To determine whether insulin action on human skeletal muscle is entirely accounted for by a direct effect of insulin per se, we quantitated forearm glucose uptake (FGU) in two groups of normal subjects under conditions of identical forearm tissue insulinization (approximately 90 microU/ml) induced by means of systemic (group I) or intrabrachial insulin infusion (group II). With this approach, a difference of FGU between the two groups is demonstrative of the operation of indirect mechanisms in insulin action. During insulin infusion in group I, euglycemia was maintained by a variable glucose infusion, whereas arterial free fatty acid (FFA) concentration fell below 0.1 mM. In group II, arterial concentrations of both glucose and FFA remained unchanged, indicating that insulin effect was indeed restricted to the forearm tissues. With local insulin administration, FGU reached levels approximately 40% lower than those achieved with systemic insulin infusion (P less than 0.01-0.005). To determine whether this difference could be attributed to the fall in FFA concentration associated with systemic insulinization, FGU was also quantitated during a systemic insulin plus heparin infusion (group III) to maintain FFA at their basal levels. In this condition, insulin-stimulated FGU was not different from that observed in group I. These data demonstrate that 1) insulin action on skeletal muscle glucose disposal is mediated by a direct as well as an indirect component, and 2) the maintenance of basal FFA does not affect insulin-stimulated FGU, indicating that the indirect component of insulin action is mediated by a different mechanism.