The influence of glucose on nonglucose-stimulated insulin secretion was examined in two animal models with reduced B-cell mass: rats treated with streptozotocin as neonates (SZ) and rats with a partial pancreatectomy (Px). The effects of arginine and IBMX upon insulin secretion were studied at varying glucose concentrations using the in vitro, isolated, perfused pancreas. In normal rats, as expected, 16.7 mM glucose caused a biphasic insulin release and arginine-stimulated insulin secretion was markedly potentiated by an increase in background glucose concentration. In the SZ model, 16.7 mM glucose caused a minimal insulin response. However, arginine stimulated insulin release at 2.8 mM glucose as well as at higher glucose concentrations. A similar alteration in the glucose regulation of insulin secretion was shown with another secretagogue, IBMX, even though responses to this agent in the SZ rats exceeded those of the controls at both high- and low-background glucose concentrations. The less diabetic, Px model showed partial preservation of the glucose regulation of the B-cell response to arginine. Thus, a reduction in B-cell mass leads not only to a loss of glucose-stimulated insulin secretion but also to impaired glucose regulation of nonglucose-stimulated insulin secretion.