title: Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets.
abstract: OBJECTIVE
  Pro-atherogenic and pro-oxidant, oxidised LDL trigger adverse effects on pancreatic beta cells, possibly contributing to diabetes progression. Because oxidised LDL diminish the expression of genes regulated by the inducible cAMP early repressor (ICER), we investigated the involvement of this transcription factor and of oxidative stress in beta cell failure elicited by oxidised LDL.
  
  
  METHODS
  Isolated human and rat islets, and insulin-secreting cells were cultured with human native or oxidised LDL or with hydrogen peroxide. The expression of genes was determined by quantitative real-time PCR and western blotting. Insulin secretion was monitored by EIA kit. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei.
  
  
  RESULTS
  Exposure of beta cell lines and islets to oxidised LDL, but not to native LDL raised the abundance of ICER. Induction of this repressor by the modified LDL compromised the expression of important beta cell genes, including insulin and anti-apoptotic islet brain 1, as well as of genes coding for key components of the secretory machinery. This led to hampering of insulin production and secretion, and of cell survival. Silencing of this transcription factor by RNA interference restored the expression of its target genes and alleviated beta cell dysfunction and death triggered by oxidised LDL. Induction of ICER was stimulated by oxidative stress, whereas antioxidant treatment with N-acetylcysteine or HDL prevented the rise of ICER elicited by oxidised LDL and restored beta cell functions.
  
  
  CONCLUSIONS
  Induction of ICER links oxidative stress to beta cell failure caused by oxidised LDL and can be effectively abrogated by antioxidant treatment.
authors.affiliation: Service of Internal Medicine, CHUV-Hospital, Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Favre
authors.forename: G
authors.initials: G
authors.lastname: Niederhauser
authors.forename: D
authors.initials: D
authors.lastname: Fahmi
authors.forename: V
authors.initials: V
authors.lastname: Plaisance
authors.forename: S
authors.initials: S
authors.lastname: Brajkovic
authors.forename: N
authors.initials: N
authors.lastname: Beeler
authors.forename: F
authors.initials: F
authors.lastname: Allagnat
authors.forename: J A
authors.initials: JA
authors.lastname: Haefliger
authors.forename: R
authors.initials: R
authors.lastname: Regazzi
authors.forename: G
authors.initials: G
authors.lastname: Waeber
authors.forename: A
authors.initials: A
authors.lastname: Abderrahmani
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D051786:Cyclic AMP Response Element Modulator / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; C497410:CREM protein, human; C497412:Crem protein, rat; D007328:Insulin; D008077:Lipoproteins, LDL; D034741:RNA, Small Interfering; C099252:oxidized low density lipoprotein; D051786:Cyclic AMP Response Element Modulator; D006861:Hydrogen Peroxide; D000111:Acetylcysteine