Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-7073, USA.
Am J Pathol. 2010 Feb;176(2):861-9. doi: 10.2353/ajpath.2010.090532. Epub 2009 Dec 30.
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 IAPP 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 IAPP toxic oligomers are formed intracellularly within the secretory pathway in T2DM. Most striking, IAPP 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.
2 型糖尿病（T2DM）中的胰岛的特征是β细胞缺陷和胰岛淀粉样多肽（IAPP）衍生的胰岛淀粉样，IAPP 是由β细胞与胰岛素共表达的一种蛋白质。人们越来越认识到，淀粉样蛋白原性蛋白的毒性形式不是淀粉样蛋白，而是更小的膜通透性寡聚物。我们使用针对毒性寡聚物的抗体和人 IAPP 转基因小鼠、人胰岛素瘤和 T2DM 患者和非 T2DM 患者的胰腺中的冷冻免疫金标记，旨在确定 IAPP 毒性寡聚物的丰度和形成部位。我们得出的结论是，在 T2DM 中，IAPP 毒性寡聚物在分泌途径的细胞内形成。最引人注目的是，IAPP 毒性寡聚物似乎破坏了分泌途径的膜，然后当与线粒体相邻时，破坏了线粒体膜。毒性寡聚物诱导的分泌途径和线粒体膜的破坏是一种新的机制，可以解释 T2DM 中的细胞功能障碍和细胞凋亡。
