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This version published online on December 13, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1159
A more recent version of this article appeared on March 1, 2006
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Submitted on May 23, 2005
Accepted on December 5, 2005

The effect of Rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes

Amalia Gastaldelli*, Yoshinori Miyazaki, Maura Pettiti, Eleonora Santini, Demetrio Ciociaro, Ralph A DeFronzo, and Ele Ferrannini

Metabolism Unit, C.N.R. Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy; Diabetes Division, University of Texas Health Science Center, San Antonio, Texas, USA

* To whom correspondence should be addressed. E-mail: amalia{at}ifc.cnr.it.

AIMS/HYPOTHESIS: Diabetic hyperglycaemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones (TZD) have been shown to improve glycaemic control and to increase peripheral insulin sensitivity. Whether chronic TZD treatment is associated with a decrease in GNG has not been determined.

Materials and Methods: We studied 26 diet-treated type 2 diabetic patients randomly assigned to rosiglitazone (RSG, 8 mg/day, n = 13) or placebo (n = 13) for 12 weeks. At baseline and 12 weeks, we measured endogenous glucose production (EGP) (by [3H]glucose infusion) and GNG (by the [2H]2O technique) following a 15-hour fast. Peripheral insulin sensitivity was evaluated by a two-step (240 and 960 pmol·min-1·m-2) euglycaemic insulin clamp.

RESULTS: Compared with placebo, RSG reduced fasting plasma glucose (9.7 ± 0.7 to 7.4 ± 0.3 mmol/l, P < 0.001), fasting fractional GNG (-15 ± 4%, P = 0.002) and fasting GNG flux (-3.9 ± 1.2 µmol·min-1·kgffm-1, P = 0.004), with no effect on glycogenolytic flux. Changes in GNG flux and fasting glucose were tightly correlated (r=0.83, P < 0.0001). During both clamp steps, RSG enhanced insulin-mediated glucose clearance (by 26% and 31%, P = 0.01 and P < 0.02, respectively). In a subgroup of patients studied with magnetic resonance imaging, the reduction in GNG flux was correlated (r=0.65, P < 0.02) with the reduction in visceral fat area.

CONCLUSION/INTERPRETATION: Rosiglitazone increases peripheral tissue insulin sensitivity and decreases endogenous glucose release via an inhibition of gluconeogenesis.
Key words: Gluconeogenesis • Hepatic glucose production • Type 2 diabetes • Thiazolidinediones • Rosiglitazone




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