Inferences about the association between sympathetic overactivity and insulin resistance have been drawn from the infusion of sympathomimetic amines in supraphysiological doses. We used the isolated perfused human forearm to investigate the effect of reflex-induced sympathetic nervous system activation on the peripheral utilization of glucose in the skeletal muscles of 14 healthy men. Local hyperinsulinemia in the forearm (132±25 microunits/mL for 90 minutes) induced a significant increase in the utilization of glucose from baseline (16.4±3.1 mg · dL−1· min−1per 100 mL forearm volume) to a plateau (85.7±15.1 mg · dL−1· min−1per 100 mL forearm volume) between 40 and 60 minutes of insulin infusion but did not alter the utilization of oxygen. Reflex sympathetic nervous system activation was elicited by unloading of cardiopulmonary receptors with bilateral thigh cuff inflation to 40 mm Hg between 60 and 90 minutes of insulin infusion. Blood flow in the forearm was significantly decreased with inflation of thigh cuffs (average decrease of 19%,p<0.0001). As a result of thigh cuff inflation, there was a reduction in the utilization of glucose (a decrease of 23%,p<0.02), whereas oxygen utilization was unchanged. We find that an increase in sympathetic nervous system activation (within the normal range of physiological responses) can cause acute insulin resistance in the forearm of healthy volunteers. The reflex caused no change in oxygen utilization, but the same stimulus elicited a decrease in the utilization of glucose. The decrease in utilization of glucose in skeletal muscle may be caused by both the decrease in blood flow and by an adrenergic receptor-mediated resistance. The relative contributions of each of these mechanisms to insulin resistance deserves further investigation.