Extreme Adhesion Activity of Amyloid Fibrils Induces Subcutaneous Insulin Resistance
Extreme Adhesion Activity of Amyloid Fibrils Induces Subcutaneous Insulin Resistance
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DOI：
10.2337/db18-0846
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发表时间：
2019-03-01
期刊：
影响因子：
7.7
通讯作者：
Ueda, Mitsuharu
中科院分区：
文献类型：
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作者：
Nakamura, Makoto;Misumi, Yohei;Ueda, Mitsuharu
胰岛素源性淀粉样瘤，也称为胰岛素球，是胰岛素治疗的皮肤相关并发症，由在同一部位重复注射胰岛素引起，其中天然折叠胰岛素变为淀粉样纤维并形成具有肉芽肿反应的团块。胰岛素源性淀粉样瘤因其与皮下胰岛素抵抗有关而成为临床上重要的疾病，但胰岛素吸收障碍的确切影响和机制尚未阐明。我们在小鼠皮肤中产生了胰岛素源性淀粉样瘤，淀粉样瘤足够大，可以通过重复注射高浓度胰岛素淀粉样纤维进行胰岛素耐受性试验。我们证明胰岛素源性淀粉样瘤抑制胰岛素吸收。通过同时给予胰岛素和胰岛素淀粉样纤维，我们发现这种作用是由于淀粉样纤维本身在没有肉芽肿反应的情况下。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，我们发现，天然胰岛素，粘附到胰岛素淀粉样蛋白形成淀粉样蛋白纤维在生理pH值。这些结果表明，极端粘附的胰岛素淀粉样蛋白的天然胰岛素是受损的胰岛素吸收和淀粉样瘤生长的主要机制。
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.