title: Pathological endoplasmic reticulum stress mediated by the IRE1 pathway contributes to pre-insulitic beta cell apoptosis in a virus-induced rat model of type 1 diabetes.
abstract: OBJECTIVE
  We hypothesised that pathological endoplasmic reticulum (ER) stress contributes to beta cell death during development of type 1 diabetes. In this study, we investigated the occurrence of beta cell ER stress and the signalling pathways involved during discrete stages of autoimmune diabetes progression. The virus-inducible BBDR rat model was used to systematically interrogate the three main ER stress signalling pathways (IRE1 [inositol-requiring protein-1], PERK [double-stranded RNA-dependent protein kinase (PKR)-like ER kinase] and ATF6 [activating transcription factor 6]) in pancreatic beta cells during type 1 diabetes development.
  
  
  METHODS
  ER stress and apoptotic markers were assessed by immunoblot analyses of isolated pancreatic islets and immunofluorescence staining of pancreas sections from control and virus-induced rats. Various time points were analysed: (1) early stages preceding the development of insulitis and (2) a late stage during onset and progression of insulitis, which precedes overt hyperglycaemia.
  
  
  RESULTS
  The IRE1 pathway, including its downstream component X-box-binding protein 1, was specifically activated in pancreatic beta cells of virus-induced rats at early stages preceding the development of insulitis. Furthermore, ER stress-specific pro-apoptotic caspase 12 and effector caspase 3 were also activated at this stage. Activation of PERK and its downstream effector pro-apoptotic CHOP (CCAAT/-enhancer-binding-protein homologous protein), only occurred during late stages of diabetes induction concurrent with insulitis, whereas ATF6 activation in pancreatic beta cells was similar in control and virus-induced rats.
  
  
  CONCLUSIONS
  Activation of the IRE1 pathway and ER stress-specific pro-apoptotic caspase 12, before the development of insulitis, are indicative of ER stress-mediated beta cell damage. The early occurrence of pathological ER stress and death in pancreatic beta cells may contribute to the initiation and/or progression of virus-induced autoimmune diabetes.
authors.forename: Chaoxing
authors.initials: C
authors.lastname: Yang
authors.forename: Philip
authors.initials: P
authors.lastname: Diiorio
authors.forename: Agata
authors.initials: A
authors.lastname: Jurczyk
authors.forename: Bryan
authors.initials: B
authors.lastname: O'Sullivan-Murphy
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.forename: Rita
authors.initials: R
authors.lastname: Bortell
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497113:Atf6 protein, rat; C497251:Ddit3 protein, rat; C486557:Ern2 protein, rat