An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis

Background: Pancreatic β-cells are the insulin factory of an organism with a mission to regulate glucose homeostasis in the body. Due to their high secretory activity, β-cells rely on a functional and intact endoplasmic reticulum (ER). Perturbations to ER homeostasis and unmitigated stress lead to β...

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Autores principales:	Gulcan Semra Sahin, Hugo Lee, Feyza Engin
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Er stress Beta cell Type 1 diabetes NOD mice Human islets Internal medicine RC31-1245
Acceso en línea:	https://doaj.org/article/cffe1661c7714398ae1a70141d83d43b
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spelling	oai:doaj.org-article:cffe1661c7714398ae1a70141d83d43b2021-11-20T05:05:54ZAn accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis2212-877810.1016/j.molmet.2021.101365https://doaj.org/article/cffe1661c7714398ae1a70141d83d43b2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S221287782100212Xhttps://doaj.org/toc/2212-8778Background: Pancreatic β-cells are the insulin factory of an organism with a mission to regulate glucose homeostasis in the body. Due to their high secretory activity, β-cells rely on a functional and intact endoplasmic reticulum (ER). Perturbations to ER homeostasis and unmitigated stress lead to β-cell dysfunction and death. Type 1 diabetes (T1D) is a chronic inflammatory disease caused by the autoimmune-mediated destruction of β-cells. Although autoimmunity is an essential component of T1D pathogenesis, accumulating evidence suggests an important role of β-cell ER stress and aberrant unfolded protein response (UPR) in disease initiation and progression. Scope of review: In this article, we introduce ER stress and the UPR, review β-cell ER stress in various mouse models, evaluate its involvement in inflammation, and discuss the effects of ER stress on β-cell plasticity and demise, and islet autoimmunity in T1D. We also highlight the relationship of ER stress with other stress response pathways and provide insight into ongoing clinical studies targeting ER stress and the UPR for the prevention or treatment of T1D. Major conclusions: Evidence from ex vivo studies, in vivo mouse models, and tissue samples from patients suggest that β-cell ER stress and a defective UPR contribute to T1D pathogenesis. Thus, restoration of β-cell ER homeostasis at various stages of disease presents a plausible therapeutic strategy for T1D. Identifying the specific functions and regulation of each UPR sensor in β-cells and uncovering the crosstalk between stressed β-cells and immune cells during T1D progression would provide a better understanding of the molecular mechanisms of disease process, and may reveal novel targets for development of effective therapies for T1D.Gulcan Semra SahinHugo LeeFeyza EnginElsevierarticleEr stressBeta cellType 1 diabetesNOD miceHuman isletsInternal medicineRC31-1245ENMolecular Metabolism, Vol 54, Iss , Pp 101365- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Er stress Beta cell Type 1 diabetes NOD mice Human islets Internal medicine RC31-1245
spellingShingle	Er stress Beta cell Type 1 diabetes NOD mice Human islets Internal medicine RC31-1245 Gulcan Semra Sahin Hugo Lee Feyza Engin An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis
description	Background: Pancreatic β-cells are the insulin factory of an organism with a mission to regulate glucose homeostasis in the body. Due to their high secretory activity, β-cells rely on a functional and intact endoplasmic reticulum (ER). Perturbations to ER homeostasis and unmitigated stress lead to β-cell dysfunction and death. Type 1 diabetes (T1D) is a chronic inflammatory disease caused by the autoimmune-mediated destruction of β-cells. Although autoimmunity is an essential component of T1D pathogenesis, accumulating evidence suggests an important role of β-cell ER stress and aberrant unfolded protein response (UPR) in disease initiation and progression. Scope of review: In this article, we introduce ER stress and the UPR, review β-cell ER stress in various mouse models, evaluate its involvement in inflammation, and discuss the effects of ER stress on β-cell plasticity and demise, and islet autoimmunity in T1D. We also highlight the relationship of ER stress with other stress response pathways and provide insight into ongoing clinical studies targeting ER stress and the UPR for the prevention or treatment of T1D. Major conclusions: Evidence from ex vivo studies, in vivo mouse models, and tissue samples from patients suggest that β-cell ER stress and a defective UPR contribute to T1D pathogenesis. Thus, restoration of β-cell ER homeostasis at various stages of disease presents a plausible therapeutic strategy for T1D. Identifying the specific functions and regulation of each UPR sensor in β-cells and uncovering the crosstalk between stressed β-cells and immune cells during T1D progression would provide a better understanding of the molecular mechanisms of disease process, and may reveal novel targets for development of effective therapies for T1D.
format	article
author	Gulcan Semra Sahin Hugo Lee Feyza Engin
author_facet	Gulcan Semra Sahin Hugo Lee Feyza Engin
author_sort	Gulcan Semra Sahin
title	An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis
title_short	An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis
title_full	An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis
title_fullStr	An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis
title_full_unstemmed	An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis
title_sort	accomplice more than a mere victim: the impact of β-cell er stress on type 1 diabetes pathogenesis
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/cffe1661c7714398ae1a70141d83d43b
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An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis

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