Male athymic "nude" mice (ANM) of the USC colony manifest spontaneous fasting hyperglycemia and reduced glucose tolerance; it has been proposed that they may represent a model of nonobese non-insulin-dependent diabetes. Following the recent demonstration that insulin secretion from the isolated, perfused pancreas of the male ANM appears to be hypersensitive to glucose, the function of individual pancreatic islet beta cells was investigated by measuring the membrane potential electrical activity. Initial studies demonstrated that the cyclic pattern of electrical activity in isolated female ANM islets is indistinguishable from that in control mouse islets. In contrast to control and female ANM beta cells, in which 11.1 mM glucose evoked approximately 50% maximal electrical activity, this concentration evoked almost 80% maximal activity in male ANM beta cells (p < 0.01). Investigating electrical responses at different glucose concentrations demonstrated that this increased sensitivity to glucose extends across the concentration range 2.8 to 22 mM. Assuming that in these islets, as in normal islets, electrical activity is associated with insulin release, these data indicate that the glucose-versus-insulin secretion dose-response is shifted to lower glucose concentrations at the level of the individual beta cell. Although this study demonstrates that altered beta-cell function occurs in the isolated islet of the male ANM, further investigation is under way to determine how the observed beta-cell glucose hypersensitivity is related to the hyperglycemia and impaired glucose tolerance that develop in these animals in vivo.