Responsiveness of glucagon secretion to various stimuli was examined in Zucker fatty rats. Epinephrine infusion and cold exposure increased the plasma glucagon level to thesame extent in fatty and lean rats, although the plasma glucose responses to these stimuli were much higher in fatty rats than in lean rats. Glucagon secretion in response to hypoglycemia due to insulin administration was markedly blunted in fatty rats. When arginine was infused, fatty rats showed enhanced secretion of glucagon and insulin, and elevation of plasma glucose as compared with lean rats. Streptozotocin (STZ)-treatment of fatty rats decreased insulin response to arginine but had no effect on exaggerated glucagon secretion. Arginine-stimulated glucagon secretion of lean rats was exaggerated by STZ treatment. From these results, glucagon secretion of fatty rats seemed unresponsive to inhibitory effects of glucose and insulin. The ventromedial hypothalamus-lesioned obese rats showed enhanced secretion of glucagon and insulin, and elevation of plasma glucose in response to arginine as observed in fatty rats. We conclude that the abnormalities of A cells in fatty rats are presumably secondary to obesity rather than caused by the fa gene.