We evaluated the effect of pioglitazone, a thiazolidinedione compound, on insulin-stimulated glucose disposal (Rd) and its efficacy on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM). Twenty NIDDM subjects (mean age 58.2+/-9.4 year, body mass index (BMI) 23.9+/-3.4 kg/ m2 (mean+/-S.D.], three with diet alone, 17 with sulfonylureas [SU]) participated in this trial from five diabetes clinics. Euglycemic (5.3 mmol/liter) hyperinsulinemic (insulin infusion rate 9 micromoles x kg[-1] x min[-1]) clamp studies were performed before and after oral administration of pioglitazone (30 mg/day) for 87+/-10 days. The Rd significantly improved from 5.5+/-2.5 to 8.3+/-3.1 mg x kg(-1) x min(-1). Fasting plasma glucose (FPG) level significantly decreased from 11.0+/-2.0 mmol/liter to 8.9+/-1.1 mmol/liter with a significant improvement in the hemoglobin A1c level from 9.2+/-1.8% to 8.3+/-1.5%. Fasting serum insulin and C peptide levels decreased from 83+/-36 pmol/liter and 0.62+/-0.21 nmol/liter to 66+/-29 pmol/liter and 0.58+/-0.25 nmol/liter, respectively. Fasting serum triglyceride and free fatty acids levels significantly decreased with concomitant increase of fasting serum HDL-cholesterol levels from 1.2+/-0.2 to 1.5+/-0.3 mmol/liter. The change in Rd between before and after pioglitazone administration correlated with baseline values of FPG (rho=0.633), serum insulin (rho=0.653), BMI (rho=0.456), Rd (rho 0.558) and 1,5-AG (rho=-0.522). These data indicate that pioglitazone enhances the insulin action in NIDDM patients on diet alone or SU, and thereby improves both plasma glucose level and lipid profiles.