title: Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis.
abstract: OBJECTIVE
  Islet amyloid in type 2 diabetes contributes to loss of beta cell mass and function. Since islets are susceptible to oxidative stress-induced toxicity, we sought to determine whether islet amyloid formation is associated with induction of oxidative stress.
  
  
  METHODS
  Human islet amyloid polypeptide transgenic and non-transgenic mouse islets were cultured for 48 or 144 h with or without the antioxidant N-acetyl-L: -cysteine (NAC) or the amyloid inhibitor Congo Red. Amyloid deposition, reactive oxygen species (ROS) production, beta cell apoptosis, and insulin secretion, content and mRNA were measured.
  
  
  RESULTS
  After 48 h, amyloid deposition was associated with increased ROS levels and increased beta cell apoptosis, but no change in insulin secretion, content or mRNA levels. Antioxidant treatment prevented the rise in ROS, but did not prevent amyloid formation or beta cell apoptosis. In contrast, inhibition of amyloid formation prevented the induction of oxidative stress and beta cell apoptosis. After 144 h, amyloid deposition was further increased and was associated with increased ROS levels, increased beta cell apoptosis and decreased insulin content. At this time-point, antioxidant treatment and inhibition of amyloid formation were effective in reducing ROS levels, amyloid formation and beta cell apoptosis. Inhibition of amyloid formation also increased insulin content.
  
  
  CONCLUSIONS
  Islet amyloid formation induces oxidative stress, which in the short term does not mediate beta cell apoptosis, but in the longer term may feed back to further exacerbate amyloid formation and contribute to beta cell apoptosis.
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington and VA Puget Sound Health Care System, 1660 South Columbian Way (151), Seattle, WA 98108, USA. zraikas@u.washington.edu
authors.forename: S
authors.initials: S
authors.lastname: Zraika
authors.forename: R L
authors.initials: RL
authors.lastname: Hull
authors.forename: J
authors.initials: J
authors.lastname: Udayasankar
authors.forename: K
authors.initials: K
authors.lastname: Aston-Mourney
authors.forename: S L
authors.initials: SL
authors.lastname: Subramanian
authors.forename: R
authors.initials: R
authors.lastname: Kisilevsky
authors.forename: W A
authors.initials: WA
authors.lastname: Szarek
authors.forename: S E
authors.initials: SE
authors.lastname: Kahn
mesh_terms: D000682:Amyloid / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D058228:Islet Amyloid Polypeptide; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D012333:RNA, Messenger; D017382:Reactive Oxygen Species