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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. [ABSTRACT FROM AUTHOR]