly progressing type 1 diabetes or latent autoimmune diabetes of adult (LADA). AIM/HYPOTHESIS: The aim of the present study was to evaluate whether the exclusion of glibenclamide in the treatment of ICA positive type 2 diabetic patients may diminish or halt the humoral autoimmune response against B-cells as well as improve metabolic control and insulin secretion. SUBJECTS AND METHODS: Fourteen type 2 diabetic patients with pancreatic autoimmunity (ICA+ and GABA+) and treated with insulin and glibenclamide (duration of disease 2.0 +/- 2.2, range 0.1-7 years and age 53 +/- 12.5, range 36-75 years) were studied. Patients were randomly assigned to two treatment groups, Group 1: insulin monotherapy (n = 8, age 53 +/- 6.4 years) (Exclusion of glibenclamide) and, Group 2: insulin plus glibenclamide (n = 6, age 53.5 +/- 16.9) (Unmodified treatment). Both groups were investigated at the beginning of the study and after one year for the following parameters: ICA and anti-GAD65 antibodies, fasting glucose and fasting C-peptide. RESULTS: In group 1, six out of eight patients became ICA negative while all patients in group 2 remained ICA positive (p = 0.0097). Fasting glucose concentrations improved in group 1 (4.6 +/- 2.8) in relation to group 2 (11.5 +/- 5.5, p = 0.0023) after one year of treatment. No differences were found for anti-GAD antibodies and fasting C-Peptide between the groups. CONCLUSIONS: These data show that exclusion of glibenclamide in the treatment of ICA+ type 2 diabetic patients partially decreases specific autoimmunity against endocrine pancreatic cells and improves metabolic control. This may reflect decreased expression of B-cell autoantigens suggesting that insulin monotherapy is a better choice for the treatment of LADA. ----P Journal_Article ----M M_Autoantibodies_MeSH S_drug_effects_MeSH Autoantibodies_drug_effects_MeSH S_immunology_MeSH Autoantibodies_immunology_MeSH M_Blood_Glucose_MeSH M_Body_Mass_Index_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_immunology_MeSH Diabetes_Mellitus__Type_I_immunology_MeSH S_physiopathology_MeSH Diabetes_Mellitus__Type_I_physiopathology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Glutamate_Decarboxylase_MeSH S_immunology_MeSH Glutamate_Decarboxylase_immunology_MeSH M_Glyburide_MeSH S_pharmacology_MeSH Glyburide_pharmacology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_immunology_MeSH Islets_of_Langerhans_immunology_MeSH M_Isoenzymes_MeSH S_immunology_MeSH Isoenzymes_immunology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12711836 ----K E ----T Evaluation of the effects of nateglinide on postprandial glycemia in patients with type 2 diabetes mellitus: a multicenter, multinational, non-randomized, non-controlled Latin American study. ----A One hundred and sixteen Latin American type 2 diabetic patients previously only on a diet were enrolled in this multicenter, multinational, nonrandomized, noncontrolled study. Only 109 completed the study. After 8 weeks of treatment with 120 mg of nateglinide, administered prior to each meal, the postprandial (2 h) glucose concentration decreased to 85.11 +/- 5.65 mg/dl (p < 0.0001), and HbA(1c) values decreased to 1.06 +/- 0.10% (p < 0.0001). No response differences were detected in relation to age, gender, or ethnicity, but we did encounter a better response in recently diagnosed patients (<or=1 year). No serious adverse events were observed. We can, therefore, conclude that nateglinide is a well-tolerated, safe, and effective insulinotropic agent. ----P Clinical_Trial Journal_Article Multicenter_Study ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Cyclohexanes_MeSH S_adverse_effects_MeSH Cyclohexanes_adverse_effects_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH P_Hyperglycemia_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH S_etiology_MeSH Hyperglycemia_etiology_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Latin_America_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_adverse_effects_MeSH Phenylalanine_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Postprandial_Period_MeSH S_drug_effects_MeSH Postprandial_Period_drug_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH ****** 12725705 ----K 3 ----T Addition of rosiglitazone to existing sulfonylurea treatment in chinese patients with type 2 diabetes and exposure to hepatitis B or C. ----A The effects of adding rosiglitazone to existing sulfonylurea (SU) treatment have not previously been studied in Chinese patients with type 2 diabetes and no known pre-existing hepatic impairment. Patients were randomized to receive rosiglitazone 2 mg twice daily (R4 + SU) or 4 mg twice daily (R8 + SU) or placebo (SU + P) for 24 weeks in addition to existing SU treatment. Most patients were taking concomitant glibenclamide (34%) or gliclazide (25%). Changes in glycosylated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), and plasma insulin concentrations were measured. Of the 530 patients enrolled (45% male, mean age 59 years), 105 were in the SU + P group, 215 in the R4 + SU group, and 210 in the R8 + SU group. The mean baseline HbA(1c) was 9.8%, and FPG was 183.8 mg/dL. Compared with placebo, addition of rosiglitazone (2 or 4 mg twice daily) produced significant decreases in mean HbA(1c) (1.04% and 1.44%, respectively; p < 0.0001) and FPG (21.6 and 36.0 mg/dL, respectively; p < 0.0001). There were statistically significant (p < 0.0001) reductions from baseline in insulin concentration of 23.3 and 30.4 pmol/L in the R4 + SU and R8 + SU groups, respectively. Despite the high prevalence of seropositivity for hepatitis B and/or C at baseline (56%), there was no evidence of hepatotoxicity. No clinically significant changes in routine hematology, biochemistry, or electrocardiogram were observed. The addition of rosiglitazone to SU produced clinically significant improvements in glycemic control in Chinese patients with type 2 diabetes. Rosiglitazone plus SU was well tolerated irrespective of hepatitis B and C serological status. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Asian_Continental_Ancestry_Group_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_China_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH P_Environmental_Exposure_MeSH M_Female_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Glyburide_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Hepatitis_B_MeSH S_prevention_&_control_MeSH Hepatitis_B_prevention_&_control_MeSH M_Hepatitis_C_MeSH S_prevention_&_control_MeSH Hepatitis_C_prevention_&_control_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH ****** 12749508 ----K I ----T Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year, randomized, double-blind assessment of metabolic parameters and cardiovascular risk factors. ----A BACKGROUND: Repaglinide and glimepiride are relatively new oral hypoglycemic agents. Few data are available concerning their effects on metabolic parameters other than measures of glycemic control. OBJECTIVES: In addition to assessing the effects of repaglinide and glimepiride on glycemic control in patients with type 2 diabetes mellitus, this study also examined the effects of these agents on 3 metabolic parameters known to be cardiovascular risk factors--lipoprotein(a) (Lp[a]), plasminogen activator inhibitor-1 (PAI-1), and homocysteine (Hcy). METHODS: This randomized, placebo-controlled, double-blind trial was conducted at a single center in Italy. Eligible patients were nonsmokers; had no hypertension or coronary heart disease; were taking no hypolipidemic drugs, diuretics, beta-blockers, or thyroxin; and