Munc18b Increases Insulin Granule Fusion, Restoring Deficient Insulin Secretion in Type-2 Diabetes Human and Goto-Kakizaki Rat Islets with Improvement in Glucose Homeostasis

Tairan Qin; Tao Liang; Dan Zhu; Youhou Kang; Li Xie; Subhankar Dolai; Shuzo Sugita; Noriko Takahashi; Claes-Goran Ostenson; Kate Banks; Herbert Y. Gaisano

doi:10.1016/j.ebiom.2017.01.030

EBioMedicine (Feb 2017)

Munc18b Increases Insulin Granule Fusion, Restoring Deficient Insulin Secretion in Type-2 Diabetes Human and Goto-Kakizaki Rat Islets with Improvement in Glucose Homeostasis

Tairan Qin,
Tao Liang,
Dan Zhu,
Youhou Kang,
Li Xie,
Subhankar Dolai,
Shuzo Sugita,
Noriko Takahashi,
Claes-Goran Ostenson,
Kate Banks,
Herbert Y. Gaisano

Affiliations

Tairan Qin: Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Tao Liang: Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Dan Zhu: Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Youhou Kang: Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Li Xie: Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Subhankar Dolai: Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Shuzo Sugita: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
Noriko Takahashi: Laboratory of Physiological Chemistry, Institute of Medicinal Chemistry, Hoshi University, Shinagawa, Tokyo 142-8501, Japan
Claes-Goran Ostenson: Department of Molecular Medicine and Surgery, Endocrinology and Diabetology Unit, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
Kate Banks: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
Herbert Y. Gaisano: Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada

DOI: https://doi.org/10.1016/j.ebiom.2017.01.030
Journal volume & issue: Vol. 16, no. C
pp. 262 – 274

Abstract

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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.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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