The secretion of insulin is a complex, multistep process. The β cell senses nutrient availability, including that of glucose, amino acids, and fatty acids, through the metabolism of these molecules. An increase in the ATP/ADP ratio stimulates closure of the K_ATP channel, thereby causing depolarization of the plasma membrane, activation of a voltage-dependent calcium channel, and insulin exocytosis. The study by Morioka et al. (5) in this issue of the JCI shows that, in the context of overnutrition, leptin attenuates insulin secretion by the β cell. First, leptin appears to function to maintain the patency of the K_ATP channel, thereby hyperpolarizing the β cell plasma membrane. This could occur either by enhancing channel activity or by rendering the channel less sensitive to changes in the ATP/ADP ratio. Second, leptin may play a role in maintaining flux through key metabolic pathways of intermediary metabolism by assuring the proper allosteric and transcriptional regulation of key metabolic enzymes. If so, impaired leptin signaling in the β cell could lead to an enhanced susceptibility to the negative effects of overnutrition, thereby causing an impairment of insulin secretion.