had normal renal function. After an initial 4-week placebo washout period, patients were randomized to receive repaglinide 1 mg/d or glimepiride 1 mg/d. The dose of study drug was optimized over an 8-week titration period, which was followed by a 12-month treatment period. Measures of glycemic control (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG], fasting plasma insulin [FPI], postprandial plasma insulin [PPI]) and the other metabolic parameters of interest were assessed after 6 and 12 months of treatment. RESULTS: One hundred twenty-four patients (63 women, 61 men) completed the study, 62 in each treatment group. There were no significant differences in demographic characteristics between groups. After 6 and 12 months of treatment, FPG levels and HbA1c values were significantly reduced from baseline in both groups (6 months, P < 0.05; 12 months, P < 0.01). After 6 months, PPG levels were significantly decreased only in the repaglinide group (P < 0.05 vs baseline); at 12 months, however, PPG levels were significantly reduced from baseline in both groups (P < 0.01 repaglinide, P < 0.05 glimepiride). No significant changes from baseline in FPI or PPI levels were seen in either group at 6 months, although FPI levels were significantly increased in the repaglinide group at 12 months (P < 0.05). Repaglinide significantly lowered levels of Lp(a), PAI-1, and Hcy after 12 months (all, P < 0.05 vs baseline). Glimepiride significantly lowered levels of Lp(a) and Hcy after 6 months (both, P < 0.05 vs baseline) and levels of Lp(a) (P < 0.01 vs baseline), Hcy (P < 0.01 vs baseline), and PAI-1 (P < 0.05 vs baseline) after 12 months. CONCLUSIONS: Repaglinide and glimepiride improved glycemic control and reduced levels of other metabolic parameters of interest in this population of patients with type 2 diabetes. It is possible that the reductions in Lp(a), PAI-1, and Hcy were the result of improved glucose metabolism; however, the possibility that repaglinide and glimepiride may have a direct effect on these parameters should not be excluded. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Blood_Pressure_MeSH S_drug_effects_MeSH Blood_Pressure_drug_effects_MeSH M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH M_Female_MeSH M_Homocysteine_MeSH S_blood_MeSH Homocysteine_blood_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipoprotein(a)_MeSH S_blood_MeSH Lipoprotein(a)_blood_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Plasminogen_Activator_Inhibitor_1_MeSH S_blood_MeSH Plasminogen_Activator_Inhibitor_1_blood_MeSH M_Risk_Factors_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Time_Factors_MeSH M_Treatment_Outcome_MeSH ****** 12773078 ----K E ----T Chromium as adjunctive treatment for type 2 diabetes. ----A OBJECTIVE: To review the chemistry, pharmacology, efficacy, and safety of trivalent chromium in the treatment of type 2 diabetes and hyperlipidemia. DATA SOURCES: The English literature was searched from 1966 through May 2002 using MEDLINE, International Pharmaceutical Abstracts, and EMBASE. The key words included chromium, glucose, lipids, and diabetes. Pertinent references from review articles and studies were used as additional sources. DATA SYNTHESIS: Trivalent chromium is an essential nutrient and has a key role in lipid and glucose metabolism. Supplementation with chromium does not appear to reduce glucose levels in euglycemia. It may, however, have some efficacy in reducing glucose levels in hyperglycemia. The effects of chromium on lipid levels are variable. Chromium in doses <1000 microg/d appears to be safe for short-term administration. Kidney function and dermatologic changes need to be monitored. CONCLUSIONS: Chromium appears to be a safe supplement and may have a role as adjunctive therapy for treatment of type 2 diabetes. Additional large-scale, long-term, randomized, double-blind studies examining the effect of various doses and forms of chromium are needed. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Chromium_MeSH S_chemistry_MeSH Chromium_chemistry_MeSH S_pharmacology_MeSH Chromium_pharmacology_MeSH S_therapeutic_use_MeSH Chromium_therapeutic_use_MeSH M_Clinical_Trials_MeSH S_statistics_&_numerical_data_MeSH Clinical_Trials_statistics_&_numerical_data_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH ****** 12789615 ----K E ----T NN-2211 Novo Nordisk. ----A Novo Nordisk A/S, under license from Scios Inc, is developing NN-2211, a stable analog of the naturally occurring peptide hormone glucagon-like peptide 1 (GLP-1), which stimulates insulin release in response to increases in blood sugar levels, for the potential treatment of type 2 diabetes. ----P Journal_Article Review Review_Literature ----M M_Animals_MeSH M_Clinical_Trials_MeSH S_statistics_&_numerical_data_MeSH Clinical_Trials_statistics_&_numerical_data_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_metabolism_MeSH Diabetes_Mellitus__Type_II_metabolism_MeSH M_Glucagon_MeSH S_analogs_&_derivatives_MeSH Glucagon_analogs_&_derivatives_MeSH S_chemical_synthesis_MeSH Glucagon_chemical_synthesis_MeSH S_pharmacology_MeSH Glucagon_pharmacology_MeSH S_therapeutic_use_MeSH Glucagon_therapeutic_use_MeSH M_Human_MeSH M_Technology__Pharmaceutical_MeSH S_legislation_&_jurisprudence_MeSH Technology__Pharmaceutical_legislation_&_jurisprudence_MeSH S_methods_MeSH Technology__Pharmaceutical_methods_MeSH ****** 12795025 ----K E ----T [Oral antidiabetic therapy and cardiovascular complications: theoretical problem or clinical evidence?] ----A Theoretical and experimental research data as well as human epidemiological studies on large populations suggest a great difference in influencing cardiovascular processes and alterations among the oral antidiabetic drugs used in the treatment of type II diabetes mellitus. Drugs delaying or inhibiting carbohydrate absorption as well as insulin sensitizers have an unambiguous reducing effect on diabetic cardiovascular complications. Only fluid retention needs precaution during the treatment with thiazolidinedions in patients suffering from heart disease. Among insulin secretizers repaglinid, glibenclamid and glipizide have an ATP-sensitive potassium channel inhibiting effect in the vascular smooth muscle cells, too, reducing hereby vasodilation. Glibenclamide also inhibits ischaemic preconditioning. Therefore, the antidiabetic drug of choice can be decisive in diabetic patients suffering from ischaemic heart diseases or peripheral obliterative disorders. In the case of secondary sulphonylurea resistance and/or severe ischaemic alterations insulin treatment becomes necessary to avoid further cardiovascular complications. