Islet amyloid polypeptide: Aggregation and fibrillogenesis in vitro and its inhibition

Abstract

The development of type 2 diabetes mellitus is associated with the dysfunction of β-cells which is correlated to the formation of deposits consisting of the islet amyloid polypeptide (IAPP). The process of human IAPP (hIAPP) selfassociation, the intermediate structures formed as well as the interaction of hIAPP with membrane systems seem to be responsible for the cytotoxicity. For monomeric hIAPP, a natively random coil conformation with transient α-helical parts could be determined in bulk solution, which rapidly converts to an amyloid structure consisting of cross β-sheets. By comparing the amyloidogenic propensities of hIAPP in the bulk and in the presence of various neutral and charged lipid bilayer systems as well as biological membranes, an enhancing effect of anionic and heterogeneous membranes to hIAPP fibril formation has been found. We also discuss the crossinteraction of hIAPP with other amyloidogenic peptides (e.g., insulin and Aβ) and present first small-molecule inhibitors of the fibrillation process of hIAPP.