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Insulin Stimulates Liver Glucose Uptake in Humans: An ¹⁸F-FDG PET Study

¹ Turku PET Centre, Departments of Nuclear Medicine and Medicine, University of Turku, Turku, Finland
² PET Centre, Institute of Clinical Physiology, CNR (National Research Council), Pisa, Italy
³ Department of Internal Medicine II, Technical University of Munich, Munich, Germany
⁴ Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy

The liver is vital for the regulation of glucose metabolism, but inaccessibility of the organ for direct assessments has limited the study of its metabolic role in vivo. Methods: The effect of insulin and insulin sensitivity (IS) on hepatic glucose uptake was investigated using PET, ¹⁸F-FDG, and graphical analysis and 3-compartment modeling in humans. We studied 16 healthy sedentary men (normal IS), 8 athletes (high IS), and 7 patients with coronary artery disease (low IS) either during fasting (n = 14) or during euglycemic hyperinsulinemia (n = 24). Results: Whole-body insulin-mediated glucose uptake was 35 ± 7 µmol/min/kg for normal-IS subjects, 65 ± 8 µmol/min/kg for high-IS subjects (P < 0.05 vs. normal IS), and 24 ± 3 µmol/min/kg for low-IS subjects (P < 0.05 vs. normal IS and high IS). Hyperinsulinemia enhanced hepatic glucose influx (2.3 ± 0.9 vs. 1.5 ± 0.7 µmol·min^-1·100 mL^-1, P < 0.05) and phosphorylation rates (0.55 ± 0.24 vs. 0.36 ± 0.19 min^-1·10^-2, P < 0.05) similarly in insulin-sensitive and -resistant subjects. During hyperinsulinemia, however, the glucose phosphorylation-to-dephosphorylation ratio was significantly lower in the low-IS group than in normal-IS subjects (P < 0.05) or high-IS subjects (P < 0.01); correspondingly, whole-body insulin-mediated glucose disposal was directly related to this ratio (r = 0.45; P < 0.05). Furthermore, glucose influx rates were inversely correlated with fasting plasma free fatty acids (P < 0.05). Both compartmental modeling and the graphical approach accurately described the data, though the latter yielded slightly lower estimates of glucose influx rates during fasting. Conclusion: Our study provided evidence that physiologic hyperinsulinemia enhances hepatic glucose uptake and that IS is related to the glucose phosphorylation-to-dephosphorylation balance in the liver. Graphical analysis and modeling proved to be applicable and complementary tools for the investigation of glucose metabolism in the liver.

Key Words: glucose uptake • liver • insulin resistance • free fatty acids • PET

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