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 - 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 -