Metal Modulates Human Islet Amyloid Polypeptide Aggregation In Type 2 Diabetes

Amyloid deposition in pancreatic islets is a common feature in human type 2 diabetes mellitus (T2DM). Human islet amyloid polypeptide (hIAPP), which is the main component of islet amyloid, contains 37 amino acid residues. Evidences have shown that fibrillogenic hIAPP amyloid is related to pancreaticβ-cell loss and hIAPP cytotoxicity mainly involves the soluble hIAPP oligomers formation, membrane destabilization and oxidative stress. Increasing evidence suggests that metal is involved in pathological amyloid protein aggregation, but the mechanism of amyloid accumulation modulated by metal is still unclear.Here we study the impact of Cu, Ni and Zn to hIAPP aggregation and cytotoxicity, as well as the mechanism of Ta surface-induced hIAPP aggregation. First, we explored an alternative pathway of copper-mediated cytotoxicity via hIAPP oligomer formation. We found that hIAPP-inducedβ-cell apoptosis by inhibiting hIAPP fibril formation and by inducing hIAPP to aggregate into granular oligomers. We also tested the effect of nickel on hIAPP aggregation, since the protein-binding characteristics of nickel are similar to those of copper, but nickel does not generate reactive oxygen species. Nickel also induced higherβ-cell cytotoxicity via hIAPP oligomer formation. These data indicate that copper-mediated hIAPP cytotoxicity is due mainly to granular oligomer formation rather than to reactive oxygen species accumulation. In contrast with Cu(II) and Ni(II), Zn(II) enhanced the fibril formation via hIAPP by inducingβ-sheet conformation. We also utilized Ta surface to study the mechanism of surface-induced hIAPP aggregation and we found that hIAPP grows into long fibrils in a two dimension manner without knot structures which are shown when hIAPP is incubated in the bulk solution. These results reveal a novel mechanism of metal-mediated cytotoxicity and illustrate the important role of metal in the progression of type 2 diabetes.