title: Low-level arsenic impairs glucose-stimulated insulin secretion in pancreatic beta cells: involvement of cellular adaptive response to oxidative stress.
abstract: BACKGROUND
  Chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with incidence of type 2 diabetes (T2D). A key driver in the pathogenesis of T2D is impairment of pancreatic beta-cell function, with the hallmark of beta-cell function being glucose-stimulated insulin secretion (GSIS). Reactive oxygen species (ROS) derived from glucose metabolism serve as one of the metabolic signals for GSIS. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress.
  
  
  OBJECTIVE
  We tested the hypothesis that activation of Nrf2 and induction of antioxidant enzymes in response to arsenic exposure impedes glucose-triggered ROS signaling and thus GSIS.
  
  
  RESULTS
  Exposure of INS-1(832/13) cells to low levels of arsenite led to decreased GSIS in a dose- and time-dependent fashion. Consistent with our hypothesis, a significantly enhanced Nrf2 activity, determined by its nuclear accumulation and induction of its target genes, was observed in arsenite-exposed cells. In keeping with the activation of Nrf2-mediated antioxidant response, intracellular glutathione and intracellular hydrogen peroxide-scavenging activity was dose dependently increased by arsenite exposure. Although the basal cellular peroxide level was significantly enhanced, the net percentage increase in glucose-stimulated intracellular peroxide production was markedly inhibited in arsenite-exposed cells. In contrast, insulin synthesis and the consensus GSIS pathway, including glucose transport and metabolism, were not significantly reduced by arsenite exposure.
  
  
  CONCLUSIONS
  Our studies suggest that low levels of arsenic provoke a cellular adaptive oxidative stress response that increases antioxidant levels, dampens ROS signaling involved in GSIS, and thus disturbs beta-cell function.
authors.affiliation: Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 , USA.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fu
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Woods
authors.forename: Einav
authors.initials: E
authors.lastname: Yehuda-Shnaidman
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Victoria
authors.initials: V
authors.lastname: Wong
authors.forename: Sheila
authors.initials: S
authors.lastname: Collins
authors.forename: Guifan
authors.initials: G
authors.lastname: Sun
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D001151:Arsenic / Q000633:toxicity*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D050983:NF-E2 Transcription Factor / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007328:Insulin; D050983:NF-E2 Transcription Factor; D017382:Reactive Oxygen Species; D005947:Glucose; D001151:Arsenic