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      Endoplasmic reticulum stress and destruction of pancreatic β cells in type 1 diabetes

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          Abstract

          Type 1 diabetes (T1D) results from dysfunction of pancreatic islets β cells. Recent studies supported that endoplasmic reticulum (ER) stress takes an important role in pancreatic β cell excessive loss, resulting in T1D. Here, we aimed to review the relationship between ER stress and T1D. Additionally, we also reviewed the potential mechanisms underlying ER stress mediated T1D. Studies have shown that severe ER stress is directly involved in the pancreatic β cells destruction and pathogenesis of T1D. ER stress plays a key part in pancreatic β cells and T1D, which will help in developing new effective therapeutics for T1D.

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          Most cited references40

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          The endoplasmic reticulum: structure, function and response to cellular signaling

          The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle.
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            Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival.

            The protein kinase PERK couples protein folding in the endoplasmic reticulum (ER) to polypeptide biosynthesis by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha), attenuating translation initiation in response to ER stress. PERK is highly expressed in mouse pancreas, an organ active in protein secretion. Under physiological conditions, PERK was partially activated, accounting for much of the phosphorylated eIF2alpha in the pancreas. The exocrine and endocrine pancreas developed normally in Perk-/- mice. Postnatally, ER distention and activation of the ER stress transducer IRE1alpha accompanied increased cell death and led to progressive diabetes mellitus and exocrine pancreatic insufficiency. These findings suggest a special role for translational control in protecting secretory cells from ER stress.
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              Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes.

              The progression from insulin resistance to type 2 diabetes is caused by the failure of pancreatic beta cells to produce sufficient levels of insulin to meet the metabolic demand. Recent studies indicate that nutrient fluctuations and insulin resistance increase proinsulin synthesis in beta cells beyond the capacity for folding of nascent polypeptides within the endoplasmic reticulum (ER) lumen, thereby disrupting ER homeostasis and triggering the unfolded protein response (UPR). Chronic ER stress promotes apoptosis, at least in part through the UPR-induced transcription factor C/EBP homologous protein (CHOP). We assessed the effect of Chop deletion in multiple mouse models of type 2 diabetes and found that Chop-/- mice had improved glycemic control and expanded beta cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved beta cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop-/- mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in beta cells under conditions of increased insulin demand.
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                Author and article information

                Journal
                Chin Med J (Engl)
                Chin. Med. J
                CM9
                Chinese Medical Journal
                Wolters Kluwer Health
                0366-6999
                2542-5641
                05 January 2020
                05 January 2020
                : 133
                : 1
                : 68-73
                Affiliations
                Department of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
                Author notes
                Correspondence to: Xiao-Bo Hu, Department of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, ChinaE-Mail: huxiaobo@ 123456foxmail.com
                Article
                CMJ-2019-1046 00009
                10.1097/CM9.0000000000000583
                7028193
                31923106
                0a4cf62d-dbd2-4fcb-9d58-5e74ad3c82f3
                Copyright © 2019 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                : 09 July 2019
                Categories
                Review Article
                Custom metadata
                TRUE

                endoplasmic reticulum stress,inflammation,autoimmunity,type 1 diabetes

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