Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
UCL Respiratory Medicine, University College London, London WC1E 6BN, UK; Institute of Structural and Molecular Biology/Birkbeck, University of London, London WC1E 7HX, UK.
Dev Cell. 2021 Mar 22;56(6):747-760.e6. doi: 10.1016/j.devcel.2021.02.011. Epub 2021 Mar 4.
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 α-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α-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.
通过细胞凋亡导致胰岛素分泌的胰腺β细胞丧失是 2 型糖尿病进展的原因，但潜在机制仍不清楚。在这里，我们发现了一条途径，在这条途径中，细胞死亡抑制剂 ARC 反常地在糖尿病中成为了一种杀手。虽然细胞质 ARC 维持β细胞活力和胰腺结构，但在患有糖尿病的人和几种病理生理上不同的小鼠模型中，ARC 的一个池体会重新定位到细胞核，诱导β细胞凋亡。β细胞死亡是通过丝氨酸蛋白酶抑制剂（serpins）的协调下调引起的，这些丝氨酸蛋白酶抑制剂以前不知道是由β细胞合成和分泌的。细胞外空间中 α1-抗胰蛋白酶的丧失会释放弹性蛋白酶，从而破坏β细胞的锚定，随后导致细胞死亡。将α1-抗胰蛋白酶施用于糖尿病小鼠可防止β细胞死亡和代谢异常。这些数据揭示了 2 型糖尿病中β细胞丧失的途径，并确定了一种已获得 FDA 批准的药物，该药物可能阻碍该综合征的进展。
