Insulin activation of plasma nonesterified fatty acid uptake in metabolic syndrome

Objective-Insulin control of fatty acid metabolism has long been deemed dominated by suppression of adipose lipolysis. The goal of the present study was to test the hypothesis that this single role of insulin is insufficient to explain observed fatty acid dynamics. Methods and Results-Fatty acid kinetics were measured during a meal tolerance test and insulin sensitivity assessed by intravenous glucose tolerance test in overweight human subjects (n=15; body mass index, 35.8±7.1 kg/m). Non-steady state tracer kinetic models were formulated and tested using ProcessDB software. Suppression of adipose fatty acid release, by itself, could not account for postprandial nonesterified fatty acid concentration changes, but adipose suppression combined with insulin activation of fatty acid uptake was consistent with the measured data. The observed insulin Km for nonesterified fatty acid uptake was inversely correlated with both insulin sensitivity of glucose uptake (intravenous glucose tolerance test insulin sensitivity; r=-0.626; P=0.01) and whole body fat oxidation after the meal (r=-0.538; P=0.05). Conclusion-These results support insulin regulation of fatty acid turnover by both release and uptake mechanisms. Activation of fatty acid uptake is consistent with the human data, has mechanistic precedent in cell culture, and highlights a new potential target for therapies aimed at improving the control of fatty acid metabolism in insulin-resistant disease states.