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Cardiovascular_Diseases_MeSH S_chemically_induced_MeSH Cardiovascular_Diseases_chemically_induced_MeSH S_metabolism_MeSH Cardiovascular_Diseases_metabolism_MeSH S_prevention_&_control_MeSH Cardiovascular_Diseases_prevention_&_control_MeSH M_Cardiovascular_System_MeSH S_drug_effects_MeSH Cardiovascular_System_drug_effects_MeSH S_metabolism_MeSH Cardiovascular_System_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_chemistry_MeSH Hypoglycemic_Agents_chemistry_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Ischemic_Preconditioning_MeSH M_Potassium_Channels_MeSH S_drug_effects_MeSH Potassium_Channels_drug_effects_MeSH ****** 12797714 ----K I ----T The effect of prandial glucose regulation with repaglinide on treatment satisfaction, wellbeing and health status in patients with pharmacotherapy naive Type 2 diabetes: a placebo-controlled, multicentre study. ----A This prospective, 16-week, randomised, double-blind, parallel-group study assessed the differential impact of the prandial glucose regulating oral hypoglycaemic drug, repaglinide, and placebo upon perceptions of quality of life (QoL) and treatment satisfaction in pharmacotherapy-naive patients with Type 2 diabetes. In addition, the study assessed whether these outcomes were influenced by the patients' level of glycaemic control. A total of 253 patients were randomised in a 2:1 ratio of repaglinide: placebo, with doses taken flexibly with main meals (2-4 per day), whenever they were eaten. Repaglinide was initiated at 0.5 mg per meal, increased to 1 mg after 4 weeks if fasting plasma glucose exceeded 7.8 mmol/l. QoL and treatment satisfaction outcomes were compared using generic and disease-specific self-assessment measures, previously applied in diabetes: the WHO Wellbeing Questionnaire (WHO-WBQ), WHO Diabetes Treatment Satisfaction Questionnaire (WHO-DTSQ) and EuroQoL EQ-5D. Over the trial period, repaglinide-treated patients reported a significant 9% improvement in (WHO-DTSQ) treatment satisfaction score (p < 0.05). No significant increase was associated with placebo. The correlation between decrease in glycated haemoglobin (HbA1c) and increase in treatment satisfaction (WHO-DTSQ) was -0.22 (p < 0.01). Scores obtained with the other measures did not change significantly during the trial in either group, but the cohort exhibited only a slight reduction in wellbeing (WHO-WBQ) and health status (EQ-5D) at baseline compared with the background population. In conclusion, flexible mealtime dosing with oral medication appears to be well accepted by pharmacotherapy-naive patients with Type 2 diabetes. The results suggest that repaglinide provides a higher level of treatment satisfaction than placebo, and this may in part relate to improved glycaemic control. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Carbamates_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Double-Blind_Method_MeSH P_Health_Status_MeSH M_Health_Status_Indicators_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Patient_Satisfaction_MeSH M_Piperidines_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Prospective_Studies_MeSH P_Quality_of_Life_MeSH M_Questionnaires_MeSH M_Support__Non-U_S__Gov't_MeSH M_Translating_MeSH ****** 12808879 ----K E ----T Thiazolidinediones in diabetes: current status and future outlook. ----A Thiazolidinediones have recently emerged as promising antidiabetic drugs. Unlike other oral antidiabetic drugs, thiazolidinediones function to ameliorate insulin resistance, a primary factor for the development of type 2 diabetes. Thiazolidinediones are ligands of the nuclear receptor, peroxisome proliferator-activated receptor-gamma, and their antidiabetic effects appear to be mediated by activation of this receptor. The two currently marketed thiazolidinediones, rosiglitazone and pioglitazone, display similar efficacies in their glucose lowering activities, but interestingly display slightly different clinical and side effect profiles. Understanding the molecular basis for these differences will help in the development of next generation thiazolidinediones that are more efficacious and safer for the treatment of type 2 diabetes. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Evaluation__Preclinical_MeSH M_Hepatitis__Toxic_MeSH S_pathology_MeSH Hepatitis__Toxic_pathology_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Thiazoles_MeSH S_adverse_effects_MeSH Thiazoles_adverse_effects_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH M_Weight_Gain_MeSH S_drug_effects_MeSH Weight_Gain_drug_effects_MeSH ****** 12808887 ----K E ----T NN-414. Novo Nordisk. ----A Novo Nordisk is developing NN-414, an orally active beta-cell-selective regulator of insulin release, for the potential treatment of type 1 and type 2 diabetes. Phase 1 efficacy trials were underway by November 2000; these trials were ongoing in February 2002 and had been concluded by February 2003. ----P Journal_Article Review Review__Tutorial ----M M_Animals_MeSH M_Bicyclo_Compounds__Heterocyclic_MeSH S_adverse_effects_MeSH Bicyclo_Compounds__Heterocyclic_adverse_effects_MeSH S_metabolism_MeSH Bicyclo_Compounds__Heterocyclic_metabolism_MeSH S_pharmacology_MeSH Bicyclo_Compounds__Heterocyclic_pharmacology_MeSH S_therapeutic_use_MeSH Bicyclo_Compounds__Heterocyclic_therapeutic_use_MeSH M_Clinical_Trials__Phase_I_MeSH M_Cyclic_S-Oxides_MeSH S_adverse_effects_MeSH Cyclic_S-Oxides_adverse_effects_MeSH S_metabolism_MeSH Cyclic_S-Oxides_metabolism_MeSH S_pharmacology_MeSH Cyclic_S-Oxides_pharmacology_MeSH S_therapeutic_use_MeSH Cyclic_S-Oxides_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_I_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_I_drug_therapy_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_contraindications_MeSH Hypoglycemic_Agents_contraindications_MeSH S_metabolism_MeSH Hypoglycemic_Agents_metabolism_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Structure-Activity_Relationship_MeSH ****** 12809451 ----K E ----T Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. ----A BACKGROUND: Patients with type 2 diabetes are often treated with oral antidiabetic agents plus a basal insulin. OBJECTIVE: To investigate the efficacy and safety of glimepiride combined with either morning or bedtime insulin glargine or bedtime neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. DESIGN: Open-label, randomized, controlled trial. SETTING: 111 centers in 13 European countries. PATIENTS: 695 patients with type 2 diabetes who were previously treated with oral antidiabetic agents. INTERVENTION: Randomization to treatment with morning insulin glargine, bedtime NPH insulin, or bedtime insulin glargine for 24 weeks in addition to 3 mg of glimepiride. The insulin dose was titrated by using a predefined regimen to achieve fasting blood glucose levels of 5.56 mmol/L or lower (< or =100 mg/dL). MEASUREMENTS: Hemoglobin A(1c) values, blood glucose levels, insulin dose, and body weight. RESULTS: Hemoglobin A(1c) levels improved by -1.24% (two-sided 90% CI, -1.10% to -1.38%) with morning insulin glargine, by -0.96% (CI, -0.81% to -1.10%) with bedtime insulin glargine, and by -0.84% (CI, -0.69% to -0.98%) with bedtime NPH insulin. Hemoglobin A(1c) improvement was more pronounced with morning insulin glargine than with NPH insulin (0.40% [CI, 0.23% to 0.58%]; P = 0.001) or bedtime insulin glargine (0.28% [CI, 0.11% to 0.46%]; P = 0.008). Baseline to end-point fasting blood glucose levels improved similarly in all three groups. Nocturnal hypoglycemia was less frequent with morning (39 of 236 patients [17%]) and bedtime insulin glargine (52 of 227 patients [23%]) than with bedtime NPH insulin (89 of 232 patients [38%]) (P < 0.001). CONCLUSION: The risk for nocturnal hypoglycemia was lower with glimepiride in combination with morning and bedtime insulin glargine than with glimepiride in combination with bedtime NPH insulin in patients with type 2 diabetes. Morning insulin glargine provided better glycemic control than did bedtime insulin glargine or bedtime NPH insulin. