Pioglitazone Decreases Fasting and Postprandial Endogenous Glucose Production in Proportion to Decrease in Hepatic Triglyceride Content

OBJECTIVE—Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes. RESEARCH DESIGN AND METHODS—Ten subjects with type 2 diabetes on sulfonylurea therapy were treated with pioglitazone (30 mg daily) for 16 weeks. EGP was measured using a dynamic isotopic methodology after a standard liquid test meal both before and after pioglitazone treatment. Liver and muscle triglyceride levels were measured by (1)H magnetic resonance spectroscopy, and intra-abdominal fat content was measured by magnetic resonance imaging. RESULTS—Pioglitazone treatment reduced mean plasma fasting glucose and mean peak postprandial glucose levels. Fasting EGP decreased after pioglitazone treatment (16.6 ± 1.0 vs. 12.2 ± 0.7 μmol · kg(−1) · min(−1), P = 0.005). Between 80 and 260 min postprandially, EGP was twofold lower on pioglitazone (2.58 ± 0.25 vs. 1.26 ± 0.30 μmol · kg(−1) · min(−1), P < 0.001). Hepatic triglyceride content decreased by ∼50% (P = 0.03), and muscle (anterior tibialis) triglyceride content decreased by ∼55% (P = 0.02). Hepatic triglyceride content was directly correlated with fasting EGP (r = 0.64, P = 0.01) and inversely correlated to percentage suppression of EGP (time 150 min, r = −0.63, P = 0.02). Muscle triglyceride, subcutaneous fat, and visceral fat content were not related to EGP. CONCLUSIONS—Reduction in hepatic triglyceride by pioglitazone is very closely related to improvement in fasting and postprandial EGP in type 2 diabetes.