title: ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes.
abstract: Components of the unfolded protein response (UPR) modulate beta cell inflammation and death in early type 1 diabetes (T1D). The UPR is a mechanism by which cells react to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). It aims to restore cellular homeostasis, but in case of chronic or overwhelming ER stress the persistent activation of the UPR triggers apoptosis, contributing to the loss of beta cells in both T1D and type 2 diabetes. It remains to be determined how and why the transition from 'physiological' to 'pathological' UPR takes place. A key component of the UPR is the ER transmembrane protein IRE1α (inositol-requiring enzyme 1α). IRE1α activity is modulated by both intra-ER signals and by the formation of protein complexes at its cytosolic domain. The amplitude and duration of IRE1α signaling is critical for the transition between the adaptive and cell death programs, with particular relevance for the activation of the pro-apoptotic c-Jun N-terminal kinase (JNK) in beta cells. In the present review we discuss the available information on IRE1α-regulating proteins in beta cells and their downstream targets, and the important differences observed between cytokine-induced UPR in human and rodent beta cells.
authors.affiliation: a ULB Center for Diabetes Research, Medical Faculty , Université Libre de Bruxelles (ULB) , Brussels , Belgium.
authors.forename: Flora
authors.initials: F
authors.lastname: Brozzi
authors.affiliation: a ULB Center for Diabetes Research, Medical Faculty , Université Libre de Bruxelles (ULB) , Brussels , Belgium.
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000818:Animals; D017209:Apoptosis; D003600:Cytosol / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D056811:Unfolded Protein Response
chemical_list: C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; D004722:Endoribonucleases
keywords: Apoptosis; ER stress; IRE1α; c-Jun N-terminal kinase; cytokines; type 1 diabetes