SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes

JCI Insight. 2020 Feb 13;5(3):e129694. doi: 10.1172/jci.insight.129694.


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.

Keywords: Beta cells; Diabetes; Endocrinology; Insulin; Metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Exocytosis*
  • Glucose / metabolism
  • Homeostasis
  • Humans
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Mice, Knockout
  • Patch-Clamp Techniques
  • Qb-SNARE Proteins / genetics
  • Qb-SNARE Proteins / metabolism*
  • Qc-SNARE Proteins / genetics
  • Qc-SNARE Proteins / metabolism*
  • Rats
  • Synaptosomal-Associated Protein 25 / metabolism*


  • Calcium Channels
  • Insulin
  • Qb-SNARE Proteins
  • Qc-SNARE Proteins
  • SNAP23 protein, human
  • SNAP25 protein, human
  • Synaptosomal-Associated Protein 25
  • Glucose