Oxidative fuel metabolism during mild hypoglycemia: critical role of free fatty acids

We examined oxidative fuel metabolism (indirect calorimetry) during mild insulin-induced hypoglycemia in normal subjects. Four groups of studies (4 h each) were performed: 1) insulin alone (0.3 mU.kg-1.min-1, 2) insulin plus heparin, 3) insulin plus propranolol, and 4) insulin plus propranolol plus heparin (starting at 75 min). In all groups, insulin rose threefold (approximately 20 microU/ml), whereas glucose concentrations fell by approximately 20 mg/dl (to 65-70 mg/dl) due to a transient decrease in glucose production; glucose uptake did not change. During insulin alone, carbohydrate oxidation rose markedly during the 1st 60-90 min (by 85%, P less than 0.05) as circulating free fatty acids (FFA) and fat oxidation declined. Subsequently, FFA rose and carbohydrate oxidation declined toward base line. The latter changes were completely abolished by propranolol and restored when propranolol-induced suppression of FFA was overcome by addition of heparin. Heparin, by preventing the insulin-induced fall in FFA, also blocked the early rise in carbohydrate oxidation. We conclude that small increments in insulin markedly stimulate carbohydrate oxidation without increasing glucose uptake. This effect is due to the exquisite sensitivity of lipolysis to insulin and is overcome by catecholamine release during hypoglycemia. Mild hyperinsulinemia promotes glucose metabolism primarily through indirect effects on FFA.