Acute effect of glimepiride on insulin-stimulated glucose metabolism in glucose-tolerant insulin-resistant offspring of patients with type 2 diabetes

OBJECTIVE - This study addressed whether acute infusion of glimepiride influences glucose metabolism independent of its effect on insulin secretion. RESEARCH DESIGN AND METHODS - Ten healthy, glucose-tolerant but insulin-resistant probands were subjected to a placebo-controlled, double-blind, cross-over study. Each individual received infusions of either 0.15 moll saline or glimepiride in randomized order on two separate occasions. A three-step hyperinsulinemic (0.5, 1.0, and 1.5 mU . kg(-1) . min(-1))-euglycemic glucose clamp was performed on both occasions to determine insulin sensitivity. Glimepiride-induced insulin secretion was inhibited by octreotide. Endogenous glucose production and glucose elimination were measured with the hot glucose infusion method using U-[C-13] glucose as tracer. Glucose oxidation was determined from indirect calorimetry. Lipolysis was evaluated by measurements of nonesterified fatty acid (NEFA) and glycerol concentration and measurement of glycerol production. RESULTS - Plasma glucose and insulin concentrations were not significantly different between glimepiride or saline infusions. There was a significant increase in the rate of glucose infusion necessary to maintain euglycemia during infusion of glimepiride during the low (12.2 +/- 1.1 vs. 16.1 +/- 1.7 mumol . kg(-1) . min(-1)) and intermediate-dose insulin infusion (24.4 +/- 1.7 vs. 30.0 +/- 2.8 mumol . kg(-1) . min(-1)). This was explained by an increased rate of glucose elimination and to a lesser degree by a decrease in glucose production. Glucose oxidation rate was not different. NEFA and glycerol concentration and glycerol production were equally suppressed. CONCLUSIONS - Glimepiride improves peripheral glucose uptake and decreases endogenous glucose production independent of its insulin secretagogue action. The effects shown in this acute study are, however, too small to be considered therapeutically beneficial for the individual patient.