Akdag, M.; Ferreira, S.; Menezes, R.; Sinnige, T.

The progressive loss of pancreatic {beta}-cells is one of the defining features of Type 2 Diabetes Mellitus (T2DM), and is thought to be driven by the aggregation of islet amyloid polypeptide (IAPP). This highly amyloidogenic pancreatic hormone is co-secreted with insulin, and its elevated secretion can lead to toxic fibrillar aggregation. Despite numerous studies focusing on understanding the molecular mechanisms of IAPP aggregation, few therapeutic strategies exist to counter its toxicity. Urolithin B is a natural metabolite derived from the digestion and intestinal microbiota action on ellagitannin-rich foods. This compound was suggested to counteract IAPP aggregation and toxicity in silico and in yeast models expressing human IAPP. In this study, we focused on the protective potential of urolithin B using our previously characterised transgenic Caenorhabditis elegans IAPP-GFP model. We report that urolithin B reduces the levels of insoluble IAPP-GFP in the body wall muscle cells, while the mitochondrial association of IAPP-GFP remains unaltered. We show that the C. elegans model exhibits a reduced lifespan compared to controls, providing in vivo evidence of the toxic effects associated with IAPP-GFP expression. The lifespans of IAPP-GFP versus control animals were differentially modulated by urolithin B treatment, suggesting an interplay between the metabolite and IAPP-GFP mediated toxicity. To further elucidate the mode of action of urolithin B, we conducted in vitro assays and found no evidence of direct interaction with lipid-associated IAPP, suggesting that its effects are not mediated by interference with IAPP-membrane interactions. These results pave the way for further therapeutic developments targeting IAPP aggregation in T2DM.