title: Acute exposure to streptozotocin but not human proinflammatory cytokines impairs neonatal porcine islet insulin secretion in vitro but not in vivo.
abstract: BACKGROUND
  Neonatal porcine islets (NPI) are a potentially useful source of beta cells for transplantation to treat type 1 diabetes mellitus. However, cytokine exposure following xenotransplantation is likely to prevent successful NPI xenograft survival. In this study, we examined the effects of human proinflammatory cytokines (IL-1 beta, IFN gamma, TNFalpha) on NPI function and cell death. These cytokines have been shown to be cytotoxic to beta cells, in part through the generation of nitric oxide. Therefore, we also examined NPI function after acute oxidative stress caused by streptozotocin (STZ), a nitric oxide-generating beta cell cytotoxin.
  
  
  METHODS
  Cultured NPI were exposed to human IL-1 beta, TNFalpha and IFN gamma for 48 h or STZ for 30 min in vitro. Cytokine exposed islets were transplanted into diabetic mice and assessed for function. Mice transplanted with control NPI were injected with STZ and also assessed metabolically.
  
  
  RESULTS
  In vitro exposure to STZ, but not cytokines, significantly reduced NPI glucose stimulated insulin secretion (1.1 +/- 0.1 vs. 4.3 +/- 1.3-fold stimulation index in STZ vs. control, P < 0.05) in addition to cellular DNA recovery (57.6 +/- 4.4%, P < 0.05). Total cellular insulin content was significantly reduced in NPI exposed to either cytokines (56.6 +/- 8.1%) or STZ (45.7 +/- 1.6%) compared to controls (P < 0.05). Interestingly, both STZ and cytokines did not appear to negatively affect NPI function post-transplant.
  
  
  CONCLUSIONS
  The potent nitric oxide generating cytotoxin STZ is able to impair in vitro NPI beta cell insulin release whereas human cytokines (IL-1 beta, TNFalpha, IFN gamma) do not affect the secretory response nor are they cytotoxic in vitro. These results may have implications for the development of anti-rejection protocols to be used in clinical NPI xenotransplants.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Harb
authors.forename: Jeff
authors.initials: J
authors.lastname: Toreson
authors.forename: Janette
authors.initials: J
authors.lastname: Dufour
authors.forename: Gregory
authors.initials: G
authors.lastname: Korbutt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D013311:Streptozocin / Q000494:pharmacology*; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D016207:Cytokines; D007328:Insulin; D013311:Streptozocin; D053148:Caspase 3; D005947:Glucose