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.
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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.
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