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

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

Author information

1
Herman B. Wells Center for Pediatric Research (E.O., N.D.S., R.G.M., D.C.T.), Basic Diabetes Group, Department of Pediatrics, and Departments of Medicine (R.G.M.), Cellular and Integrative Physiology (R.G.M., D.C.T.), and Biochemistry and Molecular Biology (R.G.M., D.C.T.), Indiana University School of Medicine, Indianapolis, Indiana 46202.

Abstract

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.

PMID:
24552216
PMCID:
PMC4010690
DOI:
10.1210/jc.2013-2221
[Indexed for MEDLINE]
Free PMC Article

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