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, (18)F-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 micro mol/min/kg for normal-IS subjects, 65 +/- 8 micro mol/min/kg for high-IS subjects (P < 0.05 vs. normal IS), and 24 +/- 3 micro mol/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 micro mol x min(-1) x 100 mL(-1), P < 0.05) and phosphorylation rates (0.55 +/- 0.24 vs. 0.36 +/- 0.19 min(-1) x 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.