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Cited by 64Pancreatic function and diabetesCellular transport and secretionCalcium signaling and nucleotide metabolism

Munc18c Depletion Selectively Impairs the Sustained Phase of Insulin Release

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Oh, Eunjin, Thurmond, Debbie C.·2009·Diabetes
DOI 10.2337/db08-1059PMC PMC2671048
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Abstract

OBJECTIVE: The Sec1/Munc18 protein Munc18c has been implicated in Syntaxin 4–mediated exocytosis events, although its purpose in exocytosis has remained elusive. Given that Syntaxin 4 functions in the second phase of glucose-stimulated insulin secretion (GSIS), we hypothesized that Munc18c would also be required and sought insight into the possible mechanism(s) using the islet β-cell as a model system. RESEARCH DESIGN AND METHODS: Perifusion analyses of isolated Munc18c- (−/+) or Munc18c-depleted (RNAi) mouse islets were used to assess biphasic secretion. Protein interaction studies used subcellular fractions and detergent lysates prepared from MIN6 β-cells to determine the mechanistic role of Munc18c in Syntaxin 4 activation and docking/fusion of vesicle-associated membrane protein (VAMP)2-containing insulin granules. Electron microscopy was used to gauge changes in granule localization. RESULTS: Munc18c (−/+) islets secreted ∼60% less insulin selectively during second-phase GSIS; RNAi-mediated Munc18c depletion functionally recapitulated this in wild-type and Munc18c (−/+) islets in a gene dosage-dependent manner. Munc18c depletion ablated the glucose-stimulated VAMP2–Syntaxin 4 association as well as Syntaxin 4 activation, correlating with the deficit in insulin release. Remarkably, Munc18c depletion resulted in aberrant granule localization to the plasma membrane in response to glucose stimulation, consistent with its selective effect on the second phase of secretion. CONCLUSIONS: Collectively, these studies demonstrate an essential positive role for Munc18c in second-phase GSIS and suggest novel roles for Munc18c in granule localization to the plasma membrane as well as in triggering Syntaxin 4 accessibility to VAMP2 at a step preceding vesicle docking/fusion.

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  • Munc18-3 knockout mice are not viable, but heterozygous knockouts are glucose-intolerant, an effect at least partially due to reduced GIIS.

    “Munc18-3 (Stxbp3/STXBP3) knockout mice are not viable but heterozygous knockouts (Stxbp3+/-) are glucose-intolerant, an effect that is at least partially due to reduced GIIS (486).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [486]

    The Methods section says homozygous Munc18c knockout mice fail to survive beyond embryonic day 7.5, and the Results report about 60% less second-phase glucose-stimulated insulin secretion from heterozygous mouse islets. The paper does not establish that reduced secretion causes the heterozygous mice’s glucose intolerance; glucose intolerance appears in the title of an earlier study listed in the References. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Authors
Oh, E., & Thurmond, D. C.
Affiliations
Indiana University Indianapolis (US)
Corresponding author
Thurmond, Debbie C.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2009-02-02
Volume
58
Issue
5
Pages
1165-1174
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db08-1059
PMC
PMC2671048
OpenAlex
W2116498561
Cited by
64
References
4
Citations by year
2026: 3 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 5 · 2016: 1 · 2015: 2 · 2014: 8 · 2013: 4 · 2012: 7
FWCI
8.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
  • Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by-nc-nd)
Funders
  • American Heart Association
  • National Institutes of Health (DK067912)
  • School of Medicine, Indiana University
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 076614, DK-067912, R01DK076614, R01DK067912, R56DK067912)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
Munc18c, syntaxin 4, VAMP2, glucose-stimulated insulin secretion, second-phase insulin secretion, exocytosis, vesicle docking and fusion, pancreatic beta cells, MIN6 cells, gene dosage, RNAi knockdown
MeSH terms
Insulin Secretion, Animals, Cricetulus, Diabetes Mellitus, Type 2, Exocytosis, Female, Cricetinae, Insulin, Islets of Langerhans, RNA, Messenger, Transfection, CHO Cells, DNA Primers, Mice, Knockout, Polymorphism, Single Nucleotide, Gene Silencing, Insulin-Secreting Cells, Vesicle-Associated Membrane Protein 2, Mice, Munc18 Proteins

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