To evaluate the sequential changes in secretion of insulin and glucagon by the pancreas of Zucker fa/fa rats, we examined the secretion of these peptides by the perfused pancreas of the rats and by that of their lean littermates aged 9, 18, and 54 wks. Obese rats weighed significantly more than lean rats at all ages and had increased plasma insulin except for those at 54 wks of age. Isolated pancreas of obese rats at 9 wks showed greater insulin secretion response to glucose and arginine than that of lean rats at the same age. Insulin secretion response to arginine from pancreas of obese rats at 18 wks was also greater than that from pancreas of lean rats at 18wks. Increased glucose concentration in the perfusion medium caused less suppression in obese rats than in lean rats. 10mM arginine stimulation resulted in a higher secretion response in lean rats than in obese rats at 18 and 54wks. Impairment of glucagon secretion was observed even at 54wks of age, when the obese rats no longer had significantly increased plasma insulin. This suggested that abnormal glucagon secretion was due not only to hyperinsulinemia, but also to a possible defect in the secretory mechanism.