期刊
DIABETOLOGIA
卷 55, 期 10, 页码 2693-2702出版社
SPRINGER
DOI: 10.1007/s00125-012-2640-z
关键词
Exocytosis; GLP-1; Insulin granules; Munc13-1; TIRFM
资金
- Canadian Institutes for Health Research [MOP 86544]
- Canadian Diabetes Association
- Banting and Best Diabetes Centre, University of Toronto
We have previously reported that the haplodeficient Munc13-1 (+/-) mouse exhibits impaired biphasic glucose-stimulated insulin secretion (GSIS), causing glucose intolerance mimicking type 2 diabetes. Glucagon-like peptide-1 (GLP-1) can bypass these insulin-secretory defects in type 2 diabetes, but the mechanism of exocytotic events mediated by GLP-1 in rescuing insulin secretion is unclear. The total internal reflection fluorescence microscopy (TIRFM) technique was used to examine single insulin granule fusion events in mouse islet beta cells. There was no difference in the density of docked granules in the resting state between Munc13-1 (+/+) and Munc13-1 (+/-) mouse islet beta cells. While exocytosis of previously docked granules in Munc13-1 (+/-) beta cells is reduced during high-K+ stimulation as expected, we now find a reduction in additional exocytosis events that account for the major portion of GSIS, namely two types of newcomer granules, one which has a short docking time (short-dock) and another undergoing no docking before exocytosis (no-dock). As mammalian homologue of Caenorhabditis elegans unc-13-1 (Munc13-1) is a phorbol ester substrate, phorbol ester could partially rescue biphasic GSIS in Munc13-1-deficient beta cells by enhancing recruitment of short-dock newcomer granules for exocytosis. The more effective rescue of biphasic GSIS by GLP-1 than by phorbol was due to increased recruitment of both short-dock and no-dock newcomer granules. Phorbol ester and GLP-1 potentiation of biphasic GSIS are brought about by recruitment of distinct populations of newcomer granules for exocytosis, which may be mediated by Munc13-1 interaction with syntaxin-SNARE complexes other than that formed by syntaxin-1A.
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