Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration

While islet amyloid polypeptide (IAPP) aggregation is associated with beta-cell death in type-II diabetes (T2D), environmental elements of beta-cell granules - e.g. high concentrations of insulin and Zn2+ - inhibit IAPP aggregation in healthy individuals. The inhibition by insulin is experimentally known, but the role of Zn2+ is controversial as both correlations and anti-correlations at the population level are observed between T2D risk and the activity of a beta-cell specific zinc ion transporter, ZnT8. Since Zn2+ concentration determines insulin oligomer equilibrium, we computationally investigated interactions of IAPP with different insulin oligomers and compared with IAPP homodimer formation. We found that IAPP binding with insulin oligomers competes with the formation of both higher-molecular-weight insulin oligomers and IAPP homodimers. Therefore, zinc deficiency due to loss-of-function ZnT8 mutations shifts insulin oligomer equilibrium toward zinc-free monomers and dimers, which bind IAPP monomers more efficiently compared to zinc-bound hexamers. The hetero-molecular complex formation prevents IAPP from self-association and subsequent aggregation, reducing T2D risk.