182-OR: Maternal Glucose and Insulin Are Associated with Lipid Metabolism and Adipogenesis Pathways in Human Umbilical Cord-Derived Mesenchymal Stem Cells: The Healthy Start Echo Cohort

Abstract

We have reported that umbilical cord mesenchymal stem cells (MSCs) from infants born to mothers with obesity have less AMP-activated protein kinase [AMPK] and less inhibitory phosphorylation of glycogen synthase kinase 3 [GSK3]β, a regulator of MSC differentiation. This is accompanied by a greater capacity for in vitro adipogenesis, which positively correlates with infant adiposity. Here we hypothesized that, independent of maternal pre-pregnancy (pp)BMI, maternal glucose and insulin would be associated with GSK3β and AMPK in undifferentiated infant MSCs. We studied 67 women (ppBMI 18-42 kg/m2) at mid (15-23 weeks) and late (24-32 weeks) gestation without preeclampsia or gestational diabetes, as well as their infants’ MSCs. We ran linear models to test the effect of fasting maternal glucose and insulin on each phosphorylated MSC protein, with infant sex and gestational age as covariates, ± ppBMI as a covariate to account for collinearity with metabolic measures. Linear model p-values and Pearson correlations are reported. Maternal glucose at mid (p = 0.03, r = 0.26) and late (p = 0.009, r = 0.35) gestation had a significant effect on AMPKThr172, with no effect of ppBMI, indicating greater AMPK activity with higher maternal glucose. Mid gestation insulin (p = 0.04, r = -0.21) was associated with GSK3βSer9, with the same trend for HOMA-IR—but not when ppBMI was included as a covariate, as it was also negatively associated with GSK3βSer9 (p = 0.02, r = -0.24), showing collinearity of ppBMI and insulin (r = 0.40). This signifies higher ppBMI and insulin with less GSK3β inhibition, which we have previously linked to greater adipogenesis. These results demonstrate the novel finding that maternal glucose during pregnancy is associated with perturbations to lipid metabolism pathways in infant MSCs across a wide range of ppBMI, giving important clues as to how maternal metabolism may impact infant metabolic disease risk. Disclosure M. Keleher: None. D. Dabelea: None. J.E. Friedman: Consultant; Self; Janssen Research & Development. K.E. Boyle: None. Funding National Institutes of Health (4UH3OD023248-03)