| First Author | McKimpson WM | Year | 2021 |
| Journal | Dev Cell | Volume | 56 |
| Issue | 6 | Pages | 747-760.e6 |
| PubMed ID | 33667344 | Mgi Jnum | J:303708 |
| Mgi Id | MGI:6515850 | Doi | 10.1016/j.devcel.2021.02.011 |
| Citation | McKimpson WM, et al. (2021) Conversion of the death inhibitor ARC to a killer activates pancreatic beta cell death in diabetes. Dev Cell 56(6):747-760.e6 |
| abstractText | Loss of insulin-secreting pancreatic beta 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 beta cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce beta cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. beta cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by beta cells. Loss of the serpin alpha1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of beta cell anchorage and subsequent cell death. Administration of alpha1-antitrypsin to mice with diabetes prevents beta cell death and metabolic abnormalities. These data uncover a pathway for beta cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome. |
