To evaluate the effects of glimepiride on insulin action in peripheral tissues, we investigated insulin-induced glucose uptake in normal and diabetic rats using the euglycemic clamp procedure (insulin infusion rates: 6 and 30 mU/kg/min). Normal rats: After oral administration of glimepiride (0.1 mg/kg/day; NG) or saline (NC) for 2 weeks, euglycemic clamp procedures were performed. During submaximal hyperinsulinemia (620 +/- 35 pmol/l, mean +/- S.E.M.), metabolic clearance rates of glucose (MCR) in NG were significantly higher than in NC (25.1 +/- 2.1 vs. 18.3 +/- 1.2 ml/kg/min, P < 0.05). During maximal hyperinsulinemia (5235 +/- 270 pmol/l), MCRs in NG were higher than in NC, but there was no statistical significance (43.3 +/- 2.8 and 38.9 +/- 2.8). Diabetic rats: streptozotocin-induced diabetic rats were divided into four groups, GI (glimepiride treatment, 0.1 mg/kg/day p.o., with insulin, 5 U/day s.c.), SI (insulin alone), SG (glimepiride alone), and SC (saline). MCRs in the four groups were similar during 6 mU/kg/min clamps. During 30 mU/kg/min clamps, MCRs in GI were significantly higher than those in SC, SG or SI (23.4 +/- 2.8 vs. 12.2 +/- 1.9 and 8.9 +/- 0.8, P < 0.01, and vs. 17.4 +/- 1.5, P < 0.05). Although MCRs in SI tended to be higher than in SC, there was no significant statistical difference between these two groups. These results suggest that glimepiride enhances insulin action in peripheral tissues, and that glimepiride treatment with insulin improves the insulin resistance observed in streptozotocin-induced diabetic rats.