Pioglitazone (AD-4833) Ameliorates Insulin Resistance in Patients with NIDDM

Abstract

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 μmoles·kg⁻¹·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·kg⁻¹·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 A_1C 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 (ρ=0.633), serum insulin (ρ=0.653), BMI (ρ=0.456), Rd (ρ=−0.558) and 1,5-AG (ρ=−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.