Abstract
BackgroundIntrauterine exposure to a disturbed maternal glucose metabolism is associated with adverse offspring outcomes. DNA methylation is a potential mechanism underlying these associations. We examined whether maternal early-pregnancy glucose and insulin concentrations are associated with newborn DNA methylation. In a population-based prospective cohort study among 935 pregnant women, maternal plasma concentrations of non-fasting glucose and insulin were measured at a median of 13.1 weeks of gestation (95% range 9.4–17.4). DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Ilumina). We analyzed associations of maternal early-pregnancy glucose and insulin concentrations with single-CpG DNA methylation using robust linear regression models. Differentially methylated regions were analyzed using the dmrff package in R. We stratified the analyses on normal weight versus overweight or obese women. We also performed a look-up of CpGs and differently methylated regions from previous studies to be associated with maternal gestational diabetes, hyperglycemia or hyperinsulinemia, or with type 2 diabetes in adults.ResultsMaternal early-pregnancy glucose and insulin concentrations were not associated with DNA methylation at single CpGs nor with differentially methylated regions in the total group. In analyses stratified on maternal BMI, maternal early-pregnancy glucose concentrations were associated with DNA methylation at one CpG (cg03617420, XKR6) among normal weight women and at another (cg12081946, IL17D) among overweight or obese women. No stratum-specific associations were found for maternal early-pregnancy insulin concentrations. The two CpGs were not associated with birth weight or childhood glycemic measures (p values > 0.1). Maternal early-pregnancy insulin concentrations were associated with one CpG known to be related to adult type 2 diabetes. Enrichment among nominally significant findings in our maternal early-pregnancy glucose concentrations was found for CpGs identified in a previous study on adult type 2 diabetes.ConclusionsMaternal early-pregnancy glucose concentrations, but not insulin concentrations, were associated with DNA methylation at one CpG each in the subgroups of normal weight and of overweight or obese women. No associations were present in the full group. The role of these CpGs in mechanisms underlying offspring health outcomes needs further study. Future studies should replicate our results in larger samples with early-pregnancy information on maternal fasting glucose metabolism.
Highlights
Intrauterine exposure to a disturbed maternal glucose metabolism is associated with adverse offspring outcomes
The analyses stratified on maternal body mass index (BMI) showed that among normal weight women, maternal early-pregnancy glucose concentrations were associated with DNA methylation at one Cytosine-phosphate-guanine sites (CpGs) (cg03617420 in XKR6; effect estimate = 7.3 × 10−3 (standard error (SE) 1.3 × 10−3), p value = 7.4 × 10−9) (Fig. 1a)
Look-up of maternal glucose metabolism and adult type 2 diabetes-associated CpGs In a look-up in our results of CpGs and Differentially methylated region (DMR) identified in previous studies to be associated with maternal glucose metabolism or with adult type 2 diabetes, we found that one CpG, cg1680945 at MDN1, known to be related to adult type 2 diabetes was significantly associated with maternal early-pregnancy insulin concentrations (effect estimate = − 3.3 × 10−3 (SE 1.1 × 10−3), p value = 2.2 × 10−3) [27]
Summary
Intrauterine exposure to a disturbed maternal glucose metabolism is associated with adverse offspring outcomes. Intrauterine exposure to maternal gestational diabetes or impaired glucose tolerance measured in mid-pregnancy and late pregnancy is associated with increased risks of adverse maternal and fetal perinatal outcomes and of diabetes and obesity in the offspring [5,6,7,8]. These associations of increased risks on perinatal outcomes are already present for higher maternal glucose concentrations below the threshold of gestational diabetes [9, 10]. Early pregnancy may be an important time window for the effects of suboptimal maternal glycemic measures and as such an influential period for future interventions
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