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Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes

McKimpson, WM; Chen, Y; Irving, JA; Zheng, M; Weinberger, J; Tan, WLW; Tiang, Z; ... Kitsis, RN; + view all (2021) Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes. Developmental Cell , 56 (6) 747-760.e6. 10.1016/j.devcel.2021.02.011. Green open access

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Abstract

Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. β cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by β cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents β cell death and metabolic abnormalities. These data uncover a pathway for β cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome.

Type: Article
Title: Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.devcel.2021.02.011
Publisher version: https://doi.org/10.1016/j.devcel.2021.02.011
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: ARC, alpha-1 antitrypsin, cell death, diabetes, serpins
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > VP: Health
URI: https://discovery.ucl.ac.uk/id/eprint/10123622
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