Unraveling the contribution of pancreatic beta-cell suicide in autoimmune type 1 diabetes.
In type 1 diabetes, an autoimmune disease mediated by autoreactive T-cells that attack insulin-secreting pancreatic beta-cells, it has been suggested that disease progression may additionally require protective mechanisms in the target tissue to impede such auto-destructive mechanisms. We hypothesize that the autoimmune attack against beta-cells causes endoplasmic reticulum stress by forcing the remaining beta-cells to synthesize and secrete defective insulin. To rescue beta-cell from the endoplasmic reticulum stress, beta-cells activate the unfolded protein response to restore protein homeostasis and normal insulin synthesis. Here we investigate the compensatory role of unfolded protein response by developing a multi-state model of type 1 diabetes that takes into account beta-cell destruction caused by pathogenic autoreactive T-cells and apoptosis triggered by endoplasmic reticulum stress. We discuss the mechanism of unfolded protein response activation and how it counters beta-cell extinction caused by an autoimmune attack and/or irreversible damage by endoplasmic reticulum stress. Our results reveal important insights about the balance between beta-cell destruction by autoimmune attack (beta-cell homicide) and beta-cell apoptosis by endoplasmic reticulum stress (beta-cell suicide). It also provides an explanation as to why the unfolded protein response may not be a successful therapeutic target to treat type 1 diabetes.
Department of Physiology, McGill University, Montreal, QC, Canada H3G 1Y6. Electronic address: majid.jaberi-douraki@mail.mcgill.ca.
Majid
M
Jaberi-Douraki
Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Brehm Center for Diabetes Research, University of Michigan Medical School, Ann Arbor, MI 48105, USA. Electronic address: schnells@umich.edu.
Santiago
S
Schnell
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Brehm Center for Diabetes Research, University of Michigan Medical School, Ann Arbor, MI 48105, USA. Electronic address: maxtp@med.umich.edu.
Massimo
M
Pietropaolo
Department of Physiology, McGill University, Montreal, QC, Canada H3G 1Y6. Electronic address: anmar.khadra@mcgill.ca.
Anmar
A
Khadra
D000465:Algorithms; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000276:immunology; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008954:Models, Biological; D056811:Unfolded Protein Response
D007328:Insulin
Beta-cell homicide and suicide; ER-stress in T1D; Mathematical model; Uncertainty and sensitivity analysis; Unfolded protein response