title: Divergent effects of sulforaphane on basal and glucose-stimulated insulin secretion in β-cells: role of reactive oxygen species and induction of endogenous antioxidants.
abstract: OBJECTIVE
  Oxidative stress is implicated in pancreatic β-cell dysfunction, yet clinical outcomes of antioxidant therapies on diabetes are inconclusive. Since reactive oxygen species (ROS) can function as signaling intermediates for glucose-stimulated insulin secretion (GSIS), we hypothesize that exogenously boosting cellular antioxidant capacity dampens signaling ROS and GSIS.
  
  
  METHODS
  To test the hypothesis, we formulated a mathematical model of redox homeostatic control circuit comprising known feedback and feedforward loops and validated model predictions with plant-derived antioxidant sulforaphane (SFN).
  
  
  RESULTS
  SFN acutely (30-min treatment) stimulated basal insulin secretion in INS-1(832/13) cells and cultured mouse islets, which could be attributed to SFN-elicited ROS as N-acetylcysteine or glutathione ethyl ester suppressed SFN-stimulated insulin secretion. The mathematical model predicted an adapted redox state characteristic of strong induction of endogenous antioxidants but marginally increased ROS under prolonged SFN exposure, a state that attenuates rather than facilitates glucose-stimulated ROS and GSIS. We validated the prediction by demonstrating that although 24-h treatment of INS-1(832/13) cells with low, non-cytotoxic concentrations of SFN (2-10 μM) protected the cells from cytotoxicity by oxidative insult, it markedly suppressed insulin secretion stimulated by 20 mM glucose.
  
  
  CONCLUSIONS
  Our study indicates that adaptive induction of endogenous antioxidants by exogenous antioxidants, albeit cytoprotective, inhibits GSIS in β-cells.
authors.affiliation: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, Durham, North Carolina 27709, USA.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Woods
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Zheng
authors.forename: Bei
authors.initials: B
authors.lastname: Yang
authors.forename: Weidong
authors.initials: W
authors.lastname: Qu
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013454:Sulfoxides
chemical_list: D000975:Antioxidants; D007328:Insulin; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; D013454:Sulfoxides; C016766:sulforaphane; D005947:Glucose