Triggering and Augmentation Mechanisms, Granule Pools, and Biphasic Insulin Secretion
- Troitza K. Bratanova-Tochkova,
- Haiying Cheng,
- Samira Daniel,
- Subhadra Gunawardana,
- Yi-Jia Liu,
- Jennifer Mulvaney-Musa,
- Thomas Schermerhorn,
- Susanne G. Straub,
- Hiroki Yajima and
- Geoffrey W.G. Sharp
- From the Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York
The insulin secretory response by pancreatic β-cells to an acute “square wave” stimulation by glucose is characterized by a first phase that occurs promptly after exposure to glucose, followed by a decrease to a nadir, and a prolonged second phase. The first phase of release is due to the ATP-sensitive K+ (KATP) channel-dependent (triggering) pathway that increases [Ca2+]i and has been thought to discharge the granules from a “readily releasable pool.” It follows that the second phase entails the preparation of granules for release, perhaps including translocation and priming for fusion competency before exocytosis. The pathways responsible for the second phase include the KATP channel-dependent pathway because of the need for elevated [Ca2+]i and additional signals from KATP channel-independent pathways. The mechanisms underlying these additional signals are unknown. Current hypotheses include increased cytosolic long-chain acyl-CoA, the pyruvate-malate shuttle, glutamate export from mitochondria, and an increased ATP/ADP ratio. In mouse islets, the β-cell contains some 13,000 granules, of which ∼100 are in a “readily releasable” pool. Rates of granule release are slow, e.g., one every 3 s, even at the peak of the first phase of glucose-stimulated release. As both phases of glucose-stimulated insulin secretion can be enhanced by agents such as glucagon-like peptide 1, which increases cyclic AMP levels and protein kinase A activity, or acetylcholine, which increases diacylglycerol levels and protein kinase C activity, a single “readily releasable pool” hypothesis is an inadequate explanation for insulin secretion. Multiple pools available for rapid release or rapid conversion of granules to a rapidly releasable state are required.
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Accepted for publication 18 June 2001.
CAPS, Ca2+-dependent activator protein for secretion; DAG, diacylglycerol; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucogon-like peptide 1; KATP, ATP-sensitive K+; NSF, N-ethylmaleimide-sensitive factor; PAC, pituitary adenylyl cyclase activating peptide; PK, protein kinase; SNAP-25, synaptosomal-associated protein 25; SNARE, NSF attachment protein receptor; t-SNARE, target-SNARE; VAMP-2, vesicle associated membrane protein 2; VIP, vasoactive intestinal peptide; v-SNARE, vesicle-SNARE.
The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.