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Human islet amyloid polypeptide (hIAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Mature hIAPP, a 37-aa peptide, is natively unfolded in its monomeric state but forms islet amyloid in T2DM. In common with other misfolded and aggregated proteins, amyloid formation involves aggregation of monomers of hIAPP into oligomers, fibrils, and ultimately mature amyloid deposits. hIAPP is coproduced and stored with insulin by the pancreatic islet β-cells and is released in response to the stimuli that lead to insulin secretion. Accumulating evidence suggests that hIAPP amyloid deposits that accompany T2DM are not just an insignificant phenomenon derived from the disease progression but that hIAPP aggregation induces processes that impair the functionality and the viability of β-cells. In this review, we particularly focus on hIAPP structure, hIAPP aggregation, and hIAPP-membrane interactions. We will also discuss recent findings on the mechanism of hIAPP-membrane damage and on hIAPP-induced cell death. Finally, the development of successful antiamyloidogenic agents that prevent hIAPP fibril formation will be examined.

International audience; The extracellular deposition of insoluble amyloid fibrils resulting from the aggregation of the amyloid-beta (A beta) is a pathological feature of neuronal loss in Alzheimer's disease (AD). Numerous small molecules have been reported to interfere with the process of A beta aggregation. Compounds containing aromatic structures, hydrophobic amino acids and/or the alpha-aminoisobutyric acid (Aib) as beta-sheet breaker elements have been reported to be effective inhibitors of A beta aggregation. We synthesized two peptides, one containing the Aib amino acid and the other including its trifluoromethylated analog (R)-alpha-Trifluoromethylalanine ((R)-Tfm-Alanine) and we evaluated the impact of these peptides on A beta amyloid formation. The compounds were tested by standard methods such as thioflavin-T fluorescence spectroscopy and transmission electron microscopy but also by circular dichroism, liquid state nuclear magnetic resonance (NMR) and NMR saturation transfer difference (STD) experiments to further characterize the effect of the two molecules on A beta structure and on the kinetics of depletion of monomeric, soluble A beta. Our results demonstrate that the peptide containing Aib reduces the quantity of aggregates containing beta-sheet structure but slightly inhibits A beta fibril formation, while the molecule including the trifluoromethyl (Tfm) group slows down the kinetics of A beta fibril formation, delays the random coil to beta-sheet structure transition and induces a change in the oligomerization pathway. These results suggest that the hydrophobic Tfm group has a better affinity with A beta than the methyl groups of the Aib and that this Tfm group is effective and important in preventing the A beta aggregation.