Inhibition of human islet amyloid polypeptide aggregation and cellular toxicity by oleuropein and derivatives from olive oil

Loss of beta-cell function and beta-cell death is the key feature of type 2 diabetes mellitus (T2DM). One hypothesis for the mechanism of this feature is amyloid formation by the human islet amyloid polypeptide (hIAPP). Despite the global prevalence of T2DM, there are no therapeutic strategies for the treatment of or prevention of amylin amyloidosis. Clinical trials and population studies indicate the healthy virtues of the Mediterranean diet, especially the extra virgin olive oil (EVOO) found in this diet. This oil is enriched in phenolic compounds shown to be effective against several aging and lifestyle diseases. Oleuropein (Ole), one of the most abundant polyphenols in EVOO, has been reported to be anti-diabetic. Some of Ole's main derivative have attracted our interest due to their multi-targetted effects, including interference with amyloid aggregation path. However, the structure function relationship of Ole and its metabolites in T2DM are not yet clear. We report here a broad biophysical approach and cell biology techniques that enabled us to characterize the different molecular mechanisms by which tyrosol (TYR), hydroxytyrosol (HT), oleuropein (Ole) and oleuropein aglycone (OleA) modulate the hIAPP fibrillation in vitro and their effects on cell cytotoxicity. The OleA formed by enolic acid and hydroxytyrosol moiety was found to be more active than the Ole and HT at low micromolar concentrations. We further demonstrated that OleA inhibit the cytotoxicity induced by hIAPP aggregates by protecting more the cell membrane from permeabilization and then from death. These findings highlight the benefits of consuming EVOO and the great potential of its polyphenols, mainly OleA. Moreover, they support the possibility to validate and optimize the possible pharmacological use of EVOO polyphenols for T2DM prevention and therapy and also for many other amyloid related diseases. (c) 2020 The Author. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).