1965-LB: Metabolomic and Transcriptomic Signatures of Gestational Diabetes Mellitus (GDM) Suggest Nutritional and Inflammatory Pathways in Intergenerational Transfer of Risk

Introduction 25 kg/m2 (controls, n= 13), obesity (BMI 30 kg/m2, n=14) and GDM (n=12) were used. RNA sequencing of placenta tissue and metabolite profiling of cord plasma were performed (LC-MS, HILIC-positive and C18 negative modes). Cord blood c-peptide and fructosamine concentrations were measured by ELISA. Results: Pregnancy age was similar across the groups (34.0 5.7 years, p =0.35); pre-gravida BMI (p 0.01) and gravidity (p = 0.01) were higher for obesity/GDM; but not offspring birthweight (p = 0.76). The GDM and obesity placental transcriptomic showed upregulation of intracellular protein transport, steroid hormone signaling, cellular cycle processing, histone modification and methylation, DNA alkylation and methylation compared to controls (FDR 0.05). Metabolite pathways related to biopterin, arachidonic acid, amino acids (tyrosine, histidine, alanine, aspartate, tryptophan), urea cycle and vitamins (B6, B1, B2 and biotin) were upregulated with obesity and GDM (FDR 0.05). Cord plasma fructosamine was elevated (p 0.01); c-peptide was higher in obesity/GDM, but not statistically significant (p =0.17). INSR expression was higher in obesity/GDM. Conclusions: Placental transcriptomic changes, nutrient transport abnormalities, and inflammatory processes, potentially driven by maternal hormones, may significantly impact methylation and other epigenetic changes. These changes provide a mechanistic hypothesis for the intergenerational inheritance of metabolic risk. Disclosure V.V. Thaker: None. M. Firestein: None. C. Masson: None. Z. Liu: None. U. Reddy: None. D. Gallagher: None. C.A. LeDuc: None. Funding Naomi Berrie Diabetes Research Center Pre-Translational Research Award, Columbia University to VVT and CAL