Journal article
Proinflammatory stress activates neutral sphingomyelinase 2-based generation of a ceramide-enriched ß-cell ev subpopulation
Diabetes (New York, N.Y.), Vol.74(11), pp.1964-1975
11/01/2025
DOI: 10.2337/db24-0341
PMCID: PMC12585158
PMID: 40896819
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.
Details
- Title: Subtitle
- Proinflammatory stress activates neutral sphingomyelinase 2-based generation of a ceramide-enriched ß-cell ev subpopulation
- Creators
- Jerry Xu - Indiana University School of MedicineIrene Amalaraj - Indiana University School of MedicineAndre De Oliveira - Indiana University School of MedicineArianna Harris-Kawano - Indiana University School of MedicineJacob R. Enriquez - University of ChicagoRaghavendra G. Mirmira - University of ChicagoJosie G. Eder - Pacific Northwest National LaboratoryMeagan C. Burnet - Pacific Northwest National LaboratoryIvo Díaz Ludovico - Pacific Northwest National LaboratoryJavier E. Flores - Pacific Northwest National LaboratoryErnesto S. Nakayasu - Pacific Northwest National LaboratoryEmily K. Sims - Indiana University School of Medicine
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.74(11), pp.1964-1975
- DOI
- 10.2337/db24-0341
- PMID
- 40896819
- PMCID
- PMC12585158
- NLM abbreviation
- Diabetes
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Publisher
- AMER DIABETES ASSOC; ALEXANDRIA
- Grant note
- National Institutes of Health (http://data.elsevier.com/vocabulary/SciValFunders/100000002) 62288; P30DK020595; U01DK127786; R01DK105588; R01DK060581 / John Templeton Foundation (http://data.elsevier.com/vocabulary/SciValFunders/100000925) Doris Duke Charitable Foundation (http://data.elsevier.com/vocabulary/SciValFunders/100000862) P30CA082709; R01DK133881; U01DK127382; R01DK121929 / National Cancer Institute (http://data.elsevier.com/vocabulary/SciValFunders/100000054) T32AI153020; R01DK138335 / National Institute of Allergy and Infectious Diseases (http://data.elsevier.com/vocabulary/SciValFunders/100000060)
- Language
- English
- Date published
- 11/01/2025
- Academic Unit
- Biostatistics
- Record Identifier
- 9985112968602771
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