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The Effect of Rosiglitazone on the Liver: Decreased Gluconeogenesis in Patients with Type 2 Diabetes

Metabolism Unit, National Research Center, Institute of Clinical Physiology (A.G., M.P., E.S., D.C., E.F.), and Department of Internal Medicine, University of Pisa School of Medicine, 56100 Pisa, Italy; and Diabetes Division, University of Texas Health Science Center (A.G., Y.M., R.A.D., E.F.), San Antonio, Texas 78229

Address all correspondence and requests for reprints to: Dr. Amalia Gastaldelli, Metabolism Unit, National Research Center, Institute of Clinical Physiology, Via Moruzzi 1, 56100 Pisa, Italy. E-mail: amalia{at}ifc.cnr.it.

Aims/Hypothesis: Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones have been shown to improve glycemic control and increase peripheral insulin sensitivity. Whether chronic thiazolidinedione 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/d; n = 13) or placebo (n = 13) for 12 wk. At baseline and 12 wk, we measured endogenous glucose production (by [³H]glucose infusion) and GNG (by the [²H]₂O technique) after a 15-h fast. Peripheral insulin sensitivity was evaluated by a two-step (240 and 960 pmol/min/m^–2) euglycemic insulin clamp.

Results: Compared with placebo, RSG reduced fasting plasma glucose (9.7 ± 0.7 to 7.4 ± 0.3 mmol/liter; P < 0.001), fasting fractional GNG (–15 ± 4%; P = 0.002), and fasting GNG flux (–3.9 ± 1.2 µmol/min/kg fat-free mass; 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: RSG increases peripheral tissue insulin sensitivity and decreases endogenous glucose release via an inhibition of gluconeogenesis.

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