Tongji School of Pharmacy , Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China , 430030.
Department of Pharmacy, The Central Hospital of Wuhan , Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China , 430014.
ACS Chem Biol. 2019 Mar 15;14(3):486-496. doi: 10.1021/acschembio.8b01128. Epub 2019 Feb 13.
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 β-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 B29 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 β-cells death and further deteriorates T2DM.
人胰岛淀粉样多肽（hIAPP）的聚集是 2 型糖尿病（T2DM）的触发因素之一。hIAPP 与胰岛素在胰岛β细胞中共同合成、共同储存和共同分泌，而胰岛素抑制 hIAPP 聚集。在 T2DM 患者中，长期高血糖导致近 10%的总胰岛素发生糖化。糖化不仅改变了胰岛素的结构，还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，使用了四种生理相关的单糖，即甲基乙二醛、葡萄糖、果糖和核糖，对人胰岛素和两种 C 端截断的胰岛素类似物进行糖化。糖化胰岛素单体或低分子量寡聚物（如二聚体）显著加重了 hIAPP 的细胞毒性。值得注意的是，胰岛素的糖化诱导交联抑制了 hIAPP 的聚集、膜破坏和细胞毒性，这一结果通过使用 EGS 诱导胰岛素或溶菌酶交联的对照研究得到了证实。胰岛素 B 链 C 端 B29 的缺失不仅消除了糖化诱导的交联，还减弱了糖化胰岛素对 hIAPP 细胞毒性的加重作用。总之，这项研究揭示了 T2DM 中的一个恶性循环，即高血糖驱动的胰岛素糖化加重了 hIAPP 的细胞毒性，从而加速了β细胞的死亡，并进一步恶化了 T2DM。
