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

Abstract

The biphasic secretory response of pancreatic beta-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 beta-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.

Massive Augmentation of Stimulated Insulin Secretion Induced by Fatty Acid–Free BSA in Rat Pancreatic Islets

“…The second phase was augmented to a greater extent than the first. As the first phase is thought to be due to the release of an "immediately releasable" pool of granules docked at the ␤-cell plasma membrane (20,28), augmentation of this phase implies an increase in the size of the immediately releasable pool. The fact that the rate of insulin secretion at the nadir was not augmented (P ϭ 0.13, n ϭ 6, Fig.…”

“…The prompt increase and augmentation of the rate of insulin secretion during the first phase in response to glucose indicates that the size of the immediately releasable pool has been increased. The size of this pool and of the first phase of release are thought to be due to a rate-limiting step that converts granules in a readily releasable pool to an immediately releasable pool, a pool that has a limit to the number of granules contained within it (28). Also, the magnitude of the second phase of release is thought to be due to the rate at which this conversion between the pools takes place (28).…”

“…The size of this pool and of the first phase of release are thought to be due to a rate-limiting step that converts granules in a readily releasable pool to an immediately releasable pool, a pool that has a limit to the number of granules contained within it (28). Also, the magnitude of the second phase of release is thought to be due to the rate at which this conversion between the pools takes place (28). After 40 min of stimulation by glucose at the very high rates of secretion that are induced by a 4-h exposure to 100 mol/l fatty acid-free BSA, the number of docked granules in the rat ␤-cell is reduced by two-thirds (S.G.S., G. Shanmugam, and G.W.G.S., unpublished observation).…”

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…There are believed to be three functionally different pools of insulin secretory vesicles in β cells Straub and Sharp, 2004). These are the reserve pool (RP) located deep in the cytoplasm, and two pools located close to the membrane, the readily release pool (RRP) and the immediately releasable pool (IRP).…”

In Vivo and In Vitro Glucose-Induced Biphasic Insulin Secretion in the Mouse

“…The second phase requires both continuous production of the triggering signal (elevation of [Ca 2ϩ ] c ) and amplification of the action of Ca 2ϩ on exocytosis by a K ATP channel-independent mechanism. The molecular mechanisms of this amplification are still undefined (19) but could involve a refilling of the readily releasable pool by granule priming or translocation (17,18). It is generally agreed that the amplifying pathway is not involved in the first phase of glucose-induced insulin secretion, but this issue has not been directly tested.…”