A schematic presentation of glucose-induced biphasic insulin secretion by islet β cells. Stimulation by a high concentration of glucose elicits a rapid increase in insulin secretion within 1–2 minutes (first phase). Within 10 minutes, in the presence of the same stimulatory concentration of glucose, the secretion rate is decreased, and it gradually begins to increase again thereafter (second phase). Second-phase insulin release is more prominent in rat and human than in mouse β cells. First-phase insulin release is generated by fusion of β granules already in the RRP and the plasma membrane, which is called triggering. For the second phase, granules translocate from the RP to the RRP, which yields expansion and/or replenishment of the RRP. The first and second phases of insulin secretion are due to K_ATP channel–dependent and –independent glucose signaling, respectively, as outlined in Figure 1.