Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to β-cell death in type 2 diabetes. We previously showed that extracellular hIAPP aggregates promote Fas-mediated β-cell apoptosis. Here, we tested if hIAPP aggregates can trigger the mitochondrial apoptotic pathway (MAP). hIAPP aggregation in Ad-hIAPP transduced INS-1 and human islet β-cells promoted cytochrome c release, caspase-9 activation and apoptosis, which were reduced by Bax inhibitor. Amyloid formation in hIAPP-expressing mouse islets during culture increased caspase-9 activation in β-cells. Ad-hIAPP transduced islets from Cytc^KA/KA and BaxBak βDKO mice (models of blocked MAP), had lower caspase-9-positive and apoptotic β-cells than transduced wild-type islets, despite comparable amyloid formation. Blocking Fas (markedly) and Bax or caspase-9 (modestly) reduced β-cell death induced by extracellular hIAPP aggregates. These findings suggest a role for MAP in amyloid-induced β-cell death and a potential strategy to reduce intracellular amyloid β-cell toxicity by blocking cytochrome c apoptotic function.

胰岛淀粉样蛋白由人胰岛淀粉样蛋白多肽 (hIAPP) 聚集形成，可导致 2 型糖尿病中的 β 细胞死亡。我们之前表明细胞外 hIAPP 聚集体促进 Fas 介导的 β 细胞凋亡。在这里，我们测试了 hIAPP 聚集体是否可以触发线粒体凋亡途径 (MAP)。Ad-hIAPP 转导的 INS-1 和人胰岛 β 细胞中的 hIAPP 聚集促进了细胞色素c的释放、caspase-9 的活化和细胞凋亡，而 Bax 抑制剂降低了这些。培养过程中表达 hIAPP 的小鼠胰岛中的淀粉样蛋白形成增加了 β 细胞中 caspase-9 的活化。来自Cytc ^KA/KA和BaxBak的 Ad-hIAPP 转导的胰岛βDKO 小鼠（阻断 MAP 的模型）与转导的野生型胰岛相比，具有较低的 caspase-9 阳性和凋亡 β 细胞，尽管淀粉样蛋白形成相当。阻断 Fas（显着）和 Bax 或 caspase-9（适度）减少了由细胞外 hIAPP 聚集体诱导的 β 细胞死亡。这些发现表明 MAP 在淀粉样蛋白诱导的 β 细胞死亡中的作用，以及通过阻断细胞色素c凋亡功能来降低细胞内淀粉样蛋白 β 细胞毒性的潜在策略。