Syntaxin 4 up-regulation increases efficiency of insulin release in pancreatic islets from humans with and without type 2 diabetes mellitus

J Clin Endocrinol Metab. 2014 May;99(5):E866-70. doi: 10.1210/jc.2013-2221. Epub 2014 Feb 19.


Context: Evidence suggests that dysfunctional β-cell insulin release precedes type 1 and type 2 diabetes (T1D and T2D, respectively) and that enhancing the efficiency of insulin release from pancreatic islet β-cells may delay/prevent these diseases. We took advantage of the rare opportunity to test this paradigm using islets from human type 2 diabetic individuals.

Objectives: Insulin release capacity is limited by the abundance of fusogenic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Because enrichment of Syntaxin 4, a plasma membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein, enhances β-cell function in mice, we investigated its potential to restore functional insulin secretion to human diabetic islets.

Design: Human islets from type 2 diabetic and healthy individuals transduced to overexpress Syntaxin 4 were examined by perifusion analysis. Streptozotocin-induced diabetic recipient mice transplanted with Syntaxin 4-enriched or normal islets were assessed for rescue of diabetes in vivo.

Results: Syntaxin 4 up-regulation in human islets enhanced β-cell function by approximately 2-fold in each phase of secretion. Syntaxin 4 abundance in type 2 diabetes islets was approximately 70% reduced, and replenishment significantly improved insulin secretion. Islets from Syntaxin 4 overexpressing transgenic mice more effectively attenuated streptozotocin-induced diabetes than did control islets.

Conclusions: These data show that the addition of just Syntaxin 4 is sufficient to significantly improve insulin secretory function to human type 2 diabetes islets retaining low levels of residual function and provide proof of concept that by building a more efficient β-cell with up-regulated Syntaxin 4, fewer islets may be required per patient, clearing a major barrier in transplantation therapy.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism*
  • Mice
  • Qa-SNARE Proteins / genetics
  • Qa-SNARE Proteins / metabolism*
  • Transduction, Genetic
  • Up-Regulation*


  • Insulin
  • Qa-SNARE Proteins