Sulfonylurea is known to lower glucose levels by stimulating pancreatic insulin secretion. Glimepiride, a new agent of sulfonylurea, is unique in that the glucose-lowering efficacy is similar but the ability to stimulate insulin secretion is lower in comparison with conventional sulfonylureas such as glibenclamide, glipizide, and gliclazide (1). Thus, glimepiride is hypothesized to have greater extrapancreatic effect, such as an improvement in insulin resistance (1). The previous report by Muller et al. (1) supports the hypothesis that insulin-resistant diabetic KK-Ay mice can be well controlled by glimepiride, but not by glibenclamide and gliclazide. Glimepiride is reported to increase insulin-stimulated glycogen synthesis in cultured human skeletal muscle cells. Very recently, Tsunekawa et al. (2) clearly demonstrated that glimepiride actually increases insulin sensitivity in type 2 diabetic patients. They also proposed that the increase in insulin sensitivity might be associated with increased adiponectinemia. Here we report our data regarding the effects of glimepiride on insulinemia, insulin sensitivity, and serum adiponectin levels in type 2 diabetic subjects. In addition, the effects of glimepiride are compared with those achieved by metformin, which has been proven to have little effect on body weight during glycemic control.

A total of 28 Japanese patients with type 2 diabetes (19 men and 9 women, aged 59 ± 2 years [mean ± SE], BMI 26.5 ± 0.8 kg/m2) were investigated before and after treatment with glimepiride. The treatment duration was 3 months, and the daily dose of glimepiride was 1.9 ± 0.2 mg (range 1.0–3.0). Changes in indices were analyzed by Wilcoxon’s sign-rank test. After the treatment, fasting plasma glucose (166 ± 7 vs. 147 ± 7 mg/dl, P = 0.009) and HbA1c (7.9 ± 0.3 vs. 7.4 ± 0.2%, P = 0.006) levels fell significantly. Both fasting insulin (11.7 ± 1.5 vs. 9.4 ± 1.0 μU/ml, P = 0.007) and homeostasis model assessment for insulin resistance (HOMA-IR) (3) (5.0 ± 0.8 vs. 3.8 ± 0.6, P = 0.005) decreased, suggesting an amelioration of insulin resistance. Serum adiponectin concentration, measured by Linco RIA kits (St. Charles, MO), increased significantly (22.1 ± 2.7 vs. 28.5 ± 2.8 μg/ml, +29%, P = 0.015), whereas no significant change was observed in BMI (26.5 ± 0.9 vs. 26.5 ± 0.8 kg/m2, P = 0.748). There was also no change in serum concentrations of total (214 ± 6 vs. 210 ± 6 mg/dl, P = 0.125) and HDL (54 ± 3 vs. 53 ± 3 mg/dl, P = 0.438) cholesterol and triglyceride (123 ± 10 vs. 120 ± 10 mg/dl, P = 0.387) before and after the treatment.

In a separate group of type 2 diabetic patients matched with the glimepiride group for sex, age, BMI, glycemia, and insulinemia (seven men and five women, aged 58 ± 3 years, and BMI 25.7 ± 0.7 kg/m2), the effect of metformin (daily dose 750 mg) was evaluated. Three months of the metformin treatment also decreased both fasting glucose (159 ± 4 to 135 ± 4 mg/dl, P = 0.006) and HbA1c (7.9 ± 0.2 to 7.1 ± 0.2%, P = 0.013) levels. In contrast to the glimepiride treatment, fasting insulin (12.4 ± 2.0 vs. 13.8 ± 4.3 μU/ml, P = 0.689) and HOMA-IR (4.8 ± 0.7 vs. 4.1 ± 1.0, P = 0.695) remained unchanged, whereas serum adiponectin concentration was increased slightly but significantly (18.7 ± 3.0 vs. 20.6 ± 3.3 μg/ml, +10%, P = 0.034). No significant change was observed in BMI and serum lipid concentrations (data not shown).

Our present finding supports the notion that one of the glucose-lowering mechanisms of glimepiride is to improve insulin resistance. In accordance with a recent article (2), the glimepiride treatment increased serum adiponectin levels without affecting BMI. In the present study, serum adiponectin levels were also increased by the treatment of metformin, which, unlike insulin-sensitizing thiazolidinediones, is known to not affect circulating adiponectin concentration (4). Therefore, it seems possible that the increase in adiponectinemia by the glimepiride treatment could be, in part, due to an effect of glycemic control per se. Another difference between the glimepiride and metformin groups is the change in insulinemia; fasting insulin was decreased in the former group and unchanged in the latter. Since insulin seems to suppress expression and secretion of adiponectin in both in vitro and in vivo studies (5,6), the decrease in insulinemia by glimepiride may conversely increase circulating adiponectin concentration.

We agree that the improvement in glycemic control, insulinemia, and adiponectinemia by glimepiride is of potential benefit to decrease risk factors of atherosclerosis in type 2 diabetic patients. The mechanisms of the increased adiponectinemia by glimepiride may be complex and multifactorial. It also remains to be elucidated whether conventional sulfonylureas would increase adiponectinemia in subjects with type 2 diabetes.

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Diabetes Res Clin Pract
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