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Aged_MeSH M_Blood_Glucose_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Administration_Schedule_MeSH M_Female_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_metabolism_MeSH Hemoglobin_A__Glycosylated_metabolism_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_adverse_effects_MeSH Insulin_adverse_effects_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH M_Insulin__Isophane_MeSH S_administration_&_dosage_MeSH Insulin__Isophane_administration_&_dosage_MeSH S_adverse_effects_MeSH Insulin__Isophane_adverse_effects_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Risk_Factors_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Weight_Gain_MeSH S_drug_effects_MeSH Weight_Gain_drug_effects_MeSH ****** 12814458 ----K 3 ----T Comparison of the micro- and macro-vascular effects of glimepiride and gliclazide in metformin-treated patients with Type 2 diabetes: a double-blind, crossover study. ----A AIMS: To compare the metabolic and vascular effects of two sulphonylureas (SU), gliclazide (specific for the pancreatic [SUR1] receptor) and glimepiride (a nonspecific agent that also binds to vascular and cardiac [SUR2] receptors), during chronic administration in metformin-treated patients with Type 2 diabetes (T2DM). METHODS: A randomized, double-blind, crossover study of gliclazide 80 mg BID and glimepiride 2 mg OD, each for 4 weeks as add-on therapy to metformin, with a 4-week washout period. Patients attended four study mornings after first dose and 4 weeks' SU treatment for measurements of arterial distensibility (Ax), pressor responsiveness to i.v. angiotensin II (ANGII), and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS: Glycaemic responses were similar (e.g. serum fructosamine was 315 vs 329 micro mol l-1 after 4 weeks), and there was no change in augmentation index during treatment with either SU (9.1 vs 9.8 mmHg after 4 weeks [95% confidence interval -8.1, 10.5]). Similarly, there were no differences between treatments in pressor responsiveness (e.g. PD10[dose of agonist required to increase mean BP by 10 mmHg] for ANGII was 1.37 vs 1.68 ng kg-1 min-1[-4.3, 6.9]) or cutaneous microvascular vasodilator responses (peak ACh response 68 +/- 36 vs 63 +/- 34 perfusion units [-82.7, 79.1]). CONCLUSIONS: There is no evidence that SUR1-specific and nonspecific SUs have differential effects on arterial distensibility, endothelial function or vasodilator mechanisms in metformin-treated patients with T2DM. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Aged_MeSH M_Comparative_Study_MeSH M_Cross-Over_Studies_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Gliclazide_MeSH S_therapeutic_use_MeSH Gliclazide_therapeutic_use_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Metformin_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Microcirculation_MeSH S_drug_effects_MeSH Microcirculation_drug_effects_MeSH M_Middle_Aged_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Vasodilation_MeSH S_drug_effects_MeSH Vasodilation_drug_effects_MeSH ****** 12817528 ----K I ----T Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide. ----A The object of this study was to analyze drug interactions between repaglinide, a short-acting insulin secretagogue, and five other drugs interacting with CYP3A4: ketoconazole, rifampicin, ethinyloestradiol/levonorgestrel (in an oral contraceptive), simvastatin, and nifedipine. In two open-label, two-period, randomized crossover studies, healthy subjects received repaglinide alone, repaglinide on day 5 of ketoconazole treatment, or repaglinide on day 7 of rifampicin treatment. In three open-label, three-period, randomized crossover studies, healthy subjects received 5 days of repaglinide alone; 5 days of ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine alone; or 5 days of repaglinide concomitant with ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. Compared to administration of repaglinide alone, concomitant ketoconazole increased mean AUC0-infinity for repaglinide by 15% and mean Cmax by 7%. Concomitant rifampicin decreased mean AUC0-infinity for repaglinide by 31% and mean Cmax by 26%. Concomitant treatment with CYP3A4 substrates altered mean AUC0-5 h and mean Cmax for repaglinide by 1% and 17% (ethinyloestradiol/levonorgestrel), 2% and 27% (simvastatin), or 11% and 3% (nifedipine). Profiles of blood glucose concentration following repaglinide dosing were altered by less than 8% by both ketoconazole and rifampicin. In all five studies, most adverse events were related to hypoglycemia, as expected in a normal population given a blood glucose regulator. The safety profile of repaglinide was not altered by pretreatment with ketoconazole or rifampicin or by coadministration with ethinyloestradiol/levonorgestrel. The incidence of adverse events increased with coadministration of simvastatin or nifedipine compared to either repaglinide or simvastatin/nifedipine treatment alone. No clinically relevant pharmacokinetic interactions occurred between repaglinide and the CYP3A4 substrates ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. The pharmacokinetic profile of repaglinide was altered by administration of potent inhibitors or inducers, such as ketoconazole or rifampicin, but to a lesser degree than expected. These results are probably explained by the metabolic pathway of repaglinide that involves other enzymes than CYP3A4, reflected to some extent by a small change in repaglinide pharmacodynamics. Thus, careful monitoring of blood glucose in repaglinide-treated patients receiving strong inhibitors or inducers of CYP3A4 is recommended, and an increase in repaglinide dose may be necessary. No safety concerns were observed, except a higher incidence in adverse events in patients receiving repaglinide and simvastatin or nifedipine. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Adult_MeSH M_Area_Under_Curve_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH P_Carbamates_MeSH S_blood_MeSH Carbamates_blood_MeSH S_pharmacokinetics_MeSH Carbamates_pharmacokinetics_MeSH S_pharmacology_MeSH Carbamates_pharmacology_MeSH M_Cytochrome_P-450_Enzyme_System_MeSH S_drug_effects_MeSH Cytochrome_P-450_Enzyme_System_drug_effects_MeSH S_metabolism_MeSH Cytochrome_P-450_Enzyme_System_metabolism_MeSH P_Drug_Interactions_MeSH M_Female_MeSH M_Half-Life_MeSH M_Human_MeSH P_Hypoglycemic_Agents_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Ketoconazole_MeSH S_pharmacology_MeSH Ketoconazole_pharmacology_MeSH M_Male_MeSH P_Piperidines_MeSH S_blood_MeSH Piperidines_blood_MeSH S_pharmacokinetics_MeSH Piperidines_pharmacokinetics_MeSH S_pharmacology_MeSH Piperidines_pharmacology_MeSH M_Rifampin_MeSH S_pharmacology_MeSH Rifampin_pharmacology_MeSH M_Simvastatin_MeSH S_pharmacology_MeSH Simvastatin_pharmacology_MeSH M_Support__Non-U_S__Gov't_MeSH ****** 12822388 ----K E ----T [Glimepiride--an oral antidiabetic agent] ----A Glimepiride is the oral antidiabetic, second-generation sulfonylurea. It is structurally similar to glyburide. Glimepiride exhibited more potent glucose-lowering effects than glyburide and longer duration of hypoglycemic effect. Glimepiride is useful in the treatment of non-insulin-dependent (type II) diabetes mellitus. Glimepiride is indicated as an adjunct to diet and exercise for non-insulin dependent diabetes mellitus. Glimepiride reduces glucose levels blood by stimulating insulin release from functional pancreatic beta cells in response to glucose. Glimepiride in daily dose 1 to 8 mg is causing a dose-related decrease blood glucose levels and glycosylated hemoglobin fasting state and postprandially. If the maximum dose of glimepiride fails to lower blood glucose sufficiently, metformine or insuline may be added to glimepiride monotherapy. Glimepiride is very safe drug and adverse effects causing by glimepiride are very rare. The risk of hypoglycemia after use of glimepiride is very small, therefore is the therapy with glimepiride is more preferable than the therapy