Intrauterine 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. Maternal 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. Maternal 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.

中文翻译：

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母亲早孕血糖和胰岛素浓度与新生儿 DNA 甲基化的关系。

宫内暴露于母亲葡萄糖代谢紊乱与后代不良结局相关。DNA甲基化是这些关联的潜在机制。我们检查了母体早期妊娠葡萄糖和胰岛素浓度是否与新生儿 DNA 甲基化有关。在一项针对 935 名孕妇的基于人群的前瞻性队列研究中，在中位妊娠 13.1 周时测量了母体血浆非空腹血糖和胰岛素浓度（95% 范围为 9.4-17.4）。使用 Infinium HumanMethylation450 BeadChip (Ilumina) 测量 DNA 甲基化。我们使用稳健的线性回归模型分析了母体早孕葡萄糖和胰岛素浓度与单 CpG DNA 甲基化的关联。使用 R 中的 dmrff 包分析差异甲基化区域。我们对正常体重与超重或肥胖女性的分析进行了分层。我们还从之前的研究中查找了与母体妊娠糖尿病、高血糖或高胰岛素血症或成人 2 型糖尿病相关的 CpG 和不同甲基化区域。母体早期妊娠葡萄糖和胰岛素浓度与单个 CpG 的 DNA 甲基化无关，也与总组中的差异甲基化区域无关。在对母体 BMI 进行分层的分析中，母体早期妊娠葡萄糖浓度与正常体重女性的一个 CpG (cg03617420, XKR6) 和超重或肥胖女性的另一个 (cg12081946, IL17D) 的 DNA 甲基化相关。未发现母体早孕胰岛素浓度存在特定层级关联。这两个 CpG 与出生体重或儿童血糖测量值无关（p 值 > 0.1）。产妇早孕胰岛素浓度与一种已知与成人 2 型糖尿病相关的 CpG 相关。在先前一项关于成人 2 型糖尿病的研究中发现的 CpG 中发现了我们母亲妊娠早期葡萄糖浓度中名义上显着的结果的富集。在正常体重和超重或肥胖女性的亚组中，母亲妊娠早期的葡萄糖浓度，但与胰岛素浓度无关，与 DNA 甲基化相关，每个 CpG 为 1。整个组中没有关联。这些 CpG 在后代健康结果机制中的作用需要进一步研究。