{"doi":"10.1210/endocr/bqaf067","title":"Lipotoxicity Induces β-cell Small Extracellular Vesicle–Mediated β-cell Dysfunction in Male Mice","abstract":"Chronically elevated circulating excess free fatty acids (ie, lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet β-cells by reducing glucose-stimulated insulin secretion (GSIS), altering β-cell transcriptional identity, and promoting apoptosis. While β-cell-derived small extracellular vesicles (sEV) have been shown to contribute to β-cell failure in T2D, their specific role in lipotoxicity-mediated β-cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from β-cells, which exhibit altered proteomic and lipidomic profiles. These palmitate (PAL)-exposed extracellular vesicles (EVs) induce β-cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFβ/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFβI/II receptor improved PAL EV-induced β-cell dysfunction, underscoring their involvement in activating the TGFβ/Smad3 pathway during this process. We have comprehensively characterized lipotoxic β-cell sEVs and implicated their role in inducing β-cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve β-cell health in metabolic disorders.","journal":"Endocrinology","year":2025,"id":525446,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1350808,"name":"Alexandra Hoff","orcid":null,"position":1,"is_corresponding":false},{"id":429704,"name":"Tracy K. Her","orcid":"0000-0002-6335-7651","position":2,"is_corresponding":false},{"id":1350809,"name":"Gallage Ariyaratne","orcid":null,"position":3,"is_corresponding":false},{"id":1400188,"name":"Raquel Bartolomé Gutiérrez","orcid":"0000-0003-2013-9053","position":4,"is_corresponding":false},{"id":1400606,"name":"M H D Noor Tahawi","orcid":null,"position":5,"is_corresponding":false},{"id":1098391,"name":"Kamalnath Sankaran Rajagopalan","orcid":null,"position":6,"is_corresponding":false},{"id":1400189,"name":"Matthew Brown","orcid":"0000-0003-4256-7745","position":7,"is_corresponding":false},{"id":1400190,"name":"Kazuno Omori","orcid":"0000-0001-5766-6047","position":8,"is_corresponding":false},{"id":1400607,"name":"Sean Lewis-Brinkman","orcid":null,"position":9,"is_corresponding":false},{"id":400653,"name":"Thanh Nguyen","orcid":"0000-0002-8440-1594","position":10,"is_corresponding":false},{"id":1400191,"name":"Alondra Soto-González","orcid":"0000-0003-1094-0584","position":11,"is_corresponding":false},{"id":281308,"name":"Quinn P. Peterson","orcid":"0000-0001-8701-0575","position":12,"is_corresponding":false},{"id":241936,"name":"Aleksey V. Matveyenko","orcid":"0000-0001-7761-4842","position":13,"is_corresponding":false},{"id":473668,"name":"Naureen Javeed","orcid":"0000-0003-0833-9239","position":14,"is_corresponding":false},{"id":421899,"name":"Abhishek Roy","orcid":"0000-0001-6737-3571","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:50:21.274116Z","pmid":"40179251","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}