This study was designed to evaluate the influence of iv infusion (50 ng kg-1 min-1) of epinephrine, norepinephrine, and isoproterenol on glucose homeostasis in normal man. Epinephrine infusion produced a 40-45 mg/dl increment of plasma glucose concentration which resulted from both a transient 85-90% rise in glucose production (P<0.005) and the failure of glucose uptake to increase consistently in response to hyperglycemia. Plasma insulin increased slightly (20-25%), while plasma glucagon remained unchanged. Norepinephrine infusion produced a much smaller increase in glucose production (25-30%) and plasma glucose (10-15 mg/dl) compared to epinephrine (P<0.01 and P<0.025, respectively). The increase in glucose output was very transient and was not followed by a significant elevation of glucose uptake. Plasma insulin and glucagon levels remained unchanged. The infusion of isoproterenol resulted in a 30-35% increase in glucose production (P<0.025) which remained at levels significantly above baseline throughout the entire study period and was accompanied by a proportional and sustained increase in glucose uptake (P<0.025). As a consequence, plasma glucose increased by only 8-10 mg/dl. Plasma insulin rose 2- to 3-fold in response to isoproterenol (P<0.05), whereas plasma glucagon was unaffected. It is concluded that 1) epinephrine-induced hyperglycemia in normal man is mediated by a transient stimulation of hepatic glucose output and a sustained inhibition of glucose uptake; 2) norepinephrine produces a small and very transient stimulation of glucose output and has no effect on glucose uptake (in contrast, isoproterenol causes a sustained activation of glucose production followed by a proportional elevation of glucose uptake); and 3) the stimulatory effect of epinephrine, norepinephrine, and isoproterenol on hepatic glucose output is not mediated by glucagon hypersecretion.