Regulation of Insulin Action and Insulin Secretion by SNARE-Mediated Vesicle Exocytosis

Thurmond, Debbie C.

doi:10.1007/978-0-387-72204-7_3

Cited by 6 publications

(7 citation statements)

References 200 publications

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“…Moreover, several animal models of insulin resistance and insulin secretory dysfunction lack normal levels of SNARE proteins (rev. in 5 ), and experimental induction of diabetes using streptozotocin results in loss of expression of SNARE proteins ( 6 ). In contrast, increasing amounts of select SNARE proteins leads to enhanced insulin sensitivity via increasing glucose uptake into skeletal muscle as well as enhancing insulin release in vivo ( 7 , 8 ) and has also been shown to restore normal insulin secretion in diabetic rodent models ( 9 ).…”

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confidence: 99%

Munc18c Depletion Selectively Impairs the Sustained Phase of Insulin Release

Thurmond

2009

Diabetes

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OBJECTIVEThe 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 METHODSPerifusion 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.RESULTSMunc18c (−/+) 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.CONCLUSIONSCollectively, 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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confidence: 99%

Munc18c Depletion Selectively Impairs the Sustained Phase of Insulin Release

Thurmond

2009

Diabetes

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“…In synaptic vesicles, a much studied model, this fusion is mediated by the SNARE protein VAMP2 (also called synaptobrevin2 (Syb2)) anchored in the outer leaf of the vesicle membrane interacting in a zipperlike fashion with syntaxin1a (Syx1a) and SNAP25 anchored in the target plasma membrane (68,(71)(72)(73)(74)(75). These proteins are also found in the beta cell (68,(77)(78)(79)(80)(81)(82)(83).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Phospholipids in Insulin Secretory Granules and Mitochondria in Pancreatic Beta Cells and Their Changes with Glucose Stimulation

MacDonald

Ade

Ntambi

et al. 2015

Journal of Biological Chemistry

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Background: Phospholipids in insulin granules were characterized. Results: Phosphatidylserine and phospholipids with unsaturated or short fatty acids were concentrated in granules and increased with glucose stimulation. Conclusion: Phosphatidylserine enhances the interaction between proteins in granules and plasma membranes. Unsaturated and short FA increase the fluidity and curvature of lipid bilayers. Significance: Fusion of granules to PM and insulin exocytosis is enhanced.

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“…Glucose-stimulated insulin secretion (GSIS) from the pancreatic beta cell and glucose uptake in the muscle and adipose are both mediated by the same SNARE protein isoforms: syntaxin 4, SNAP23, and VAMP2 (for reviews, see Refs. 29,131). Additionally, beta cells use t-SNARE isoforms syntaxin 1 and SNAP25 to mediate the first phase of insulin secretion (27).…”

Section: Snare-mediated Exocytosismentioning

confidence: 98%

Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4

Jewell

Thurmond

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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106

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Type 2 diabetes has been coined "a two-hit disease," as it involves specific defects of glucose-stimulated insulin secretion from the pancreatic beta cells in addition to defects in peripheral tissue insulin action required for glucose uptake. Both of these processes, insulin secretion and glucose uptake, are mediated by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein core complexes composed of syntaxin, SNAP-23/25, and VAMP proteins. The SNARE core complex is regulated by the Sec1/Munc18 (SM) family of proteins, which selectively bind to their cognate syntaxin isoforms with high affinity. The process of insulin secretion uses multiple Munc18-syntaxin isoform pairs, whereas insulin action in the peripheral tissues appears to use only the Munc18c-syntaxin 4 pair. Importantly, recent reports have linked obesity and Type 2 diabetes in humans with changes in protein levels and single nucleotide polymorphisms (SNPs) of Munc18 and syntaxin isoforms relevant to these exocytotic processes, although the molecular mechanisms underlying the observed phenotypes remain incomplete (5, 104, 144). Given the conservation of these proteins in two seemingly disparate processes and the need to design and implement novel and more effective clinical interventions, it will be vitally important to delineate the mechanisms governing these conserved SNARE-mediated exocytosis events. Thus, we provide here an up-to-date historical review of advancements in defining the roles and molecular mechanisms of Munc18-syntaxin complexes in the pathophysiology of Type 2 diabetes.

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Regulation of Insulin Action and Insulin Secretion by SNARE-Mediated Vesicle Exocytosis

Cited by 6 publications

References 200 publications

Munc18c Depletion Selectively Impairs the Sustained Phase of Insulin Release

Munc18c Depletion Selectively Impairs the Sustained Phase of Insulin Release

Characterization of Phospholipids in Insulin Secretory Granules and Mitochondria in Pancreatic Beta Cells and Their Changes with Glucose Stimulation

Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4

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