Plasma FFA oxidation (measured by infusion of 14C-palmitate) and net lipid oxidation (indirect calorimetry) are both inhibited by insulin. The present study was designed to examine whether these insulin-mediated effects on lipid metabolism resulted from a decline in circulating FFA levels or from a direct action of the hormone on FFA/lipid oxidation. Nine subjects participated in two euglycemic insulin clamps, performed with and without heparin. During each insulin clamp study insulin was infused at two rates, 4 and 20 mU/m2.min for 120 min. The studies were performed with indirect calorimetry and 3-3H-glucose and 14C-palmitate infusion. During the control study plasma FFA fell from 610 +/- 46 to 232 +/- 42 to 154 +/- 27 mumol/liter, respectively. When heparin was infused basal plasma FFA concentration remained constant. During the control study, FFA/lipid oxidation rates decreased in parallel with the fall in the plasma FFA concentration. During the insulin/heparin study, plasma 14C-FFA oxidation remained unchanged while net lipid oxidation decreased. In conclusion, when the plasma FFA concentration is maintained unchanged by heparin infusion, insulin has no direct effect on FFA turnover and disposal. These results thus suggest that plasma FFA oxidation is primarily determined by the plasma FFA concentration, while net lipid oxidation is regulated by both the plasma FFA and the insulin level.