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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 5

SNAP23 depletion increases GSIS in T2D human islets.

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SNAP23 depletion increases GSIS in T2D human islets.
(A) Western blots o...
(A) Western blots of T2D human islets (see Supplemental Table 1 for T2D patients’ donor information) show reduction of Stx-1A and SNAP25 as previously reported (24), but with normal levels of SNAP23 and several other syntaxins. Shown are representative of 3 experiments with analysis of n = 3 in Supplemental Figure 4B. (B) Ad-SNAP23 shRNA/mCherry treatment to deplete SNAP23 in T2D human islets increased first- and second-phase GSIS compared with Ad-scrambled shRNA/mCherry (Control)-treated T2D islets. n = 4 for each group, from 4 independent experiments. *P < 0.05. Statistical significance was assessed by 2-tailed Student’s t test.

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