Macroautophagy in homeostasis of pancreatic β-cell
Macroautophagy in homeostasis of pancreatic β-cell
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DOI：
10.4161/auto.5.2.7518
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发表时间：
2009-02-16
期刊：
影响因子：
13.3
通讯作者：
Lee, Myung-Shik
中科院分区：
文献类型：
--
作者：
Jung, Hye Seung;Lee, Myung-Shik
糖尿病的特征是胰岛素分泌和作用减少。胰岛素分泌减少是由于胰腺β细胞质量和功能减少所致。细胞凋亡、氧化应激、线粒体功能障碍和包括JNK激活在内的内质网应激反应被认为是2型糖尿病胰腺β细胞变化的机制，但其根本原因尚不清楚。自噬是细胞内的一个过程，通过组成性或响应环境条件的细胞器的降解和再循环，在细胞内稳态中起着至关重要的作用。我们使用β细胞特异性缺失Atg7（自噬相关7）基因的小鼠研究了自噬在胰腺β细胞中的作用。Atg7突变小鼠表现出细胞凋亡增加和β细胞增殖减少，导致β细胞质量减少。由于β细胞质量减少和胰岛素颗粒数量减少，胰腺胰岛素含量降低。β细胞的形态学分析显示泛素化蛋白的积累、肿胀的线粒体和膨胀的ER。离体胰岛素分泌功能也受损。结果，自噬缺陷小鼠表现出低胰岛素血症和高血糖症。这些结果表明，自噬是必要的，以维持结构，质量和功能的胰腺β细胞。在这里，我们讨论了胰腺β细胞自噬的意义及其与糖尿病发展的潜在相关性。
Diabetes mellitus is characterized by decreased insulin secretion and action. Decreased insulin secretion results from a reduction in pancreatic beta-cell mass and function. Apoptosis, oxidative stress, mitochondrial dysfunction, and ER stress responses including JNK activation have been suggested as mechanisms of the changes of pancreatic beta-cells in type 2 diabetes, however, the underlying causes were not clearly elucidated. Autophagy is an intracellular process that plays a crucial role in cellular homeostasis through degradation and recycling of organelles constitutively or in response to the environmental condition. We studied the role of autophagy in pancreatic beta-cells using mice with beta-cell-specific deletion of the Atg7 (autophagy-related 7) gene. Atg7-mutant mice showed increased apoptosis and decreased proliferation of beta-cells with resultant reduction in beta-cell mass. Pancreatic insulin content was decreased due to the decreased beta-cell mass and reduced number of insulin granules. Morphological analysis of beta-cells revealed accumulation of ubiquitinated proteins, swollen mitochondria, and distended ER. Insulin secretary function ex vivo was also impaired. As a result, autophagy-deficient mice showed hypoinsulinemia and hyperglycemia. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic beta-cells. Here we discuss the significance of autophagy in pancreatic beta-cells with its potential relevance to the development of diabetes.