Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion

Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 The biphasic secretory response of pancreatic -cells to abrupt and sustained exposure to glucose is well documented. Some of the ATP-sensitive K + (K ATP ) channel-dependent mechanisms underlying the first phase of insulin release are known; the mechanisms underlying the second phase are less well known. The hypothesis we propose is that one rate-limiting step, controlling the conversion of granules in a readily releasable (RR) docked granule pool to an immediately releasable (IR) pool, is responsible for the magnitude of both phases of release. Furthermore, we propose that the K ATP channel-independent signaling pathway regulates this rate-limiting step. The size of the IR pool of granules that constitutes the first phase is determined under resting conditions by the forward and reverse rates of conversion of granules in the RR and IR pools. The resulting equilibrium position determines the maximum number of -cell granules available for release during the first phase upon exposure to glucose. At the nadir between the two phases, the IR pool has been depleted so that the rate of granule release is equal to the low forward rate for the conversion of RR to IR granules. After the nadir, the forward rate is accelerated during the rising portion of the second phase until it reaches a maximum rate at the plateau. glucose signaling pathways; granule pools Address for reprint requests and other correspondence: G. W. G. Sharp, Dept. of Molecular Medicine, College of Veterinary Medicine, Cornell Univ., Ithaca, NY 14853 (E-mail: gws2{at}cornell.edu ).