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Diabetologia. 2012 Oct;55(10):2693-2702. doi: 10.1007/s00125-012-2640-z. Epub 2012 Jul 20.

Role of mammalian homologue of Caenorhabditis elegans unc-13-1 (Munc13-1) in the recruitment of newcomer insulin granules in both first and second phases of glucose-stimulated insulin secretion in mouse islets.

Author information

1
Departments of Medicine & Physiology, University of Toronto, Room 7368, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
2
Departments of Medicine & Physiology, University of Toronto, Room 7368, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. herbert.gaisano@utoronto.ca.

Abstract

AIMS/HYPOTHESIS:

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.

METHODS:

The total internal reflection fluorescence microscopy (TIRFM) technique was used to examine single insulin granule fusion events in mouse islet beta cells.

RESULTS:

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.

CONCLUSIONS/INTERPRETATION:

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.

PMID:
22814762
DOI:
10.1007/s00125-012-2640-z
[Indexed for MEDLINE]

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