The Effect of Pioglitazone on the Liver

• Published in: Diabetes care Vol. 29; no. 10; pp. 2275 - 2281
• Main Authors: Gastaldelli, Amalia, Miyazaki, Yoshinori, Mahankali, Archana, Berria, Rachele, Pettiti, Maura, Buzzigoli, Emma, Ferrannini, Eleuterio, DeFronzo, Ralph A.
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01.10.2006
• ISSN: 0149-5992; 1935-5548
• DOI: 10.2337/dc05-2445

The Effect of Pioglitazone on the Liver Role of adiponectin Amalia Gastaldelli , PHD 1 2 , Yoshinori Miyazaki , MD 2 , Archana Mahankali , MD 2 , Rachele Berria , MD 2 , Maura Pettiti , PHD 1 , Emma Buzzigoli , BS 1 , Eleuterio Ferrannini , MD 1 2 and Ralph A. DeFronzo , MD 2 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 Abstract 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- 3 H-glucose infusion), GNG (D 2 O technique), and insulin sensitivity by two-step hyperinsulinemic-euglycemic clamp (240 and 960 pmol/min per m 2 ). 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 ΔFPG ( r = −0.54, P < 0.03), ΔGNG flux ( r = −0.47, P < 0.05), and Δinsulin sensitivity ( r = 0.65, P < 0.005). Plasma free fatty acids decreased after pioglitazone and correlated with ΔGNG 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. 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 Footnotes R.A.D. has been on an advisory board and speakers bureau for and has received grant/research support from Takeda. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact. Accepted June 22, 2006. Received December 13, 2005. DIABETES CARE