Summary Insulin secretion in mice with hereditary diabetes was measured in vitro by incubation of pancreatic tissue in the presence of glucose and theophylline. When compared with normal mice of the same age, the absolute secretory capacity of the pancreas from young diabetic mice is either normal or increased; in all cases, however, the pancreas from these young diabetic mice mobilizes a greater fraction of its stores of insulin in response to glucose or the combination of glucose and theophylline. Older mice with more severe diabetes are characterized by depletion of the pancreatic stores of insulin and impairment of the secretory ability. However, maintenance of the hyperactive state is seen occasionally in older diabetic mice that had past histories of consistently mild hyperglycemia.