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Munc18b Increases Insulin Granule Fusion, Restoring Deficient Insulin Secretion in Type-2 Diabetes Human and Goto-Kakizaki Rat Islets with Improvement in Glucose Homeostasis
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Description
Reduced pancreatic islet levels of Munc18a/SNARE complex proteins have been postulated to contribute to the deficient glucose-stimulated insulin secretion (GSIS) in type-2 diabetes (T2D). Whereas much previous work has purported Munc18a/SNARE complex (Syntaxin-1A/VAMP-2/SNAP25) to be primarily involved in predocked secretory granule (SG) fusion, less is known about newcomer SGs that undergo minimal docking time at the plasma membrane before fusion. Newcomer SG fusion has been postulated to involve a distinct SM/SNARE complex (Munc18b/Syntaxin-3/VAMP8/SNAP25), whose levels we find also reduced in islets of T2D humans and T2D Goto-Kakizaki (GK) rats. Munc18b overexpression by adenovirus infection (Ad-Munc18b), by increasing assembly of Munc18b/SNARE complexes, mediated increased fusion of not only newcomer SGs but also predocked SGs in T2D human and GK rat islets, resulting in rescue of the deficient biphasic GSIS. Infusion of Ad-Munc18b into GK rat pancreas led to sustained improvement in glucose homeostasis. However, Munc18b overexpression in normal islets increased only newcomer SG fusion. Therefore, Munc18b could potentially be deployed in human T2D to rescue the deficient GSIS.
Journal
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- EBioMedicine
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EBioMedicine 16 262-274, 2017-02
Elsevier BV
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Keywords
- Male
- Medicine (General)
- Synaptosomal-Associated Protein 25
- Blotting, Western
- R-SNARE Proteins
- Islets of Langerhans
- R5-920
- Munc18 Proteins
- Insulin Secretion
- Animals
- Homeostasis
- Humans
- Insulin
- Aged
- Microscopy, Confocal
- Qa-SNARE Proteins
- R
- Rats, Inbred Strains
- Middle Aged
- Glucose
- Diabetes Mellitus, Type 2
- Multiprotein Complexes
- Medicine
- Female
- Research Paper
Details 詳細情報について
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- CRID
- 1360567182056568448
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- ISSN
- 23523964
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- PubMed
- 28163042
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- Article Type
- journal article
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- Data Source
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- Crossref
- KAKEN
- OpenAIRE