title: 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.
abstract: OBJECTIVE
  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
  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.
authors: Departments of Medicine & Physiology, University of Toronto, Room 7368, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
authors: L
authors: L
authors: Xie
authors: Departments of Medicine & Physiology, University of Toronto, Room 7368, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
authors: D
authors: D
authors: Zhu
authors: 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.
authors: H Y
authors: HY
authors: Gaisano
mesh_terms: D000818:Animals; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000502:physiology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010703:Phorbol Esters / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D050765:Qa-SNARE Proteins / Q000502:physiology; D050600:SNARE Proteins / Q000502:physiology; D050827:Syntaxin 1 / Q000502:physiology
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; D010703:Phorbol Esters; D050765:Qa-SNARE Proteins; D050600:SNARE Proteins; D050827:Syntaxin 1; C503321:Unc13a protein, mouse; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D011188:Potassium