Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
Garvan Institute of Medical Research, Sydney, Australia.
Diabetes. 2021 Jun;70(6):1229-1241. doi: 10.2337/dbi20-0014. Epub 2021 May 20.
Insulin-producing pancreatic β-cells are central to glucose homeostasis, and their failure is a principal driver of diabetes development. To preserve optimal health β-cells must withstand both intrinsic and extrinsic stressors, ranging from inflammation to increased peripheral insulin demand, in addition to maintaining insulin biosynthesis and secretory machinery. Autophagy is increasingly being appreciated as a critical β-cell quality control system vital for glycemic control. Here we focus on the underappreciated, yet crucial, roles for selective and organelle-specific forms of autophagy as mediators of β-cell health. We examine the unique molecular players underlying each distinct form of autophagy in β-cells, including selective autophagy of mitochondria, insulin granules, lipid, intracellular amyloid aggregates, endoplasmic reticulum, and peroxisomes. We also describe how defects in selective autophagy pathways contribute to the development of diabetes. As all forms of autophagy are not the same, a refined view of β-cell selective autophagy may inform new approaches to defend against the various insults leading to β-cell failure in diabetes.
产生胰岛素的胰腺β细胞是葡萄糖稳态的核心，其功能衰竭是糖尿病发展的主要驱动因素。为了保持最佳健康，β细胞必须耐受内在和外在的应激源，包括炎症、外周胰岛素需求增加，以及维持胰岛素生物合成和分泌机制。自噬越来越被认为是一种关键的β细胞质量控制系统，对血糖控制至关重要。在这里，我们重点关注选择性和细胞器特异性自噬作为β细胞健康介质的未被充分认识但至关重要的作用。我们研究了每种不同形式的自噬在β细胞中所依赖的独特分子机制，包括线粒体、胰岛素颗粒、脂质、细胞内淀粉样蛋白聚集物、内质网和过氧化物酶体的选择性自噬。我们还描述了选择性自噬途径的缺陷如何导致糖尿病的发生。由于所有形式的自噬都不相同，对β细胞选择性自噬的更精细的观察可能为对抗导致糖尿病β细胞衰竭的各种损伤提供新的方法。
