Proinflammatory Stress Activates Neutral Sphingomyelinase 2-Based Generation of a Ceramide-Enriched β-Cell EV Subpopulation.

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.