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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 7

Pancreatic SNAP23 depletion in type-2 diabetic GK rats rescues insulin secretory deficiency and restores glucose homeostasis.

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Pancreatic SNAP23 depletion in type-2 diabetic GK rats rescues insulin s...
Ad-SNAP23 shRNA/mCherry (6.6 × 109 PFU) versus Ad-mCherry (same dose) was infused via pancreatic duct into GK rats. IPGTTs (blood glucose and insulin levels obtained) were performed after infusion at 1 (A), 2 (B), 4 (C), and 8 weeks (D). Glybenclamide treatment of age- and sex-matched GK rats as conventional treatment for T2D was also performed; IPGTT was then performed at the same time points. Graphs on the right show AUCs encompassing 180 minutes of the IPGTTs. Glybenclamide group: n = 6 and Ad-SNAP23 shRNA/mCherry group: n = 6 for 1, 2, and 4 weeks after infusion, and n = 5 for 8 weeks after infusion. Ad-mCherry control groups: n = 6 for 1 and 2 weeks after infusion, and n = 5 for 4 and 8 weeks after infusion. We also performed vehicle control in GK rats compared with glybenclamide treatment, and conducted IPGTTs as shown in Supplemental Figure 6. *P < 0.05; **P < 0.01; ***P < 0.001. Statistical significance was assessed by repeated-measures ANOVA.

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