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

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

Developmental cell (2021-03-06)
Wendy M McKimpson, Yun Chen, James A Irving, Min Zheng, Jeremy Weinberger, Wilson Lek Wen Tan, Zenia Tiang, Alistair M Jagger, Streamson C Chua, Jeffrey E Pessin, Roger S-Y Foo, David A Lomas, Richard N Kitsis
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-PARP1 antibody produced in mouse, Prestige Antibodies® Powered by Atlas Antibodies, clone CL2220, purified immunoglobulin, buffered aqueous glycerol solution
Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, clone DM1A, ascites fluid
Roche
In Situ Cell Death Detection Kit, Fluorescein, sufficient for ≤50 tests, suitable for detection