Effects of Metformin and Rosiglitazone Monotherapy on Insulin-Mediated Hepatic Glucose Uptake and Their Relation to Visceral Fat in Type 2 Diabetes
- Patricia Iozzo, MD12,
- Kirsti Hallsten, MD1,
- Vesa Oikonen, MSC1,
- Kirsi A. Virtanen, MD1,
- Riitta Parkkola, MD3,
- Jukka Kemppainen, MD1,
- Olof Solin, PHD1,
- Fredrik Lonnqvist, MD4,
- Ele Ferrannini, MD25,
- Juhani Knuuti, MD1 and
- Pirjo Nuutila, MD16
- 1Turku PET Centre, Department of Nuclear Medicine, University of Turku, Turku, Finland
- 2Institute of Clinical Physiology, PET Centre, National Research Council (CNR), Pisa, Italy
- 3Department of Radiology, University of Turku, Turku, Finland
- 4Department of Medicine, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
- 5Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy
- 6Department of Medicine, University of Turku, Turku, Finland
- Address correspondence and reprint requests to Patricia Iozzo, MD, Institute of Clinical Physiology, National Research Council (CNR), Via Moruzzi 1, 56100 Pisa, Italy. E-mail: patricia.iozzo{at}ifc.cnr.it.
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.
- FDG, 2-fluoro-2-deoxyglucose
- FFA, free fatty acid
- HGU, hepatic glucose uptake
- Ki, glucose influx rate constant
- M, whole lean body mass glucose uptake
- M/I, M normalized by the steady-state plasma insulin level of the clamp
- MRI, magnetic resonance imaging
- PET, positron emission tomography
- PPAR-γ, peroxisome proliferator-activated receptor-γ
- ROI, region of interest
- SFGU, subcutaneous fat glucose uptake
- VF, visceral fat
- VFGU, VF glucose uptake
Footnotes
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A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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- Accepted April 7, 2003.
- Received January 14, 2003.
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