ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes

Abstract Pancreatic β-cell loss through apoptosis is an important disease mechanism in type 2 diabetes. Apoptosis Repressor with CARD (ARC) is a cell death inhibitor that antagonizes multiple death programs. We previously reported that ARC is abundant in pancreatic β-cells and modulates survival of...

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Autores principales:	Wendy M. McKimpson, Min Zheng, Streamson C. Chua, Jeffrey E. Pessin, Richard N. Kitsis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7031996fde1a4687baa7bb1020469d40
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spelling	oai:doaj.org-article:7031996fde1a4687baa7bb1020469d402021-12-02T12:31:52ZARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes10.1038/s41598-017-07107-w2045-2322https://doaj.org/article/7031996fde1a4687baa7bb1020469d402017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07107-whttps://doaj.org/toc/2045-2322Abstract Pancreatic β-cell loss through apoptosis is an important disease mechanism in type 2 diabetes. Apoptosis Repressor with CARD (ARC) is a cell death inhibitor that antagonizes multiple death programs. We previously reported that ARC is abundant in pancreatic β-cells and modulates survival of these cells in vitro. Herein we assessed the importance of endogenous ARC in maintaining islet structure and function in vivo. While generalized loss of ARC did not result in detectable abnormalities, its absence in ob/ob mice, a model of type 2 diabetes, induced a striking pancreatic phenotype: marked β-cell death, loss of β-cell mass, derangements of islet architecture, and impaired glucose-stimulated insulin secretion in vivo. These abnormalities contributed to worsening of hyperglycemia and glucose-intolerance in these mice. Mechanistically, the absence of ARC increased levels of C/EBP homologous protein (CHOP) in wild type isolated islets stimulated with ER stress and in ob/ob isolated islets at baseline. Deletion of CHOP in ob/ob; ARC −/− mice led to reversal of β-cell death and abnormalities in islet architecture. These data indicate that suppression of CHOP by endogenous levels of ARC is critical for β-cell viability and maintenance of normal islet structure in this model of type 2 diabetes.Wendy M. McKimpsonMin ZhengStreamson C. ChuaJeffrey E. PessinRichard N. KitsisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-7 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wendy M. McKimpson Min Zheng Streamson C. Chua Jeffrey E. Pessin Richard N. Kitsis ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes
description	Abstract Pancreatic β-cell loss through apoptosis is an important disease mechanism in type 2 diabetes. Apoptosis Repressor with CARD (ARC) is a cell death inhibitor that antagonizes multiple death programs. We previously reported that ARC is abundant in pancreatic β-cells and modulates survival of these cells in vitro. Herein we assessed the importance of endogenous ARC in maintaining islet structure and function in vivo. While generalized loss of ARC did not result in detectable abnormalities, its absence in ob/ob mice, a model of type 2 diabetes, induced a striking pancreatic phenotype: marked β-cell death, loss of β-cell mass, derangements of islet architecture, and impaired glucose-stimulated insulin secretion in vivo. These abnormalities contributed to worsening of hyperglycemia and glucose-intolerance in these mice. Mechanistically, the absence of ARC increased levels of C/EBP homologous protein (CHOP) in wild type isolated islets stimulated with ER stress and in ob/ob isolated islets at baseline. Deletion of CHOP in ob/ob; ARC −/− mice led to reversal of β-cell death and abnormalities in islet architecture. These data indicate that suppression of CHOP by endogenous levels of ARC is critical for β-cell viability and maintenance of normal islet structure in this model of type 2 diabetes.
format	article
author	Wendy M. McKimpson Min Zheng Streamson C. Chua Jeffrey E. Pessin Richard N. Kitsis
author_facet	Wendy M. McKimpson Min Zheng Streamson C. Chua Jeffrey E. Pessin Richard N. Kitsis
author_sort	Wendy M. McKimpson
title	ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes
title_short	ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes
title_full	ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes
title_fullStr	ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes
title_full_unstemmed	ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes
title_sort	arc is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/7031996fde1a4687baa7bb1020469d40
work_keys_str_mv	AT wendymmckimpson arcisessentialformaintainingpancreaticisletstructureandbcellviabilityduringtype2diabetes AT minzheng arcisessentialformaintainingpancreaticisletstructureandbcellviabilityduringtype2diabetes AT streamsoncchua arcisessentialformaintainingpancreaticisletstructureandbcellviabilityduringtype2diabetes AT jeffreyepessin arcisessentialformaintainingpancreaticisletstructureandbcellviabilityduringtype2diabetes AT richardnkitsis arcisessentialformaintainingpancreaticisletstructureandbcellviabilityduringtype2diabetes
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ARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes

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