Lipotoxicity Induces Beta Cell Small Extracellular Vesicle-mediated Beta Cell Dysfunction

Abstract

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 TGF{beta}/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGF{beta}I/II receptor improved lipotoxic sEV-induced {beta}-cell dysfunction, underscoring their involvement in activating the TGF{beta}/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 HighlightsO_LIDiabetogenic lipotoxic conditions enhance {beta}-cell sEV release and induce alterations in both protein and lipid content. C_LIO_LIGlobal islet transcriptional changes and alterations in {beta}-cell function were noted upon exposure to lipotoxic sEV. C_LIO_LILipotoxic sEV were shown to activate the TGF{beta}/Smad3 pathway and blockade of this pathway improved {beta}-cell function. C_LI