title: Syntaxin 4 up-regulation increases efficiency of insulin release in pancreatic islets from humans with and without type 2 diabetes mellitus.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Eunjin
authors.initials: E
authors.lastname: Oh
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Stull
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Thurmond
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: D007328:Insulin; D050765:Qa-SNARE Proteins