Lipidomes of placenta-derived extracellular vesicles reveal disrupted metabolic adaptation in type 1 diabetes

CONTEXT: Placental metabolic adaptation is dynamically orchestrated across gestation to support fetal development, yet how this process is disrupted in type 1 diabetes (T1D) and contributes to altered fetal metabolic outcomes remains unclear. Small extracellular vesicles (sEVs) may provide a minimally invasive window into placental metabolic state during pregnancy. OBJECTIVE: To determine whether lipidomic profiling of placental sEVs (P-sEVs) in maternal circulation captures dynamic placental metabolic adaptation and its dysregulation in T1D pregnancy. DESIGN AND SETTING: Prospective longitudinal cohort study conducted within the Ontario Birth Study and the Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes (CONCEPTT) study. PARTICIPANTS: Maternal plasma samples were collected across gestation (10-14, 24-32, and 34-40 weeks of gestation) from 200 normoglycemic pregnancies and 151 pregnancies from individuals with preexisting T1D. METHODS: Placental sEVs were isolated and characterized, and lipid composition was quantified using shotgun mass spectrometry-based lipidomics. Multivariate and machine learning approaches were applied to define gestational lipid trajectories and assess associations with fetal metabolic outcomes. MAIN OUTCOME MEASURES: Gestational lipid trajectories in P-sEVs from normoglycemic and T1D, and their association with maternal and fetal risk factors and clinical outcomes. RESULTS: Placental sEVs from T1D pregnancies exhibited increased vesicle size and reduced abundance. Lipidomic profiling revealed divergence in the magnitude, direction, and timing of gestational lipid trajectories compared with controls. Lipid species involved in membrane remodeling and bioactive signaling distinguished pregnancies with high vs low cord blood C-peptide, a marker of fetal endogenous insulin secretion, with strong discrimination (area under the characteristic curve = 0.85). CONCLUSION: Circulating P-sEV lipid profiles reflect disrupted placental metabolic adaptation in T1D pregnancy and are associated with fetal hyperinsulinemia at birth, supporting their potential for minimally invasive assessment of placental function.