with glibenclamide. ----P Journal_Article Review Review__Tutorial ----M M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_English_Abstract_MeSH M_Human_MeSH P_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH P_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH S_pharmacokinetics_MeSH Sulfonylurea_Compounds_pharmacokinetics_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH ****** 12828829 ----K E ----T Inadvertent sulfonylurea overdosage and hypoglycemia in an elderly woman: failure of serum hypoglycemia screening. ----A We report a case of an 82 year-old woman who had two episodes of documented hypoglycemia. Initial laboratory testing revealed hyperinsulinemia and a negative serum sulfonylurea screen. While these data suggested the presence of an insulinoma, further evaluation of the case revealed inadvertent ingestion of glimepiride, a sulfonylurea not included in the standard serum sulfonylurea screen. ----P Case_Reports Comment Journal_Article ----M M_Aged_MeSH M_Aged__80_and_over_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_C-Peptide_MeSH S_blood_MeSH C-Peptide_blood_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemia_MeSH S_chemically_induced_MeSH Hypoglycemia_chemically_induced_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Insulin_MeSH S_blood_MeSH Insulin_blood_MeSH P_Overdose_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH ****** 12828830 ----K E ----T A flaw in the use of sulfonylurea screening to diagnose sulfonylurea overdosages. ----A ----P Journal_Article ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH P_Overdose_MeSH S_diagnosis_MeSH Overdose_diagnosis_MeSH M_Reproducibility_of_Results_MeSH M_Sulfonylurea_Compounds_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH ****** 12852703 ----K I ----T Glimepiride in type 2 diabetes mellitus: a review of the worldwide therapeutic experience. ----A BACKGROUND: Sulfonylureas (SUs) have been used for many years as first-line therapy for patients with type 2 diabetes mellitus whose blood glucose levels have not been effectively controlled by diet and exercise alone. Glimepiride is a once-daily SU that was introduced in 1995. Since then, a considerable body of evidence has been amassed regarding its use in type 2 diabetes. OBJECTIVE: This review provides a comprehensive summary of available data on the pharmacology, pharmacokinetics, efficacy, and safety profile of glimepiride in the treatment of type 2 diabetes. It also examines the use of glimepiride to achieve and maintain good glycemic control in patients with type 2 diabetes in current clinical practice. METHODS: Relevant articles were identified through a search of MEDLINE for English-language studies published from 1990 to 2002. The search terms used were glimepiride, sulfonylureas, and type 2 diabetes mellitus. The manufacturer of glimepiride provided additional information. RESULTS: Glimepiride differs from other SUs in a number of respects. In clinical studies, glimepiride was generally associated with a lower risk of hypoglycemia and less weight gain than other SUs. Results of other studies suggest that glimepiride can be used in older patients and those with renal compromise. There is evidence that glimepiride preserves myocardial preconditioning, a protective mechanism that limits damage in the event of an ischemic event. Glimepiride can be used in combination with other oral antidiabetic agents or insulin to optimize glycemic control. CONCLUSION: Based on the evidence to date, glimepiride is an effective and well-tolerated once-daily antidiabetic drug and provides an important treatment option for the management of type 2 diabetes. ----P Journal_Article Review Review__Tutorial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Clinical_Trials_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Sulfonylurea_Compounds_MeSH S_therapeutic_use_MeSH Sulfonylurea_Compounds_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH M_World_Health_MeSH ****** 12852706 ----K I ----T Multicenter, randomized, double-masked, parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulfonylurea. ----A BACKGROUND: Many patients with type 2 diabetes mellitus (DM) with inadequate long-term blood glucose control with sulfonylurea or metformin monotherapy require additional treatment. The synergistic effects of combining glipizide with metformin on glucose control may be realized by treating the primary effects of type 2 DM, impaired insulin secretion, and insulin resistance. OBJECTIVE: This study assessed therapy with glipizide/metformin combination tablets in patients with type 2 DM that is uncontrolled by at least half the maximum labeled daily dose of a sulfonylurea. METHODS: In this multicenter, double-masked, parallel-group, active-controlled study, patients were randomized to receive glipizide 30-mg, metformin 500-mg, or glipizide/metformin 5/500 mg tablets for 18 weeks (metformin and glipizide/metformin doses were titrated to achieve blood glucose control). Maximum total daily doses were glipizide 30 mg, metformin 2000 mg, and glipizide/ metformin 20/2000 mg. RESULTS: A total of 247 patients were included in the study. The mean (SD) age was 56.2 (10.1) years; 61.5% of patients were male; 70.0% were white, 15.8% were Hispanic/Latino, 13.0% were black, and 1.2% were Asian/Pacific Islanders. Patients were, on average, obese (mean [SD] body mass index, 31.3 [4.7] kg/m2), had moderate to severe hyperglycemia (mean [SD] glycated hemoglobin [HbA1c], 8.7% [1.1]), and had a mean (SD) DM duration of 6.5 (4.9) years. Glipizide/ metformin tablets controlled the HbA1c level more effectively than did either glipizide or metformin monotherapies (mean treatment differences, in favor of glipizide/ metformin, of -1.06% and -0.98%, respectively, P < 0.001). At study end, an HbA1c level < 7.0% was achieved in approximately 4-fold more patients who were treated with glipizide/metformin (36.3%) compared with glipizide (8.9%) or metformin (9.9%) monotherapies. Glipizide/metformin tablets also reduced the fasting plasma glucose (FPG) level and the 3-hour postprandial glucose area under the concentration-time curve more effectively than did either monotherapy, without increasing the fasting insulin level. The greater blood glucose control with glipizide/ metformin tablets was achieved at a mean daily dose of glipizide/metformin 17.5/1747 mg, compared with mean doses of glipizide 30.0 mg or metformin 1927 mg. Treatments were well tolerated, with a low incidence of symptoms of hypoglycemia evidenced by a fingerstick blood glucose measurement < or = 50 mg/dL in the combination group (12.6%); 1 patient discontinued the study treatment for this reason. No patient required medical assistance for hypoglycemia. CONCLUSIONS: Glipizide/metformin tablets were more effective than either glipizide or metformin monotherapy in controlling HbA1c and in reducing FPG compared with baseline in patients with blood glucose that was uncontrolled with previous sulfonylurea treatment. In addition, patients receiving glipizide/ metformin were more likely to achieve an HbA1c level < 7.0%. These results were consistent with the synergistic effects on insulin resistance and beta cell dysfunction. Glipizide/metformin was well tolerated, with a low incidence of hypoglycemia. ----P Clinical_Trial Journal_Article Multicenter_Study Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Double-Blind_Method_MeSH M_Drug_Therapy__Combination_MeSH M_Fasting_MeSH S_blood_MeSH Fasting_blood_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH ****** 12859222 ----K 5 ----T