Glycated Insulin Exacerbates the Cytotoxicity of Human Islet Amyloid Polypeptides: a Vicious Cycle in Type 2 Diabetes
Glycated Insulin Exacerbates the Cytotoxicity of Human Islet Amyloid Polypeptides: a Vicious Cycle in Type 2 Diabetes
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糖化胰岛素加剧人胰岛淀粉样多肽的细胞毒性：2 型糖尿病的恶性循环
DOI：
10.1021/acschembio.8b01128
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发表时间：
2019-03-01
影响因子：
4
通讯作者：
Huang, Kun
中科院分区：
文献类型：
--
作者：
Ma, Liang;Yang, Chen;Huang, Kun
人胰岛淀粉样多肽（hIAPP）聚集是2型糖尿病（T2DM）的诱发因素之一。hIAPP在胰腺β细胞中与胰岛素共合成、共储存和共分泌，胰岛素抑制hIAPP聚集。在T2DM患者中，长期高血糖导致近10%的总胰岛素糖化。糖基化不仅改变胰岛素，而且使胰岛素交联成低聚物。然而，糖化人胰岛素对hIAPP聚集的影响尚不清楚。在这项研究中，四种生理相关的单糖，甲基乙二醛，葡萄糖，果糖和核糖被用于糖基化人胰岛素和两种c端截断的胰岛素类似物。糖化胰岛素单体或低分子量低聚物（如二聚体）显著加重hIAPP的细胞毒性。值得注意的是，糖基化诱导的胰岛素交联抑制了hIAPP的聚集、膜破坏和细胞毒性，这一点在egs诱导的胰岛素或溶菌酶交联的对照研究中得到了证实。去除胰岛素B链C端B29LYS不仅可以消除糖基化诱导的交联，还可以减轻糖基化胰岛素对hIAPP细胞毒性的加重作用。综上所述，本研究揭示了T2DM的恶性循环，高血糖驱动的胰岛素糖化加剧了hIAPP的细胞毒性，从而加速了β细胞的死亡，进一步恶化了T2DM。
The aggregation of human islet amyloid polypeptide (hIAPP) is one of the triggering factors of type 2 diabetes mellitus (T2DM). hIAPP is cosynthesized, costored, and cosecreted with insulin in pancreatic beta-cells, and insulin inhibits hIAPP aggregation. In T2DM patients, long-term hyperglycemia causes glycation of near 10% of total insulin. The glycation not only modifies insulin but also cross-links insulin into oligomers. However, the effect of glycated human insulin on hIAPP aggregation is unknown. In this study, four physiologically relevant monosaccharides, methylglyoxal, glucose, fructose, and ribose were used to glycate human insulin and two C-terminus truncated insulin analogues. Glycated insulin monomers or low molecular weight oligomers such as dimers significantly exacerbated the cytotoxicity of hIAPP. Notably, glycation-induced cross-linking of insulin inhibited the aggregation, membrane disruption, and cytotoxicity of hIAPP, which was corroborated by a control study using EGS-induced cross-linking of insulin or lysozyme. Removal of B29LYS on the C terminus of the insulin B chain not only abolished glycation-induced cross-linking but also attenuated the aggravation effect of glycated insulin on hIAPP cytotoxicity. Taken together, this study reveals a vicious cycle in T2DM, that hyperglycemia-driven insulin glycation exacerbates the cytotoxicity of hIAPP, which accelerates beta-cells death and further deteriorates T2DM.