Open AccessARC is essential for maintaining pancreatic islet structure and β-cell viability during type 2 diabetes
Author(s) -
Wendy M. McKimpson,
Min Zheng,
Streamson C. Chua,
Jeffrey E. Pessin,
Richard N. Kitsis
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-07107-w
Subject(s) - islet , type 2 diabetes , diabetes mellitus , arc (geometry) , pancreatic islets , type 1 diabetes , viability assay , medicine , endocrinology , bioinformatics , computational biology , microbiology and biotechnology , biology , cell , biochemistry , mathematics , geometry
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.