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The exact mechanism of the efficacy of glimepiride in the achievement of glycemic control has not yet been clearly defined.This study was conducted to examine the influence of glimepiride on insulin secretion and sensitivity in patients with type 2 diabetes mellitus (DM) of recent onset.This 24-week, open-label, controlled trial was conducted at the Division of Endocrinology and Metabolism, Veterans Affairs Medical Center (Phoenix, Arizona). Study participants were aged 32 to 75 years and had recent-onset (established by a short duration of symptoms 6 weeks to 6 months prior to the study) type 2 DM, or were age-matched healthy volunteers (control group). In the diabetic patients, glimepiride tablets were administered orally, initially at 2 mg once daily in the morning, with the dosage increased by 1 mg every 2 weeks until fasting plasma glucose (FPG) decreased to 6.7 mmol/L; the dosage was then maintained for the remainder of the 24-week study period. Oral glucose tolerance tests (OGTTs) were conducted in the control group and before treatment and at 24 weeks after the achievement and maintenance of glycemic control (glycosylated hemoglobin7.0%) in the diabetic group. For OGTT, plasma insulin and glucose levels were determined after the subjects fasted overnight and then at every 15 minutes for 2 hours after glucose challenge.Fourteen diabetic men (mean [SEM] age, 50 [6] years; range, 32-75 years) and 10 male healthy controls (mean [SD] age, 48 [5] years; range, 30-68 years) were enrolled. In the DM group, FPG decreased significantly after treatment ( P0.001); fasting plasma insulin was markedly elevated before treatment (P0.001 vs controls) and decreased after treatment ( P0.01) but did not normalize; first-phase insulin secretion was markedly inhibited before treatment ( P0.001 vs controls) and normalized after treatment ( P0.001) total insulin secretion significantly improved after treatment ( P0.01) but did not normalize. Finally, the pretreatment insulin sensitivity index decreased significantly (P0.01) after treatment and normalized in 6 of 14 patients (42.9%) with type 2 DM.In this study, glimepiride achieved desirable glycemic control in patients with recent-onset type 2 DM through improvement in insulin secretion and sensitivity.