Evidence for Proteotoxicity in β Cells in Type 2 Diabetes Toxic Islet Amyloid Polypeptide Oligomers Form Intracellularly in the Secretory Pathway
Evidence for Proteotoxicity in β Cells in Type 2 Diabetes Toxic Islet Amyloid Polypeptide Oligomers Form Intracellularly in the Secretory Pathway
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DOI：
10.2353/ajpath.2010.090532
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发表时间：
2010-02-01
影响因子：
6
通讯作者：
Butler, Peter C.
中科院分区：
文献类型：
--
作者：
Gurlo, Tatyana;Ryazantsev, Sergey;Butler, Peter C.
2 型糖尿病 (T2DM) 中的胰岛的特点是 β 细胞和源自胰岛淀粉样多肽 (IAPP) 的胰岛淀粉样蛋白缺乏，IAPP 是一种由 β 细胞与胰岛素共表达的蛋白质。人们越来越认识到，淀粉样蛋白的毒性形式不是淀粉样蛋白，而是较小的膜渗透寡聚体。在人类 LAPP 转基因小鼠、人类胰岛素瘤和患有或未患有 T2DM 的人类胰腺中使用有毒寡聚体特异性抗体和冷冻免疫金标记，我们试图确定 IAPP 有毒寡聚体的丰度和形成位点。我们得出结论，LAPP 毒性寡聚体是在 T2DM 的分泌途径内细胞内形成的。最引人注目的是 LAPP 有毒低聚物；似乎会破坏分泌途径的膜，然后当邻近线粒体时，会破坏线粒体膜。有毒寡聚物诱导的分泌途径和线粒体膜破坏是解释 T2DM 细胞功能障碍和细胞凋亡的新机制。 （Am J Pathol 2010，176：861-869；DOI：10.2353/ajpath.2010.090532）
The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in beta cells and islet amyloid derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by beta cells. It is increasingly appreciated that the toxic form of amyloidogenic proteins is not amyloid but smaller membrane-permeant oligomers. Using an antibody specific for toxic oligomers and cryo-immunogold labeling in human LAPP transgenic mice, human insulinoma and pancreas from humans with and without T2DM, we sought to establish the abundance and sites of formation of IAPP toxic oligomers. We conclude that LAPP toxic oligomers are formed intracellularly within the secretory pathway in T2DM. Most striking, LAPP toxic oligomers; appear to disrupt membranes of the secretory pathway, and then when adjacent to mitochondria, disrupt mitochondrial membranes. Toxic oligomer-induced secretory pathway and mitochondrial membrane disruption is a novel mechanism to account for cellular dysfunction and apoptosis in T2DM. (Am J Pathol 2010, 176:861-869; DOI: 10.2353/ajpath.2010.090532)