In man, the infusion of arginine or isoproterenol elevates immunoreactive glucagon and insulin levels. Since arginine administered as a pulse stimulates the acute secretion of both hormones, and an insulin rise is observed after the bolus injection of isoproterenol, these findings probably represent a direct effect of arginine and isoproterenol on islet cells. To determine if there is an acute alpha-cell response to isoproterenol, we have administered this beta-adrenergic agonist as a bolus to healthy volunteers. Arginine administered as a pulse elicited both insulin and glucagon responses whereas pulses of isoproterenol, at half maximal and maximal insulin-stimulating doses, had little effect on glucagon levels. This relative insensitivity of the alpha cells to stimulation by isoproterenol suggests that endogenous beta-adrenergic tone may have a stronger influence on insulin than on glucagon secretion. Furthermore, these findings raise the possibility that beta-adrenergic regulation of plasma glucagon levels in vivo occurs by an indirect mechanism rather than a direct effect on the alpha cells.