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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 3

β Cell exocytotic events that account for the increased GSIS in βSNAP23-KO mice.

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β Cell exocytotic events that account for the increased GSIS in βSNAP23-...
(A) Islet perifusion assays showing that βSNAP23-KO mouse islets exhibited enhanced first- and second-phase GSIS compared with SNAP23fl/fl (Control) mouse islets; AUC analysis shown in middle. Left: Total islet insulin content was not affected in the βSNAP23-KO mice islets (n = 5 for each group). (B) Patch-clamp Cm on dispersed single β cells of βSNAP23-KO versus Control mice. Top shows representative recordings of exocytosis evoked by a train of ten 500-ms depolarizations from –70 mV to 0 mV. Bottom left: Cumulative changes in cell capacitance normalized to basal cell membrane capacitance (fF/pF) in Control and βSNAP23-KO β cells, shown as (bottom right) summary graph (Control: n = 15 cells, βSNAP23-KO: n = 13 cells). (C) TIRF microscopy imaging of exocytosis of predock and newcomer SGs. Left: Histograms of different fusion events in first phase (first 6 minutes after 16.7 mM glucose stimulation) and second phase (6–14 minutes) in Control (top) versus βSNAP23-KO β cells (bottom). Data obtained from 3 independent experiments (5–6 cells from each experiment; WT = 15 cells, βSNAP23-KO = 16 cells). Right top: Summary of the 3 modes of fusion events in first (top) and second phases (bottom). This is the sum of the different types of SG fusion events occurring during the first phase (all frames assessed in the first 6 minutes) and second phase (6–14 minutes) normalized to the PM area. Right bottom: We also obtained TIRF microscopy images of docked insulin SGs before the stimulation (basal) above, and found no change in SG density (averaged number of SGs normalized to cell PM area on each TIRF microscopy imaging frame before stimulation) between Control versus βSNAP23-KO β cells (summary graph on right). Scale bars: 2 μm. *P < 0.05; **P < 0.01. Statistical significance was assessed by 2-tailed Student’s t test.

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