Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Diabetes. 2019 Mar;68(3):609-616. doi: 10.2337/db18-0846. Epub 2018 Dec 14.
Insulin-derived amyloidoma, also called an insulin ball, is a skin-related complication of insulin therapy caused by repeated insulin injections at the same site, where native folded insulin changes into amyloid fibrils and forms a mass with a granulomatous reaction. Insulin-derived amyloidoma is a clinically important condition because of its association with subcutaneous insulin resistance, but the precise effect and mechanism of the insulin absorption impairment have not been clarified. We generated insulin-derived amyloidomas in mouse skin, with the amyloidomas large enough to perform insulin tolerance tests in the mass by repeated injections of highly concentrated insulin amyloid fibrils. We demonstrated that the insulin-derived amyloidomas inhibit insulin absorption. By simultaneous administration of insulin and insulin amyloid fibrils, we showed that this effect is due to the amyloid fibril itself in the absence of a granulomatous reaction. In vitro studies revealed that insulin amyloid fibrils have extremely strong adhesion to native human insulin and various insulin analogs. Furthermore, we showed that native insulin that had adhered to insulin amyloid forms amyloid fibrils at physiological pH. These results suggest that the extreme adhesion of insulin amyloid to native insulin is the main mechanism of impaired insulin absorption and amyloidoma growth.
胰岛素衍生淀粉样变瘤，又称胰岛素球，是胰岛素治疗的一种皮肤相关并发症，由在同一部位重复注射胰岛素引起，其中天然折叠的胰岛素转变为淀粉样纤维并形成具有肉芽肿反应的团块。胰岛素衍生淀粉样变瘤与皮下胰岛素抵抗有关，因此是一种具有临床重要意义的病症，但确切的胰岛素吸收受损的作用机制尚未阐明。我们在小鼠皮肤中产生了胰岛素衍生淀粉样变瘤，这些淀粉样变瘤足够大，可以通过反复注射高浓度胰岛素淀粉样纤维在肿块中进行胰岛素耐量试验。我们证明了胰岛素衍生淀粉样变瘤抑制了胰岛素的吸收。通过同时给予胰岛素和胰岛素淀粉样纤维，我们表明这种作用是由于淀粉样纤维本身引起的，而与肉芽肿反应无关。体外研究表明，胰岛素淀粉样纤维对天然人胰岛素和各种胰岛素类似物具有极强的粘附性。此外，我们还表明，与胰岛素淀粉样纤维结合的天然胰岛素在生理 pH 值下形成淀粉样纤维。这些结果表明，胰岛素淀粉样纤维对天然胰岛素的极端粘附是胰岛素吸收受损和淀粉样变瘤生长的主要机制。
