Roy, A.; Hoff, A.; Her, T. K.; Ariyaratne, G.; Sankaran Rajagopalan, K.; Brown, M. R.; Soto-Gonzalez, A.; Matveyenko, A. V.; Javeed, N.

Chronically elevated circulating excess free fatty acids (i.e. lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven Type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet beta cells by reducing glucose-stimulated insulin secretion (GSIS), altering beta cell transcriptional identity, and promoting apoptosis. While beta cell-derived small extracellular vesicles (sEV) have been shown to contribute to beta cell failure in T2D, their specific role in lipotoxicity-mediated beta cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from beta cells, which exhibit altered proteomic and lipidomic profiles. These lipotoxic sEV induce beta cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFbeta/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFbeta I/II receptor improved lipotoxic sEV-induced beta cell dysfunction, underscoring their involvement in activating the TGFbeta/Smad3 pathway during this process. We have comprehensively characterized lipotoxic beta cell sEVs and implicated their role in inducing beta cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve beta cell health in metabolic disorders. Article Highlights - Diabetogenic lipotoxic conditions enhance beta cell sEV release and induce alterations in both protein and lipid content. - Global islet transcriptional changes and alterations in beta cell function were noted upon exposure to lipotoxic sEV. - Lipotoxic sEV were shown to activate the TGFbeta/Smad3 pathway and blockade of this pathway improved beta cell function.