Economic model of first-line drug strategies to achieve recommended glycaemic control in newly diagnosed type 2 diabetes mellitus. ----A OBJECTIVE: To assess the short-term direct medical costs and effectiveness associated with achieving recommended glycaemic goals using commonly prescribed first-line oral antihyperglycaemic medications in type 2 diabetes mellitus. MATERIALS AND METHODS: A literature-based, decision-tree model was developed to project the number of patients achieving glycosylated haemoglobin values of <7% on oral therapies and the associated costs over a 3-year timeframe. For each first-line strategy, patients could progress to combination therapy using two or more agents prior to the introduction of insulin. The overall cost of treatment included costs (2001/2002 values; US dollars) of comprehensive medical care, laboratory tests, patient education, drug therapy, home glucose monitoring and adverse events. RESULTS: At 3 years, the overall cost of treatment for the various first-line strategies was 6,106 US dollars for glipizide gastrointestinal therapeutic system, 6,727 US dollars for metformin immediate release, 6,826 US dollars for metformin extended release, 7,141 US dollars for glibenclamide (glyburide)/metformin, 7,759 US dollars for rosiglitazone and 9,298 US dollars for repaglinide. Costs of comprehensive routine medical care ranged from approximately 1,538-2,128 US dollars in year 1 and from approximately 952-1,543 US dollars in subsequent years, for controlled and uncontrolled patients, respectively. Adverse events represented <1%, and drug therapies represented approximately 50%, of the overall cost, respectively. Substantial cost differences between the strategies were seen within the first year. Regardless of first-line therapy, patients progressed quickly to combination therapies, with effectiveness among the agents being similar. CONCLUSIONS: Short-term costs required to provide comprehensive diabetes care and achieve glycemic goals can be substantial. The model suggests a sulphonylurea strategy may provide similar effectiveness with cost savings over other agents and should be considered when selecting an initial drug therapy in newly diagnosed patients with type 2 diabetes mellitus. ----P Journal_Article ----M M_Carbamates_MeSH S_economics_MeSH Carbamates_economics_MeSH S_therapeutic_use_MeSH Carbamates_therapeutic_use_MeSH M_Cohort_Studies_MeSH M_Decision_Trees_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_economics_MeSH Diabetes_Mellitus__Type_II_economics_MeSH S_prevention_&_control_MeSH Diabetes_Mellitus__Type_II_prevention_&_control_MeSH M_Direct_Service_Costs_MeSH S_statistics_&_numerical_data_MeSH Direct_Service_Costs_statistics_&_numerical_data_MeSH M_Drug_Costs_MeSH S_statistics_&_numerical_data_MeSH Drug_Costs_statistics_&_numerical_data_MeSH M_Drug_Therapy__Combination_MeSH M_Glipizide_MeSH S_economics_MeSH Glipizide_economics_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_economics_MeSH Glyburide_economics_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_drug_effects_MeSH Hemoglobin_A__Glycosylated_drug_effects_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_classification_MeSH Hypoglycemic_Agents_classification_MeSH S_economics_MeSH Hypoglycemic_Agents_economics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Managed_Care_Programs_MeSH S_economics_MeSH Managed_Care_Programs_economics_MeSH S_utilization_MeSH Managed_Care_Programs_utilization_MeSH M_Markov_Chains_MeSH M_Metformin_MeSH S_economics_MeSH Metformin_economics_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH P_Models__Economic_MeSH M_Piperidines_MeSH S_economics_MeSH Piperidines_economics_MeSH S_therapeutic_use_MeSH Piperidines_therapeutic_use_MeSH M_Support__Non-U_S__Gov't_MeSH M_Thiazoles_MeSH S_economics_MeSH Thiazoles_economics_MeSH S_therapeutic_use_MeSH Thiazoles_therapeutic_use_MeSH P_Thiazolidinediones_MeSH M_United_States_MeSH ****** 12882864 ----K 3 ----T Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. ----A OBJECTIVE: AC2993 (synthetic exendin-4; exenatide) is a peptide that enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. AC2993 also promotes beta-cell proliferation and neogenesis in vitro and in animal models. This study examines the activity and safety of subcutaneously injected AC2993 in patients with type 2 diabetes currently treated with diet and/or oral antidiabetic agents (OAAs). RESEARCH DESIGN AND METHODS: A total of 109 patients treated with diet and a sulfonylurea and/or metformin were enrolled in a blinded study. Patients were randomly assigned to one of three subcutaneously (SC) injected regimens of AC2993 (0.08 micro g/kg) or placebo for 28 days. RESULTS: All three AC2993 regimens led to significant reductions in serum fructosamine relative to placebo (P <or= 0.004). Mean reductions ranged from 39 to 46 micro mol/l. All AC2993 groups had reductions in HbA(1c) ranging from 0.7 to 1.1% (P <or= 0.006). An end-of-study HbA(1c) <7% was achieved by 15% of AC2993 patients versus 4% of placebo patients, confirming AC2993 effects on fasting and postprandial glycemia. On days 14 and 28, the beta-cell index (homeostasis model assessment) for patients treated with AC2993 was 50-100% higher than baseline, contrasting with unchanged levels for placebo. The most common adverse event was transient mild-to-moderate nausea. CONCLUSIONS: AC2993 is a promising therapeutic for patients with type 2 diabetes. In this study, it had significant effects on HbA(1c) levels in patients not currently achieving optimal glucose control with diet and/or OAAs. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Blood_Pressure_MeSH M_Body_Weight_MeSH S_drug_effects_MeSH Body_Weight_drug_effects_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Fructosamine_MeSH S_blood_MeSH Fructosamine_blood_MeSH M_Heart_Rate_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Islets_of_Langerhans_MeSH S_drug_effects_MeSH Islets_of_Langerhans_drug_effects_MeSH S_physiology_MeSH Islets_of_Langerhans_physiology_MeSH M_Lipids_MeSH S_blood_MeSH Lipids_blood_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_adverse_effects_MeSH Metformin_adverse_effects_MeSH M_Middle_Aged_MeSH M_Peptides_MeSH S_administration_&_dosage_MeSH Peptides_administration_&_dosage_MeSH S_adverse_effects_MeSH Peptides_adverse_effects_MeSH S_pharmacokinetics_MeSH Peptides_pharmacokinetics_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_adverse_effects_MeSH Sulfonylurea_Compounds_adverse_effects_MeSH M_Support__Non-U_S__Gov't_MeSH M_Treatment_Outcome_MeSH ****** 12918894 ----K I ----T Nateglinide (Starlix): update on a new antidiabetic agent. ----A Nateglinide is a new oral antidiabetic agent that stimulates insulin release promptly after its pre-meal administration in a strongly glucose-dependent fashion. Because its insulinotropic effects are short in duration, nateglinide specifically targets postprandial hyperglycaemia with a low potential to elicit hypoglycaemia or sustained hyperinsulinaemia. Nateglinide has an excellent safety and tolerability profile, and its efficacy in reducing HbA1c in monotherapy (120 mg before meals) is comparable to that of metformin, sulphonylureas, thiazolidinediones or acarbose (-0.5 to -1.5%). When combined with metformin, which primarily reduces fasting glucose levels, nateglinide's effects are additive. In our clinical experience, nateglinide is a particularly good therapeutic option in newly diagnosed, treatment-naive patients; elderly patients in whom hypoglycaemia is a concern; patients with kidney failure or mild