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SNAP23 Depletion Enables More SNAP25/calcium Channel Excitosome Formation to Increase Insulin Exocytosis in Type 2 Diabetes

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2020

JCI Insight. 2020 Feb 13;5(3):e129694. doi: 10.1172/jci.insight.129694.

SNAP23 Depletion Enables More SNAP25/calcium Channel Excitosome Formation to Increase Insulin Exocytosis in Type 2 Diabetes

T Liang;T Qin;F Kang;Y Kang;L Xie;D Zhu;S Dolai;D Greitzer-Antes;RK Baker;D Feng;E Tuduri;CG Ostenson;TJ Kieffer;K Banks;JE Pessin;HY Gaisano

Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Michael F. Price Center for Genetic and Translational Medicine, Department of Medicine and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. Department of Molecular Medicine and. Department of Surgery, Karolinska Institutet, Stockholm, Sweden. Division of Comparative Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Service type: Knockout mice

Abstract

SNAP23 is the ubiquitous SNAP25 isoform that mediates secretion in non-neuronal cells, similar to SNAP25 in neurons. However, some secretory cells like pancreatic islet β cells contain an abundance of both SNAP25 and SNAP23, where SNAP23 is believed to play a redundant role to SNAP25. We show that SNAP23, when depleted in mouse β cells in vivo and human β cells (normal and type 2 diabetes [T2D] patients) in vitro, paradoxically increased biphasic glucose-stimulated insulin secretion corresponding to increased exocytosis of predocked and newcomer insulin granules. Such effects on T2D Goto-Kakizaki rats improved glucose homeostasis that was superior to conventional treatment with sulfonylurea glybenclamide. SNAP23, although fusion competent in slower secretory cells, in the context of β cells acts as a weak partial fusion agonist or inhibitory SNARE. Here, SNAP23 depletion promotes SNAP25 to bind calcium channels more quickly and longer where granule fusion occurs to increase exocytosis efficiency. β Cell SNAP23 antagonism is a strategy to treat diabetes.

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