Role of calcium ions in the aggregation process of hIAPP. Possible implications in T2DM.

Type 2 diabetes (T2DM), Alzheimer’s disease and other age-related neurodegenerative and systemic disorders are classified as amyloid disorders. hIAPP appears to be involved in the mechanisms underlying the pathogenesis of T2DM due to its tendency to aggregate and self-assemble. The aggregation of hIAPP is a dynamic process that leads to the formation of transient and heterogeneous oligomers which evolve to form insoluble fibrils. Oligomers appear to be more toxic to β cells than monomers and fibrils. The main target of hIAPP aggregates seems to be the plasma membrane which can undergo different types of damage, destruction of its integrity or alteration of the physical and biological properties that lead to oxidative stress. Numerous factors, both intrinsic and extrinsic to the peptide molecule, appear to influence the hIAPP aggregation process. Different metal ions are able to interact with the hIAPP molecule, modulating its secondary structure and subsequently the peptide’s capacity to aggregate. In this study, the effect of different Ca2+ concentrations on the hIAPP aggregation process was evaluated. The formation and morphology of hIAPP aggregate were respectively evaluated with Thioflavin T assays and electron microscopy, while the ability of the peptide to incorporate into POPC PLMs and form ion channels was monitored by single-channel current measurements. Ca2+ seems to favor the formation of soluble oligomers, suggesting a possible mechanism of hIAPP toxicity.