hepatic impairment; patients taking low-dose sulphonylureas who encounter problems with hypoglycaemia; and patients failing to achieve adequate glycaemic control on metformin or thiazolidinedione monotherapy. ----P Journal_Article Review Review__Tutorial ----M M_Blood_Glucose_MeSH S_physiology_MeSH Blood_Glucose_physiology_MeSH M_Cyclohexanes_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH S_therapeutic_use_MeSH Cyclohexanes_therapeutic_use_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Human_MeSH M_Hyperglycemia_MeSH S_complications_MeSH Hyperglycemia_complications_MeSH S_drug_therapy_MeSH Hyperglycemia_drug_therapy_MeSH M_Hypoglycemic_Agents_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Phenylalanine_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH S_therapeutic_use_MeSH Phenylalanine_therapeutic_use_MeSH M_Treatment_Outcome_MeSH ****** 12974145 ----K 3 ----T Lispro insulin and metformin versus other combination in the diabetes mellitus type 2 management after secondary oral antidiabetic drug failure. ----A The purpose of the study was to find out differences between treatments of diabetes type 2 after secondary oral antidiabetic drug failure. Three different methods of treatment were compared: lispro insulin in combination with metformin, glimepiride and metformin combination or two daily doses of biphasic insulin 30/70 together with bed-time NPH insulin. The study included 87 patients with diabetes mellitus type 2 randomly distributed into 3 different treatment groups. Fasting and postprandial glucose were analyzed by enzymatic colorimetric method and HbA1c was measured by ion exchange chromatography. HbA1c significantly decreased in all three study groups. The decrease was mostly expressed among patients treated with lispro and metformin. When focused on postprandial glucose control, antihyperglycemic metformin and insulin lispro therapy has greater impact on the overall metabolic control (decrease in level of HbA1c) in comparison with the above mentioned more traditional approaches. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_analysis_MeSH Blood_Glucose_analysis_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_pharmacology_MeSH Hypoglycemic_Agents_pharmacology_MeSH M_Insulin_MeSH S_administration_&_dosage_MeSH Insulin_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_pharmacology_MeSH Metformin_pharmacology_MeSH M_Middle_Aged_MeSH M_Postprandial_Period_MeSH M_Sulfonylurea_Compounds_MeSH S_administration_&_dosage_MeSH Sulfonylurea_Compounds_administration_&_dosage_MeSH S_pharmacology_MeSH Sulfonylurea_Compounds_pharmacology_MeSH M_Treatment_Outcome_MeSH ****** 12685221 ----K E ----T Insulin analogues. A critical review. ----A Multiple and important technological innovations in the field of insulin therapy have appeared in the last decade. Insulin analogues with novel pharmacokinetics have been developed. The first of these analogues to appear in the market was insulin lispro. We believe that the most part of the stu-dies carried out with this molecule in comparison with regular insulin were unfair as long as its short duration of action was ignored, since in many of these studies it was administered with meals and with only one dose of intermediate insulin given at night. Several studies done mainly by Italian investigators have proven this concept being true in studies with adequate baseline insulin coverage. Insulin aspart has appeared recently in the market in the United States with very similar effects to lispro. The FDA has recently approved a new ultralong acting analogue. The main advantages are its long, peakless action with better effects during down hours and a lower incidence of hypoglycaemia. We also review other approaches with novel insulin molecules attached to thyroxin or fatty acids in order to create a bridge for binding to plasmatic proteins. These molecules have longer effects and some of them more selective sites of action. Finally we included a brief review of other routes of insulin administration. ----P Journal_Article Review Review__Academic ----M M_Diabetes_Mellitus_MeSH S_drug_therapy_MeSH Diabetes_Mellitus_drug_therapy_MeSH M_Human_MeSH M_Insulin_MeSH S_analogs_&_derivatives_MeSH Insulin_analogs_&_derivatives_MeSH S_pharmacology_MeSH Insulin_pharmacology_MeSH S_therapeutic_use_MeSH Insulin_therapeutic_use_MeSH ****** 12885108 ----K 3 ----T Possible heart failure exacerbation associated with rosiglitazone: case report and literature review. ----A Increasing evidence suggests that neurohumoral manifestations of heart failure may lead to insulin resistance, predisposing patients with heart failure to the development of glucose intolerance or worsening of existing diabetes. Theoretically, insulin-sensitizing thiazolidinediones (TZDs) should be beneficial in this patient population. A 74-year-old man with well-compensated systolic dysfunction and longstanding type 2 diabetes mellitus treated with glyburide began therapy with rosiglitazone 4 mg/day, which was increased to 8 mg/day after 1 month. Two weeks later he was seen with a 5-kg weight gain, shortness of breath, bibasilar rales, +S3 gallop, and increased jugular venous distention. Twelve days later symptoms worsened, with pulmonary edema on chest radiograph, continued weight gain, and +4 pitting edema resistant to oral diuretics. The patient was admitted to the hospital for exacerbation of heart failure. Five days after discharge he was readmitted for similar symptoms, including an 11.8-kg weight gain. He reported adherence to drug therapy and diet. Rosiglitazone was immediately discontinued and 11 days later the man's weight stabilized to 79 kg and remained between 79 and 80 kg 2 and 3 months after discharge. This case demonstrates that TZDs may precipitate weight gain and pulmonary and peripheral edema in patients with stable heart failure. Earlier reports documented similar symptoms in patients without a history of heart failure. Although current recommendations state that TZDs should not be administered to patients with New York Heart Association class III or IV disease, practitioners should be aware that these adverse effects also may occur in patients with milder forms heart failure as well as those without heart failure. ----P Case_Reports Journal_Article Review Review__Tutorial ----M M_Aged_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Heart_Failure__Congestive_MeSH S_chemically_induced_MeSH Heart_Failure__Congestive_chemically_induced_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_adverse_effects_MeSH Hypoglycemic_Agents_adverse_effects_MeSH M_Male_MeSH M_Thiazolidinediones_MeSH S_adverse_effects_MeSH Thiazolidinediones_adverse_effects_MeSH ****** 12940610 ----K 6 ----T Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure. ----A AIMS: We evaluated the benefits and safety of nateglinide, a novel oral hypoglycemic agent, in type 2 diabetes patients with renal failure. METHODS: Single-dose pharmacokinetics were studied in 8 patients with type 2 diabetes and a low creatinine clearance (range 1.8-16.5 ml/min/1.73 m2) up to 6 hours after 90 mg nateglinide administration. Next, we treated another group of 8 patients undergoing regular hemodialysis with nateglinide 90 mg/day for 1-3 months. The effect of hemodialysis on metabolite accumulation was then tested. RESULTS: After a single 90 mg dose, nateglinide significantly increased the post-prandial secretion of insulin and thereby reduced plasma glucose levels. Mean pharmacokinetic parameters (AUC(0-6) 10.45 mg/l/h; t(1/2) 1.89 h, Cl/F 10.19 l/h) were comparable with those