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

Introduction & Objective: GDM impacts intergenerational transfer of metabolic risk. The underlying mechanisms could inform intervention strategies. The placenta nourishes the developing fetus and is influenced by the maternal milieu. We assessed placental transcriptome and cord blood metabolites to determine pathways perturbed by GDM.

Methods: Placental tissue and cord blood from 39 mother-baby dyads of gravidas with BMI < 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.