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

Aims/hypothesis We hypothesized that pathologic 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 signaling pathways involved during discrete stages of autoimmune diabetes progression. The virus inducible BBDR rat model was utilized to systematically interrogate the three main ER stress signaling pathways (IRE1, PERK, and ATF6) 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. The time points analyzed were 1) early stages preceding insulitis and 2) a late stage during onset and progression of insulitis that precedes overt hyperglycemia. Results The IRE1 pathway, including its downstream component XBP-1, was specifically activated in pancreatic beta cells of virus induced rats at early stages prior to 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, 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/interpretation Activation of the IRE1 pathway and ER stress-specific pro-apoptotic caspase 12, prior to insulitis, are indicative of ER stress-mediated beta cell damage. The early occurrence of pathologic ER stress and death in pancreatic beta cells may contribute to the initiation and/or progression of virus induced autoimmune diabetes.

Analysis of peri-islet CD45-positive leucocytic infiltrates in long-standing type 1 diabetic patients

“…[26]. In the NOD mouse and in a rat model, markers of ER stress are already increased prior to diabetes onset, supporting an important pathogenic role of peri-islet leucocytes [27,33].…”

Insulin demand regulates β cell number via the unfolded protein response

“…The work presented here suggests a possible approach to therapeutic expansion of β cell mass. However, β cells are sensitive to ER stress, which when unresolved is a primary cause of β cell loss in both autoimmune and obesity-related diabetes (3,4,6,(63)(64)(65). Placing UPR as the sensor of insulin demand that determines β cell number offers one explanation for this heightened susceptibility.…”

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

“…b-cell apoptosis ensues from strong prolonged triggers for ER stress in vitro including exposure to chemicals that directly cause protein misfolding such as tunicamycin (inhibitor of N-glycosylation in the ER) and thapsigargin (disturbs SERCA-mediated Ca 2C retention in the ER) or environmental factors such as cytokines and glucolipotoxicity (Oyadomari et al 2002, Contreras et al 2003, Cardozo et al 2005, Endo et al 2006, Ito et al 2006, Cunha et al 2008, Papa 2012, Yang et al 2013. There are several mechanisms by which UPR signalling that is above a threshold drives b-cell apoptosis with the most important being PERK/ATF4-mediated activation of CHOP and IRE1a/TRAF2/ASK1-mediated activation of JNK (reviewed in Papa (2012)).…”