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

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

SUBMITTER: McKimpson WM 

PROVIDER: S-EPMC8146085 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature