An animal model of diabetes mellitus has been developed in which neonatal rats are injected with streptozotocin at 2 days of age. After transient hyperglycemia followed by near normal glycemia, these animals develop nonketotic diabetes at about 6 wk of age that does not require insulin treatment. Secretion from the endocrine pancreas of 6–15-wk-old rats was evaluated with the isolated, perfused pancreas technique. Insulin secretion responded very poorly to high perfusate glucose concentrations, but in the presence of theophylline this meager response was enhanced. In contrast, arginine elicited an insulin response comparable to that of the control rats. Isoproterenol stimulated insulin secretion more in the diabetic model than in the controls, and tolbutamide failed to evoke insulin secretion. Glucagon secretion in response to arginine and isoproterenol was similar in both groups, but was suppressed less efficiently by glucose in the model than in controls. Evidence for enhanced basal secretion of somatostatin was also found. Thus, these hyperglycemic rats have a selective defect in glucosestimulated insulin secretion with preservation of responses to other agents. In addition, abnormalities in the secretion of glucagon and somatostatin have been found.