reported in healthy subjects. A much larger AUC value than those previously reported of M1, a major metabolite in the urine of healthy subjects, was observed, and the plasma concentration of M1 did not decline up to 6 hours after. In patients treated on a regular basis, there was marked accumulation of M1, while nateglinide could not be detected 24 hours after the last dose. Plasma M1 levels were significantly reduced by the hemodialysis sessions. CONCLUSIONS: Single 90 mg dose of nateglinide was safe and effective in patients with renal failure. However, repeated administrations could cause prolonged hypoglycemia due to accumulation of M1, which is known to have a modest hypoglycemic activity. Hemodialysis may help to eliminate excessive accumulation of M1. ----P Clinical_Trial Journal_Article ----M M_Adult_MeSH M_Aged_MeSH M_Aged__80_and_over_MeSH M_Area_Under_Curve_MeSH M_Cyclohexanes_MeSH S_administration_&_dosage_MeSH Cyclohexanes_administration_&_dosage_MeSH S_blood_MeSH Cyclohexanes_blood_MeSH S_pharmacokinetics_MeSH Cyclohexanes_pharmacokinetics_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_blood_MeSH Diabetes_Mellitus__Type_II_blood_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH M_Dose-Response_Relationship__Drug_MeSH M_Female_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_blood_MeSH Hypoglycemic_Agents_blood_MeSH S_pharmacokinetics_MeSH Hypoglycemic_Agents_pharmacokinetics_MeSH M_Kidney_Failure_MeSH S_blood_MeSH Kidney_Failure_blood_MeSH S_complications_MeSH Kidney_Failure_complications_MeSH M_Male_MeSH M_Middle_Aged_MeSH M_Phenylalanine_MeSH S_administration_&_dosage_MeSH Phenylalanine_administration_&_dosage_MeSH S_analogs_&_derivatives_MeSH Phenylalanine_analogs_&_derivatives_MeSH S_blood_MeSH Phenylalanine_blood_MeSH S_pharmacokinetics_MeSH Phenylalanine_pharmacokinetics_MeSH M_Time_Factors_MeSH ****** 14526261 ----K 5 ----T Cardiovascular risk in type 2 diabetics and pharmacological regulation of mealtime glucose excursions. ----A In type 2 diabetic patients mealtime glucose fluctuations are important determinants of overall glucose control and overall risk of diabetes cardiovascular complications. In fact, acute elevation of plasma glucose concentrations trigger an array of tissue response that may contribute to development of such vascular complications since it may result in a thrombophilic condition, causes endothelial dysfunction (possibly through a reduction of nitric oxide availability) and is responsible for non-enzymatic glycation and production of free- radicals with ensuing oxidative stress. To keep post-prandial glucose with narrow range, metiglinide analogues drugs have been developed. In particular, repaglinide and nateglinide seem the most useful ones. In fact, both drugs improve 1(st) phase insulin release but they do not affect the total daily amount of insulin released by the pancreas. Due to the mechanism of action and to pharmacokinetic properties, repaglinide and nateglinide allow diabetic patients to get a more tight metabolic glucose control with a contemporary reduction in the cases of severe hypoglycaemia. In conclusions, repaglinide and nateglinide are new and powerful pharmacological tools not only for achieving a better metabolic glucose control but also for preventing the development of diabetes-related cardiovascular complications. ----P Journal_Article Review Review__Tutorial ----M M_Administration__Oral_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH S_metabolism_MeSH Blood_Glucose_metabolism_MeSH M_Cardiovascular_Diseases_MeSH S_epidemiology_MeSH Cardiovascular_Diseases_epidemiology_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_complications_MeSH Diabetes_Mellitus__Type_II_complications_MeSH M_Diabetic_Angiopathies_MeSH S_epidemiology_MeSH Diabetic_Angiopathies_epidemiology_MeSH P_Eating_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Postprandial_Period_MeSH M_Risk_Factors_MeSH ****** 14613469 ----K 3 ----T Improvements in glycemic control in type 2 diabetes patients switched from sulfonylurea coadministered with metformin to glyburide-metformin tablets. ----A OBJECTIVE: To evaluate the change in hemoglobin A1C (A1C) in patients with type 2 diabetes switched from coadministration of a sulfonylurea (SU), glyburide or glipizide, and metformin (SU+Met) to a single glyburide-metformin tablet. METHODS: A retrospective cohort study design of patients with type 2 diabetes treated at 3 Veterans Affairs Medical Centers and 1 Department of Defense Medical Center was utilized. One hundred percent of patients receiving glyburide-metformin tablets were screened for inclusion. Patients with at least 6 months of prior SU+Met combination therapy and a baseline A1C measured within 35 days prior to or 3 days after switch to glyburide-metformin tablets were included. At least one documented follow-up A1C at >or=90 days after the switch to glyburide-metformin was required for inclusion. Glycemic control, complications, lipid parameters, concomitant medications, and weight were analyzed prior to and following the switch to glyburide-metformin. RESULTS: Seventy-two patient records were included after the disqualification criteria excluded 488 prospective patients. The mean age of the 72 patients was 62 years; average body mass index was 32.9 kg/m2, average baseline A1C was 8.3%, and the average time since diagnosis was 7.6 years. The mean reduction in A1C was 0.6% (P=0.002) at a mean follow-up of 196 days after the switch to glyburide-metformin tablets. Improvement in glycemic control was predominantly seen in patients with a baseline A1C >or=8% in whom a 1.3% mean reduction in A1C (P=0.0002) was achieved despite a lower mean final dose of glyburide. CONCLUSION: The results of this study suggest that in type 2 diabetic patients with an A1C >or=8%, switching from coadministration of a sulfonylurea plus metformin to combination glyburide-metformin tablets may provide an improvement in glycemic control in the range of a 1.2 to 1.4 absolute percentage point decrease in A1C. A randomized, prospective trial comparing these 2 methods of treatment is needed, however, to determine the precise effect provided by the unique formulation of glyburide in the glyburide-metformin tablet. ----P Clinical_Trial Journal_Article Randomized_Controlled_Trial ----M M_Administration__Oral_MeSH M_Adult_MeSH M_Aged_MeSH M_Blood_Glucose_MeSH S_drug_effects_MeSH Blood_Glucose_drug_effects_MeSH M_Comorbidity_MeSH M_Comparative_Study_MeSH M_Diabetes_Mellitus__Type_II_MeSH S_drug_therapy_MeSH Diabetes_Mellitus__Type_II_drug_therapy_MeSH S_epidemiology_MeSH Diabetes_Mellitus__Type_II_epidemiology_MeSH M_Drug_Combinations_MeSH M_Drug_Therapy__Combination_MeSH M_Female_MeSH M_Glipizide_MeSH S_administration_&_dosage_MeSH Glipizide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glipizide_therapeutic_use_MeSH M_Glyburide_MeSH S_administration_&_dosage_MeSH Glyburide_administration_&_dosage_MeSH S_therapeutic_use_MeSH Glyburide_therapeutic_use_MeSH M_Hemoglobin_A__Glycosylated_MeSH S_analysis_MeSH Hemoglobin_A__Glycosylated_analysis_MeSH M_Human_MeSH M_Hypoglycemic_Agents_MeSH S_administration_&_dosage_MeSH Hypoglycemic_Agents_administration_&_dosage_MeSH S_therapeutic_use_MeSH Hypoglycemic_Agents_therapeutic_use_MeSH M_Male_MeSH M_Metformin_MeSH S_administration_&_dosage_MeSH Metformin_administration_&_dosage_MeSH S_therapeutic_use_MeSH Metformin_therapeutic_use_MeSH M_Middle_Aged_MeSH M_Obesity_MeSH S_epidemiology_MeSH Obesity_epidemiology_MeSH M_Prospective_Studies_MeSH M_Retrospective_Studies_MeSH M_Support__Non-U_S__Gov't_MeSH