TY - JOUR
T1 - SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes
AU - Liang, Tao
AU - Qin, Tairan
AU - Kang, Fei
AU - Kang, Youhou
AU - Xie, Li
AU - Zhu, Dan
AU - Dolai, Subhankar
AU - Greitzer-Antes, Dafna
AU - Baker, Robert K.
AU - Feng, Daorong
AU - Tuduri, Eva
AU - Ostenson, Claes Goran
AU - Kieffer, Timothy J.
AU - Banks, Kate
AU - Pessin, Jeffrey E.
AU - Gaisano, Herbert Y.
N1 - Funding Information:
This work was supported by grants to HYG from the Canadian Institute of Health Research (MOP 86544 and PJT-159741). Some of the equipment used in this study was supported by the 3D (Diet, Digestive Tract and Disease) Centre funded by the Canadian Foundation for Innovation and Ontario Research Fund, project number 19442.
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/2/13
Y1 - 2020/2/13
N2 - 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.
AB - 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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U2 - 10.1172/jci.insight.129694
DO - 10.1172/jci.insight.129694
M3 - Article
C2 - 32051343
AN - SCOPUS:85081668970
SN - 2379-3708
VL - 5
JO - JCI insight
JF - JCI insight
IS - 3
M1 - e129694
ER -
