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

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.

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