Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM), Germany.
Sci Rep. 2017 Mar 13;7:44041. doi: 10.1038/srep44041.
Type II diabetes (T2D) is characterized by diminished insulin production and resistance of cells to insulin. Among others, endoplasmic reticulum (ER) stress is a principal factor contributing to T2D and induces a shift towards a more reducing cellular environment. At the same time, peripheral insulin resistance triggers the over-production of regulatory hormones such as insulin and human islet amyloid polypeptide (hIAPP). We show that the differential aggregation of reduced and oxidized hIAPP assists to maintain the redox equilibrium by restoring redox equivalents. Aggregation thus induces redox balancing which can assist initially to counteract ER stress. Failure of the protein degradation machinery might finally result in β-cell disruption and cell death. We further present a structural characterization of hIAPP in solution, demonstrating that the N-terminus of the oxidized peptide has a high propensity to form an α-helical structure which is lacking in the reduced state of hIAPP. In healthy cells, this residual structure prevents the conversion into amyloidogenic aggregates.
2 型糖尿病（T2D）的特征是胰岛素产生减少和细胞对胰岛素的抵抗。内质网（ER）应激是导致 T2D 的一个主要因素，它导致细胞向更还原的环境转变。与此同时，外周胰岛素抵抗会触发调节激素如胰岛素和人胰岛淀粉样多肽（hIAPP）的过度产生。我们表明，还原和氧化 hIAPP 的差异聚集有助于通过恢复氧化还原当量来维持氧化还原平衡。聚集因此诱导氧化还原平衡，最初可以帮助对抗 ER 应激。蛋白质降解机制的故障最终可能导致β细胞破坏和细胞死亡。我们进一步对溶液中的 hIAPP 进行结构表征，证明氧化肽的 N 端具有形成 α-螺旋结构的高倾向，而在 hIAPP 的还原状态下则缺乏这种结构。在健康细胞中，这种残留结构阻止了转化为淀粉样纤维聚集。
