Metabolic effects of metformin addition to chronic glibenclamide treatment in type 2 diabetes

Abstract

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.