Mori Wakako, Yuzu Keisuke, Lobsiger Nadine, Nishioka Hideo, Sato Hisako, Nagase Terumasa, Iwaya Keiichi, Lindgren Mikael, Zako Tamotsu
Department of Chemistry and Biology, Graduate School of Science and Engineering, Ehime University, Ehime, 790-8577, Japan.
Institute for Chemical and Bioengineering, ETH Zürich, 8093, Zürich, Switzerland.
Sci Rep. 2021 Mar 25;11(1):6857. doi: 10.1038/s41598-021-86001-y.
Insulin balls, localized insulin amyloids formed at subcutaneous insulin-injection sites in patients with diabetes, cause poor glycemic control owing to impairments in insulin absorption. Our previous study has shown that some insulin balls are cytotoxic, but others are not, implying amyloid polymorphism. Interestingly, the patient with toxic insulin balls had been treated with antibiotic minocycline, suggesting a possible relationship between toxicity of insulin balls and minocycline. However, the direct effect of minocycline on the structure and cytotoxicity of the insulin amyloid is still unclear. Herein, we demonstrated that that minocycline at physiological concentrations induced degradation of insulin amyloids formed from human insulin and insulin drug preparations used for diabetes patients. Interestingly, the process involved the initial appearance of the toxic species, which subsequently changed into less-toxic species. It is also shown that the structure of the toxic species was similar to that of sonicated fragments of human insulin amyloids. Our study shed new light on the clarification of the revelation of insulin balls and the development of the insulin analogs for diabetes therapy.
胰岛素球是糖尿病患者皮下胰岛素注射部位形成的局部胰岛素淀粉样蛋白，由于胰岛素吸收受损，导致血糖控制不佳。我们之前的研究表明，一些胰岛素球具有细胞毒性，而另一些则没有，这意味着淀粉样蛋白多态性。有趣的是，患有毒性胰岛素球的患者曾接受过抗生素米诺环素治疗，这表明胰岛素球的毒性与米诺环素之间可能存在关联。然而，米诺环素对胰岛素淀粉样蛋白结构和细胞毒性的直接影响仍不清楚。在此，我们证明生理浓度的米诺环素可诱导由人胰岛素和糖尿病患者使用的胰岛素药物制剂形成的胰岛素淀粉样蛋白降解。有趣的是，这个过程涉及有毒物种的最初出现，随后它们转变为毒性较小的物种。还表明，有毒物种的结构与人类胰岛素淀粉样蛋白的超声破碎片段相似。我们的研究为阐明胰岛素球的奥秘以及开发用于糖尿病治疗的胰岛素类似物提供了新的线索。
