Amyloid inhibitors enhance survival of cultured human islets

Abstract

BackgroundAmyloid fibrils created by misfolding and aggregation of proteins are a major pathological feature in a variety of degenerative diseases. Therapeutic approaches including amyloid vaccines and anti-aggregation compounds in models of amyloidosis point to an important role for amyloid in disease pathogenesis. Amyloid deposits derived from the β-cell peptide islet amyloid polypeptide (IAPP or amylin) are a characteristic of type 2 diabetes and may contribute to loss of β-cells in this disease. MethodsWe developed a cellular model of rapid amyloid deposition using cultured human islets and observed a correlation between fibril accumulation and β-cell death. A series of overlapping peptides derived from IAPP was generated. ResultsA potent inhibitor (ANFLVH) of human IAPP aggregation was identified. This inhibitory peptide prevented IAPP fibril formation in vitro and in human islet cultures leading to a striking increase in islet cell viability. ConclusionsThese findings indicate an important contribution of IAPP aggregation to β-cell death in situ and point to therapeutic applications for inhibitors of IAPP aggregation in enhancing β-cell survival. General significanceAnti-amyloid compounds could potentially reduce the loss of β-cell mass in type 2 diabetes and maintain healthy human islet cultures for β-cell replacement therapies.