Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy.


  • 影响因子:5.64
  • DOI:10.2337/db19-0798
  • 作者列表:"Hivert MF","Cardenas A","Allard C","Doyon M","Powe CE","Catalano PM","Perron P","Bouchard L
  • 发表时间:2020-03-01

:The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at ∼26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P < 6.94 × 10-8). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1 Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy.


: 胎盘参与妊娠期母体胰岛素敏感性变化; 然而,机制仍不清楚。我们研究了母体胰岛素敏感性和整个基因组胎盘DNA甲基化标志物之间的关联。我们分析了来自Gen3G队列中430个母子关系的数据。所有女性在孕26 ~ 周时接受了75g口服葡萄糖耐量试验; 我们使用葡萄糖和胰岛素测量来评估胰岛素敏感性 (Matsuda指数)。在分娩时,我们从胎盘 (胎儿侧) 收集样品,并使用Illumina EPIC阵列测量DNA甲基化。使用线性回归模型量化720,077胞嘧啶-鸟嘌呤二核苷酸 (CpGs) 的关联,校正产妇年龄、孕产、吸烟、BMI、儿童性别和分娩胎龄,我们鉴定了188个CpG位点,其中胎盘DNA甲基化与Matsuda指数相关 (P < 6.94 × 10-8)。在注释到这188个cpg的基因中,我们发现mirna的靶标、组蛋白修饰和亲本DNA甲基化 (包括H19/MIR675基因座 (父系印记)) 富集。我们鉴定了12个已知的胎盘印记基因,包括KCNQ1孟德尔随机化分析,揭示了5个位点,其中胎盘DNA甲基化可能会导致母体胰岛素敏感性,包括母体印记基因dlgap2。我们的研究结果表明,胎盘DNA甲基化与妊娠期母体胰岛素敏感性的调节基本相关。



作者列表:["Landon MB","Mele L","Varner MW","Casey BM","Reddy UM","Wapner RJ","Rouse DJ","Tita ATN","Thorp JM","Chien EK","Saade G","Grobman W","Blackwell SC","VanDorsten JP","Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network."]

METHODS::Objective: To determine the association of maternal glycemia with childhood obesity and metabolic dysfunction.Study design: Secondary analysis of follow-up data 5-10 years after a mild gestational diabetes mellitus (GDM) treatment trial. The relationship between maternal oral glucose tolerance testing (OGTT) at 24-31-week gestation and body mass index (BMI), fasting glucose, insulin, and anthropometric measurements (sum of skinfolds, subscapular/triceps ratio, and waist circumference) in the offspring of untreated mild GDM and non-GDM (abnormal 50-g screen/normal OGTT) women was assessed. Multivariable regression modeling controlling for maternal and neonatal characteristics was employed.Results: A cohort of 236 untreated mild GDM and 480 non-GDM offspring were analyzed. In the combined cohort, significant correlations existed between fasting, 1, 2, and 3 h maternal glucose and subscapular/triceps ratio (all p < .04) and in all OGTT values other than the 2-hour value for homeostatic model assessment-estimated insulin resistance (HOMA-IR) (all p < .04) and sum of skinfold measurements (all p < .03). No correlation was found between OGTT values and childhood BMI Z-score. Multivariable regression modeling showed that OGTT values were associated with only sum of skinfolds and subscapular/triceps ratio and not with childhood BMI Z-score. Hispanic ethnicity and prepregnancy maternal BMI were most consistently related to childhood BMI Z-score and HOMA-IR, and Hispanic ethnicity with fasting glucose.Conclusions: Among women with untreated mild GDM and those without GDM, maternal glycemia is associated with childhood anthropometric measures of obesity but not childhood BMI, fasting glucose, or insulin resistance. Hispanic ethnicity, maternal BMI, and gestational weight gain were consistently related to childhood BMI.

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METHODS::Objective: Women with gestational diabetes (GDM) have a 7-12-fold increased risk for developing type 2 diabetes later in life. Postpartum weight retention is highly predictive for future obesity, and further increases risk for type 2 diabetes. We sought to identify predictors of losing at least 75% of gestational weight gain by very early postpartum in women with recent GDM.Methods: We recruited women with GDM during pregnancy or just after delivery. Prepregnancy weight was self-reported at recruitment; gestational weight gain, mode of delivery, and insulin use were extracted from medical records. At a mean of 7.2 (±2.1) weeks postpartum we measured weight and height and administered questionnaires, including demographics, breastfeeding, Edinburgh Postnatal Depression Scale, sleep, Harvard Food Frequency, and the International Physical Activity Questionnaire. We modeled the odds of 75% loss of gestational weight gain at the study visit using multivariable logistic regression models and selected the model with the lowest Akaike information criterion (AIC) as our final model. Analyses were conducted using JMP 10-13 Pro (SAS Institute Inc.)Results: Seventy-five women with recent GDM were included in the study. The mean age of study participants was 33 (SD ±5) years old, of whom 57% were white, 30% were African American, and 20% of the women identified as Hispanic. The mean prepregnancy BMI was 31.4 kg/m2 (SD ±5.6) and the mean pregnancy weight gain was 12.5 kg (SD ±7.8). Fifty-two percent of participants lost at least 75% of their pregnancy weight gain by the early postpartum study visit. Thirty-seven women (49%) exceeded Institute of Medicine (IOM) guidelines for gestational weight gain. In a multivariate model adjusting for weeks postpartum at the time of the study visit, less gestational weight gain (OR 0.56; 95% CI 0.39-0.73), increased age (OR 1.48; 95% CI 1.13-2.20), and lack of insulin use during pregnancy (OR 0.08 for use of insulin; 95% CI 0.00-0.73) were associated with at least 75% postpartum weight loss. Prepregnancy BMI and sleep were not retained in the model. Race/ethnicity, education, breastfeeding, nulliparity, cesarean section, depressive symptoms, dietary composition, glycemic index, and physical activity did not meet criteria for inclusion in the model.Conclusions: A substantial proportion of women with recent GDM lost at least 75% of their gestational weight gain by early postpartum. Older women, those who did not use insulin during pregnancy and those who gained less weight during pregnancy were significantly more likely to have lost 75% of gestational weight by very early postpartum.

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METHODS::Background: Low-glycemic index (GI) diet might be beneficial for gestational diabetes. However, the results remained controversial. We conducted a systematic review and meta-analysis to explore the influence of low-GI diet on gestational diabetes.Methods: PubMed, EMbase, Web of Science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of low-GI diet on gestational diabetes were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. This meta-analysis was performed using the random-effect model.Results: Six RCTs involving 532 patients were included in the meta-analysis. Overall, compared with a control intervention in gestational diabetes, low-GI diet was found to significantly reduce 2 h postprandial glucose (Std. MD = -0.46; 95% CI = -0.82 to -0.10; p = .01), but demonstrated no substantial influence on fasting plasma glucose (Std. MD = -0.24; 95% CI = -0.72 to 0.24; p = .33), HbA1c (Std. MD = 0.01; 95% CI = -0.29 to 0.31; p = .94), birth weight (Std. MD = -0.17; 95% CI = -0.41 to 0.06; p = .15), macrosomia (Std. MD = 0.45; 95% CI = 0.16 to 1.30; p = .14) and insulin requirement (Std. MD = 0.91; 95% CI = 0.68 to 1.22; p = .55).Conclusions: Compared with control intervention in gestational diabetes, low-GI diet was found to significantly decrease 2 h postprandial glucose, but showed no notable impact on fasting plasma glucose, HbA1c, birth weight, macrosomia, and insulin requirement.

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