title: Elimination of negative feedback control mechanisms along the insulin signaling pathway improves beta-cell function under stress.
abstract: OBJECTIVE
  Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signaling. Here, we examined the role of Ser phosphorylation of IRS-2 in mediating the inhibitory effects of proinflammatory cytokines and cellular stress on beta-cell function.
  
  
  METHODS
  Five potential inhibitory Ser sites located proximally to the P-Tyr binding domain of IRS-2 were mutated to Ala. These IRS-2 mutants, denoted IRS-2(5A), and their wild-type controls (IRS-2(WT)) were introduced into adenoviral constructs that were infected into Min6 cells or into cultured murine islets.
  
  
  RESULTS
  When expressed in cultured mouse islets, IRS-2(5A) was better than IRS-2(WT) in protecting beta-cells from apoptosis induced by a combination of IL-1beta, IFN-gamma, TNF-alpha, and Fas ligand. Cytokine-treated islets expressing IRS2(5A) secreted significantly more insulin in response to glucose than did islets expressing IRS-2(WT). This could be attributed to the higher transcription of Pdx1 in cytokine-treated islets that expressed IRS-2(5A). Accordingly, transplantation of 200 islets expressing IRS2(5A) into STZ-induced diabetic mice restored their ability to respond to a glucose load similar to naïve mice. In contrast, mice transplanted with islets expressing IRS2(WT) maintained sustained hyperglycemia 3 days after transplantation.
  
  
  CONCLUSIONS
  Elimination of a physiological negative feedback control mechanism along the insulin-signaling pathway that involves Ser/Thr phosphorylation of IRS-2 affords protection against the adverse effects of proinflammatory cytokines and improves beta-cell function under stress. Genetic approaches that promote IRS2(5A) expression in pancreatic beta-cells, therefore, could be considered a rational treatment against beta-cell failure after islet transplantation.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Diana
authors.initials: D
authors.lastname: Gurevitch
authors.forename: Sigalit
authors.initials: S
authors.lastname: Boura-Halfon
authors.forename: Roi
authors.initials: R
authors.lastname: Isaac
authors.forename: Galit
authors.initials: G
authors.lastname: Shahaf
authors.forename: Moti
authors.initials: M
authors.lastname: Alberstein
authors.forename: Denise
authors.initials: D
authors.lastname: Ronen
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
authors.forename: Yehiel
authors.initials: Y
authors.lastname: Zick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D020169:Caspases / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000235:genetics; D007328:Insulin / Q000378:metabolism / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000502:physiology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016381:Islets of Langerhans Transplantation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012694:Serine / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics; D014162:Transfection
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D018398:Homeodomain Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D012694:Serine; D020169:Caspases; D005947:Glucose