Effects of Metformin and Rosiglitazone Monotherapy on Insulin-Mediated Hepatic Glucose Uptake and Their Relation to Visceral Fat in Type 2 Diabetes

Abstract

OBJECTIVE—Impaired insulin-mediated hepatic glucose uptake (HGU) has been implicated in the hyperglycemia of type 2 diabetes. We examined the effects of metformin (2 g/day) and rosiglitazone (8 mg/day) monotherapy on HGU and its relation to subcutaneous fat, visceral fat (VF), and whole-body insulin-mediated glucose metabolism in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—Glucose uptake was measured before and after 26 weeks of treatment using positron emission tomography with [18F]2-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia; fat depots were quantified by magnetic resonance imaging. RESULTS—Fasting plasma glucose levels were significantly decreased after either rosiglitazone (−0.9 ± 0.5 mmol/l) or metformin treatment (−1.1 ± 0.5 mmol/l) in comparison with placebo; only metformin was associated with weight loss (P < 0.02 vs. placebo). When controlling for the latter, the placebo-subtracted change in whole-body glucose uptake averaged −1 ± 4 μmol · min−1 · kg−1 in metformin-treated patients (NS) and +9 ± 3 μmol · min−1 · kg−1 in rosiglitazone-treated patients (P = 0.01). Both rosiglitazone and metformin treatment were associated with an increase in HGU; versus placebo, the change reached statistical significance when controlling for sex (placebo-subtracted values = +0.008 ± 0.004 μmol · min−1 · kg−1 · pmol/l−1, P < 0.03, for metformin; and +0.007 ± 0.004, P < 0.07, for rosiglitazone). After treatment with either drug, insulin-mediated VF glucose uptake (VFGU) was higher than with placebo. In the whole dataset, changes in HGU were negatively related to changes in HbA1c (r = 0.43, P = 0.01) and positively associated with changes in VFGU (r = 0.48, P < 0.01). CONCLUSIONS—We conclude that both metformin and rosiglitazone monotherapy increase HGU in type 2 diabetes; direct drug actions, better glycemic control, and enhanced VF insulin sensitivity are likely determinants of this phenomenon.