Free Fatty Acids—The Link Between Obesity and Insulin Resistance

Abstract

To present evidence that free fatty acids (FFA) are an important link between obesity and insulin resistance. The role of FFA in peripheral insulin resistance, hepatic insulin resistance, insulin secretion, and type 2 diabetes is discussed. Obesity is invariably associated with insulin resistance. In most obese subjects, plasma FFA levels are increased. Physiologic increases in plasma FFA levels cause insulin resistance in both diabetic and nondiabetic subjects by producing several metabolic defects: (1) FFA inhibit insulin-stimulated glucose uptake at the level of glucose transport or phosphorylation (or both); (2) FFA inhibit insulin-stimulated glycogen synthesis; and (3) FFA inhibit insulin-stimulated glucose oxidation. (This last-mentioned defect probably does not contribute to insulin resistance.) FFA probably also cause hepatic insulin resistance, which results in increased rates of endogenous glucose production in relationship to the prevailing degree of hyperinsulinemia. Lastly, FFA support between 30 and 50% of basal insulin secretion and potentiate glucose-stimulated insulin secretion in short-term and long-term settings. The stimulatory action of FFA on b-cells enables obese individuals who do not have a genetic predisposition to develop type 2 diabetes mellitus to compensate for their FFA-potentiated insulin resistance with an increase in FFA-mediated insulin secretion. In contrast, subjects who are genetically predisposed to develop type 2 diabetes may be unable to secrete sufficient amounts of insulin to compensate for their FFA-induced insulin resistance. This situation will lead to an increase in blood glucose concentration and eventually to type 2 diabetes. FFA have been shown to have an important contributing role in the pathogenesis of insulin resistance in human obesity.