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The Effect of Pioglitazone on the Liver

Role of adiponectin

¹ Institute of Clinical Physiology, National Research Council, Pisa, Italy
² Diabetes Division, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas

Address correspondence and reprint requests to Amalia Gastaldelli, PhD, Research Director, Stable Isotope Lab, Institute of Clinical Physiology-CNR, via Moruzzi 1, 56100 Pisa, Italy. E-mail: amalia{at}ifc.cnr.it

OBJECTIVE—Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on the liver is less clear. The goal of this study was to examine the effect of TZDs on GNG.

RESEARCH DESIGN AND METHODS—Twenty sulfonylurea-treated type 2 diabetic subjects were randomly assigned (double-blind study) to receive pioglitazone (PIO group; 45 mg/day) or placebo (Plc group) for 4 months to assess endogenous glucose production (EGP) (3-³H-glucose infusion), GNG (D₂O technique), and insulin sensitivity by two-step hyperinsulinemic-euglycemic clamp (240 and 960 pmol/min per m²).

RESULTS—Fasting plasma glucose (FPG) (10.0 ± 0.8 to 7.7 ± 0.7 mmol/l) and HbA_1c (9.0 ± 0.4 to 7.3 ± 0.6%) decreased in the PIO and increased in Plc group (P < 0.05 PIO vs. Plc). Insulin sensitivity increased 40% during high insulin clamp after pioglitazone (P < 0.01) and remained unchanged in the Plc group (P < 0.05 PIO vs. Plc). EGP did not change, while GNG decreased in the PIO group (9.6 ± 0.7 to 8.7 ± 0.6 µmol · min^–1 · kg_ffm^–1) and increased in the Plc group (8.0 ± 0.5 to 9.6 ± 0.8) (P < 0.05 PIO vs. Plc). Change in FPG correlated with change in GNG flux (r = 0.63, P < 0.003) and in insulin sensitivity (r = 0.59, P < 0.01). Plasma adiponectin increased after pioglitazone (P < 0.001) and correlated with FPG (r = –0.54, P < 0.03), GNG flux (r = –0.47, P < 0.05), and insulin sensitivity (r = 0.65, P < 0.005). Plasma free fatty acids decreased after pioglitazone and correlated with GNG flux (r = 0.54, P < 0.02). From stepwise regression analysis, the strongest determinant of change in FPG was change in GNG flux.

CONCLUSIONS—Pioglitazone improves FPG, primarily by reducing GNG flux in type 2 diabetic subjects.

Abbreviations: EGP, endogenous glucose production • FFA, free fatty acid • FPG, fasting plasma glucose • GNG, gluconeogenesis • OGTT, oral glucose tolerance test • PPAR, peroxisome proliferator–activated receptor • TZD, thiazolidinedione

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