Introduction: Diabetes is one of the major causes of premature illness and mortality worldwide. Disease onset and progression has been associated to intracellular aggregation of Islet Amyloid PolyPeptide (IAPP), or amylin, which impairs proper function of pancreatic beta-cells and insulin secretion. As disease progresses, amyloid deposition in the pancreas appears in 90% of individuals, constituting a histopathological hallmark of the disease. The potential inhibition of IAPP aggregation, allowing the improvement of beta-cell functionality, remains a therapeutic target yet unexplored. Diet is an essential source of bioactive compounds. Encouraged by the reported activity of dietary (poly)phenols (PP) against diabetes [1], we hypothesized that low molecular weight metabolites resulting from PP metabolism in the human body may modulate IAPP aggregation. Objectives: Benefiting from an in-house library of predicted bioavailable PP metabolites, the objectives of this study were (a) the identification of metabolites potentially preventing IAPP aggregation and (b) the characterization of their activity towards the improvement of beta-cell function. Methods: In silico testing of putative interactions of PP metabolites and IAPP (NMR structure 2L86 from Protein Data Base) was performed using Auto Dock Vina software. The best hit was assayed in cell-free systems using synthetic IAPP by means of Thioflavin-T assays and Transmission Electronic Microscopy. Metabolite-mediated protection was investigated by means of genetic (mutation analysis), biochemical (ELISA, enzymatic activity assays), cellular (fluorescence microscopy) and molecular biology (flow-cytometry, immunoblotting, RNA sequencing) approaches [2], using eukaryotic reporter systems expressing human IAPP [2,3] and INS-1 832/13 pancreatic beta-cells challenged with IAPP aggregates. Proper statistical analyses were performed using GraphPad and results of at least three biological replicates were included. Results: Among approximately 200 PP metabolites tested in silico, Urolithin B (UroB) emerged as the best performing molecule interacting with IAPP. In cell-free assays, UroB interfered with the kinetics of IAPP fibril formation and modulated the size and morphology of IAPP fibrils. The cytoprotective effects of UroB were first assessed in yeast models recapitulating human IAPP aggregation and cytotoxicity [2]. UroB prevented IAPP-induced cell death, reduced the size of IAPP aggregates and decreased IAPP insoluble fractions. Mechanistic studies revealed the involvement of autophagy, cell antioxidant responses and calcium-signaling in UroB-mediated protection. Also, UroB protection in beta-cells challenged with hyperglycemia and hyperlipidemia was associated with the attenuation of oxidative stress. Furthermore, transcriptomic analysis indicated calcium-signaling as the top molecular pathway enriched in IAPP-exposed cells treated with UroB compared to the untreated control. Consistent with these data, and the key role of calcium-signaling in insulin secretion, UroB stimulated insulin secretion in IAPP-exposed cells under hyperglycemia. Conclusions: Our data reveals UroB bioactivity for the alleviation of IAPP pathological processes by several mechanisms. UroB interacts with IAPP, and activates autophagy and antioxidant defenses to protect cells against the proteotoxic effects of IAPP accumulation. Noteworthy, UroB modulatescalcium-signaling as an important intervenient in insulin secretion. The promising results, which still need to be validated in more complex systems, open a new venue for the exploitation of dietary urolithins as inhibitors of IAPP aggregation with potential implication for diabetes.