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SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes
Tao Liang, … , Jeffrey E. Pessin, Herbert Y. Gaisano
Tao Liang, … , Jeffrey E. Pessin, Herbert Y. Gaisano
Published February 13, 2020
Citation Information: JCI Insight. 2020;5(3):e129694. https://doi.org/10.1172/jci.insight.129694.
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Research Article Endocrinology Metabolism

SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes

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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.

Authors

Tao Liang, Tairan Qin, Fei Kang, Youhou Kang, Li Xie, Dan Zhu, Subhankar Dolai, Dafna Greitzer-Antes, Robert K. Baker, Daorong Feng, Eva Tuduri, Claes-Goran Ostenson, Timothy J. Kieffer, Kate Banks, Jeffrey E. Pessin, Herbert Y. Gaisano

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Figure 1

Generation of a mouse with β cell–specific deletion of SNAP23.

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Generation of a mouse with β cell–specific deletion of SNAP23.
(A) Whole...
(A) Whole islets from SNAP23fl/fl mice (24) show that SNAP23 is abundant in β cells (confocal imaging), shown more clearly in the enlarged box 1. Scale bars: 100 μm. Quantitation can be found in Supplemental Figure 1A, bottom left. (B) Single islet β cells from human (first row) and mouse (second row) show that SNAP23 is abundant in the insulin SGs. SNAP23 is partly colocalized with Stx-1A (third row) and SNAP25 (fourth row) on the PM. Scale bars: 5 μm. Quantitation can be found in Supplemental Figure 1A, bottom middle. SNAP23 antibody controls (without primary antibody) are shown in Supplemental Figure 1A, top left, and A, top right. (C) SNAP23 is also present in glucagon-containing α cells located in the periphery of the mouse islet. Scale bars: 10 μm. Quantitation in Supplemental Figure 1A, bottom right. (D) AAV8-RIP1-Cre drives Cre expression only in β cells (top) and not in α cells (bottom). Scale bars: 100 μm. Note the cytosolic insulin surrounding the nuclear Cre shown clearly in the enlarged box 2. (E) Efficient knockdown of islet β cell SNAP23 expression is shown in (top) where Cre-positive cells are SNAP23-negative, indicating SNAP23 deletion in those cells, and (bottom) the majority of insulin-positive cells are SNAP23-negative. The few SNAP23-positive cells are likely α cells. Scale bars: 100 μm. (F) Western blots of islets from SNAP23fl/fl mice injected with the AAV8 (βSNAP23-KO) or not (Control) showed reduction of SNAP23 but not other exocytotic proteins. SNAP23 and VAMP8 are not abundant in mouse brain. Blots are representative from 3 independent experiments; analysis of n = 3 in Supplemental Figure 1B. (G) βSNAP23-KO versus SNAP23fl/fl (Control) mice show SNAP23 to be reduced only in islets but not in fat, muscle, or liver, wherein SNAP23 and cognate Munc18c and Stx-4 are putative exocytotic proteins. Shown are representative of 3 independent experiments; analysis of n = 3 in Supplemental Figure 1C.

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