The C57BL/6J mouse develops obesity and diabetes in response to a high-fat, high-simple carbohydrate diet. To determine the dynamics of glucose-induced insulin release in this animal model of NIDDM, we studied the acute insulin response to glucose of perifused islets in C57BL/6J (diabetes-prone) and A/J (diabetes-resistant) mice fed a normal control diet and of others fed a diabetogenic diet. The insulin response of normal C57BL/6J islets was almost monophasic, with a deficiency in the second phase during high glucose stimulation when compared to that of A/J control islets. The defect in C57BL/6J mice was exaggerated in animals fed a diabetogenic diet. It is suggested that a latent deficiency of second phase insulin release may contribute to the development of the diet-induced syndrome in this model.