EFFECTS OF PHYSIOLOGICAL HYPERINSULINEMIA ON THE INTRACELLULAR METABOLIC PARTITION OF PLASMA-GLUCOSE

Methodology for assessing the glycolytic and oxidative fluxes from plasma glucose, by measuring (H2O)-H-3 and (CO2)-C-14 rates of production during [3-H-3]- and [U-C-14]glucose infusion, was tested in healthy subjects. In study 1, during staircase (H2O)-H-3 infusion in six subjects, calculated rates of (H2O)-H-3 appearance agreed closely with (H2O)-H-3 infusion rates. In study 2, when [2-H-3]glucose and (NaHCO3)-C-14 were infused in four subjects in the basal state and during a 4-h euglycemic insulin (approximately 70 muU/ml) clamp, accurate estimates of the rates of [2-H-3]glucose detritiation were obtained (94-97% of the expected values), and the recovery factor of (NaHCO3)-C-14 did not change during hyperinsulinemia. In study 3, 11 subjects underwent a 4-h euglycemic insulin (approximately 70 muU/ml) clamp with [3-H-3]- and [U-C-14]glucose infusion and measurement of gaseous exchanges by indirect calorimetry to estimate the rates of total glycolysis, glycogen synthesis, glucose oxidation, nonoxidative glycolysis, hepatic glucose production, glucose recycling, and glucose conversion to fat. Hyperinsulinemia stimulated glycogen synthesis above baseline more than glycolysis [increment of 4.78 +/- 0.37 vs. 2.0 +/- 0. 17 mg . min-1 . kg-1 of lean body mass (LBM), respectively, P < 0.011 and incompletely suppressed (approximately 87%) hepatic glucose production. The major component of nonoxidative glycolysis shifted from glucose recycling in the postabsorptive state (approximately 57% of nonoxidative glycolysis) to glucose conversion to fat during hyperinsulinemia (approximately 59% of nonoxidative glycolysis). Lipid oxidation during the insulin clamp was negatively correlated with both isotopic glucose oxidation (r = -0.822, P < 0.002) and glycolysis (r = -0.582, P < 0.07). In conclusion, in healthy subjects, glycogen synthesis plays a greater role than glycolysis and glucose oxidation in determining insulin-mediated glucose disposal. Part of insulin-mediated increase in glycolysis/oxidation might be secondary to the relief of the competition between fat and glucose for oxidation.