Prevention of Inhibitory Effect of Free Fatty Acids on Insulin Binding and Action in Isolated Rat

We recently demonstrated a marked inhibitory effect of high physiological concentrations of free fatty acids (FFAs) on insulin binding, degradation, and action in isolated rat hepatocytes. To elucidate the mechanism, male rats were treated for 3 days with saline (control) or etomoxir (ethyl 2-[6-(p-chlorophenoxy)hexyl]-glycidate), a prodrug, which in vivo is converted to a specific competitive inhibitor of carnitine palmitoyltransferase, and thus, lipid oxidation. Oleic acid (0.4 mM) reduced both 125l-labeled insulin binding and insulin-stimulated [14C]aminoisobutyric acid transport- 4 0 % in cells from control animals. However, this FFA concentration was without effect in cells from etomoxir-treated animals. Etomoxir increased EC50 for the inhibitory effect of oleic acid on insulin binding approximately threefold. The data indicate that the mitochondrial oxidation of fatty acids may be important for their inhibitory effect on insulin binding and action in isolated rat hepatocytes. Diabetes 40:783-86,1991 Obese subjects with an abdominal fat distributionare, for a given degree of obesity, more insulinresistant than equally obese individuals with agluteofemoral fat distribution (1-4). Furthermore, they are more prone to develop diabetes and cardiovascular disease (5,6). The reason for this difference is unclear but has been attributed to the adipose tissue, particularly an increased free-fatty acid (FFA) release (1,3,4). Both abdominal subcutaneous (7) and intra-abdominal fat cells (8) are more responsive to lipolytic hormones than fat cells from the gluteofemoral region. These in vitro findings are paralleled by an increased FFA turnover in abdomina