Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes
Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes
复制标题
DOI：
10.1172/jci69625
复制
发表时间：
2014-08-01
影响因子：
15.9
通讯作者：
Lee, Myung-Shik
中科院分区：
文献类型：
--
作者：
Kim, Jinyoung;Cheon, Hwanju;Lee, Myung-Shik
胰岛淀粉样蛋白积聚是人类2型糖尿病（T2 D）的标志。与人胰岛淀粉样多肽（hIAPP）相反，鼠胰岛淀粉样多肽（mIAPP）不表现出淀粉样蛋白生成倾向。由于自噬在淀粉样蛋白的清除中很重要，我们研究了β细胞特异性表达hIAPP的转基因小鼠，以评估自噬在T2 D相关的hIAPP积累中的作用。在具有hIAPP的β细胞特异性表达的小鼠中，自噬的缺陷导致明显糖尿病的发展，这在单独表达hIAPP或单独缺乏自噬的小鼠中没有观察到。此外，在表达MAP的动物中缺乏自噬导致hIAPP寡聚体和淀粉样蛋白在胰岛中积累，导致死亡增加和β细胞质量减少。在纯化的猴胰岛细胞或鼠β细胞系中表达hIAPP导致pro-hIAPP二聚体形成，而在表达非淀粉样蛋白生成mIAPP或非纤维状突变hIAPP的细胞中不存在或显著减少二聚体形成。在自噬缺陷的细胞中，pro-hIAPP二聚体的积累显着增加，pro-hIAPP三聚体中检测到洗涤剂不溶性部分。自噬的增强改善了喂食高脂饮食的MAPP表达小鼠的代谢特征。这些结果表明，自噬促进淀粉样蛋白生成hIAPP的清除，自噬缺陷加剧人类T2 D的发病机制，自噬增强剂具有治疗胰岛淀粉样蛋白积聚相关的人类T2 D的潜力。
Islet amyloid accumulation is a hallmark of human type 2 diabetes (T2D). In contrast to human islet amyloid polypeptide (hIAPP), murine islet amyloid polypeptide (mIAPP) does not exhibit amyloidogenic propensity. Because autophagy is important in the clearance of amyloid-like proteins, we studied transgenic mice with beta cell-specific expression of hIAPP to evaluate the contribution of autophagy in T2D-associated accumulation of hIAPP. In mice with beta cell-specific expression of hIAPP, a deficiency in autophagy resulted in development of overt diabetes, which was not observed in mice expressing hIAPP alone or lacking autophagy alone. Furthermore, lack of autophagy in MAPP-expressing animals resulted in hIAPP oligomer and amyloid accumulation in pancreatic islets, leading to increased death and decreased mass of beta cells. Expression of hIAPP in purified monkey islet cells or a murine beta cell line resulted in pro-hIAPP dimer formation, while dimer formation was absent or reduced dramatically in cells expressing either nonamyloidogenic mIAPP or nonfibrillar mutant hIAPP. In autophagy-deficient cells, accumulation of pro-hIAPP dimers increased markedly, and pro-hIAPP trimers were detected in the detergent-insoluble fraction. Enhancement of autophagy improved the metabolic profile of MAPP-expressing mice fed a high-fat diet. These results suggest that autophagy promotes clearance of amyloidogenic hIAPP, autophagy deficiency exacerbates pathogenesis of human T2D, and autophagy enhancers have therapeutic potential for islet amyloid accumulation-associated human T2D.