Division of Metabolism, Endocrinology and Diabetes and Department of Internal Medicine, and.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
JCI Insight. 2020 Dec 17;5(24):141138. doi: 10.1172/jci.insight.141138.
Inflammatory damage contributes to β cell failure in type 1 and 2 diabetes (T1D and T2D, respectively). Mitochondria are damaged by inflammatory signaling in β cells, resulting in impaired bioenergetics and initiation of proapoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here, we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent β cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic proinflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient β cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased β cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human β cell apoptosis. Thus, mitophagy promotes β cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent β cell failure in diabetes and may be beneficial in other inflammatory conditions.
炎症损伤导致 1 型和 2 型糖尿病（T1D 和 T2D）中β细胞衰竭。β细胞中的炎症信号会损伤线粒体，导致生物能量受损和促凋亡机制的启动。因此，识别对炎症的保护反应可能会导致新的治疗靶点。在这里，我们报告说，自噬在人和啮齿动物的β细胞中作为对炎症应激的保护反应。利用体内自噬报告基因，我们观察到致糖尿病的促炎细胞因子诱导自噬以响应硝化/氧化线粒体损伤。自噬缺陷的β细胞对炎症应激敏感，导致碎片化功能失调的线粒体积累、β细胞死亡增加和高血糖。CLEC16A 的过表达，一种 T1D 基因和自噬调节剂，其在胰岛中的表达可预防 T1D，改善细胞因子诱导的人β细胞凋亡。因此，自噬通过对抗炎症损伤促进β细胞存活并预防糖尿病。靶向该途径有可能防止糖尿病中β细胞衰竭，并且在其他炎症情况下可能是有益的。
