{"doi":"10.2337/db24-0341","title":"Proinflammatory Stress Activates Neutral Sphingomyelinase 2–Based Generation of a Ceramide-Enriched β-Cell EV Subpopulation","abstract":"β-Cell extracellular vesicles (EVs) play a role as paracrine effectors in islet health, yet mechanisms connecting β-cell stress to changes in EV cargo and potential impacts on diabetes remain poorly defined. We hypothesized that β-cell inflammatory stress engages neutral sphingomyelinase 2 (nSMase2)-dependent EV formation pathways, generating ceramide-enriched small EVs that could impact surrounding β-cells. Consistent with this, proinflammatory cytokine treatment of INS-1 β-cells and human islets concurrently increased β-cell nSMase2 and ceramide abundance, as well as small EV ceramide species. Direct chemical activation or genetic knockdown of nSMase2, chemical treatment to inhibit cell death pathways, or treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist also modulated β-cell EV ceramide. RNA sequencing of ceramide-enriched EVs identified a distinct set of miRNAs linked to β-cell function and identity. EV treatment from cytokine-exposed parent cells inhibited peak glucose-stimulated insulin secretion in wild-type recipient cells; this effect was abrogated when using EVs from nSMase2 knockdown parent cells. Finally, plasma EVs in children with recent-onset type 1 diabetes showed increases in multiple ceramide species. These findings highlight nSMase2 as a regulator of β-cell EV cargo and identify ceramide-enriched EV populations as a contributor to EV-related paracrine signaling under conditions of β-cell inflammatory stress and death. ARTICLE HIGHLIGHTS: Mechanisms connecting β-cell stress to extracellular vesicle (EV) cargo and diabetes are poorly defined. Does β-cell inflammatory stress engage neutral sphingomyelinase 2 (nSMase2)-dependent EV formation to generate ceramide-enriched small EVs? Proinflammatory cytokines increased β-cell small EV ceramide via increases in nSMase2. Ceramide-enriched EVs housed distinct cargo linked to insulin signaling, and ceramide species were enriched in plasma EVs from individuals with type 1 diabetes. Ceramide-enriched EV populations are a potential contributor to β-cell EV-related paracrine signaling.","journal":"Diabetes","year":2025,"id":542217,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"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":1431775,"name":"Irene Amalaraj","orcid":null,"position":1,"is_corresponding":false},{"id":1431776,"name":"Andre De Oliveira","orcid":null,"position":2,"is_corresponding":false},{"id":1015995,"name":"Arianna Harris-Kawano","orcid":"0000-0002-5810-9274","position":3,"is_corresponding":false},{"id":347804,"name":"Jacob R. Enriquez","orcid":"0000-0002-5858-6759","position":4,"is_corresponding":false},{"id":244409,"name":"Raghavendra G. Mirmira","orcid":"0000-0002-5013-6075","position":5,"is_corresponding":false},{"id":1084897,"name":"Josie Eder","orcid":"0000-0002-2876-0496","position":6,"is_corresponding":false},{"id":255021,"name":"Meagan Burnet","orcid":"0000-0001-6747-468X","position":7,"is_corresponding":false},{"id":1060816,"name":"Ivo Díaz Ludovico","orcid":"0000-0002-3475-5191","position":8,"is_corresponding":false},{"id":1088715,"name":"Javier E. Flores","orcid":"0000-0002-1550-1655","position":9,"is_corresponding":false},{"id":262804,"name":"Ernesto Nakayasu","orcid":"0000-0002-4056-2695","position":10,"is_corresponding":false},{"id":500635,"name":"Emily K. Sims","orcid":"0000-0002-4393-954X","position":11,"is_corresponding":false},{"id":393023,"name":"Zhiwei Xu","orcid":"0000-0002-9278-2083","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:52:55.809501Z","pmid":"40896819","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":[]}