Diabetes in pregnancy and epigenetic mechanisms—how the first 9 months from conception might affect the child's epigenome and later risk of disease

Hjort, Line; Novakovic, Boris; Grunnet, Louise Groth; Maple-Brown, Louise; Damm, Peter; Desoyé, Gernot; Saffery, Richard

doi:10.1016/s2213-8587(19)30078-6

Cited by 57 publications

(50 citation statements)

References 91 publications

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“…We found enrichment for findings from one previous study on adult type 2 diabetes among the 24,935 nominally significant CpGs from the maternal early-pregnancy glucose EWAS results (Fisher combined probability p value = 0.04) [40]. No evidence for enrichment of the CpGs from other previous studies among the 24,935 nominally significant CpGs from the maternal early-pregnancy glucose cord blood analysis, nor among the 19,418 nominally significant CpGs from the maternal early-pregnancy insulin cord blood analysis was found (lowest Fisher combined probability p value = 0.15 in maternal earlypregnancy glucose EWAS results and p value = 0.12 in insulin EWAS results) [1,14,17,18,22,23,25,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42].…”

Section: Look-up Of Maternal Glucose Metabolism and Adult Type 2 Diabmentioning

confidence: 64%

“…The models were adjusted for gestational age at assessment, maternal age at intake, educational level, parity, smoking, child sex, cell type proportions, and batch that one CpG, cg1680945 at MDN1, known to be related to adult type 2 diabetes was also 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]. The look-up of other previously described CpGs and DMRs in the maternal earlypregnancy glucose and insulin EWAS results showed no associations (Additional file 8: Table S9; Additional file 9: Table S10; Additional File 10: Table S11; Additional file 11: Table S12) [1,14,17,18,22,23,25,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. We found enrichment for findings from one previous study on adult type 2 diabetes among the 24,935 nominally significant CpGs from the maternal early-pregnancy glucose EWAS results (Fisher combined probability p value = 0.04) [40].…”

Section: Look-up Of Maternal Glucose Metabolism and Adult Type 2 Diabmentioning

confidence: 89%

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Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns

et al. 2020

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Background 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. Results 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. Conclusions 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.

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Section: Look-up Of Maternal Glucose Metabolism and Adult Type 2 Diabmentioning

confidence: 64%

Section: Look-up Of Maternal Glucose Metabolism and Adult Type 2 Diabmentioning

confidence: 89%

Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns

et al. 2020

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“…EDCs are able to modulate gene expression and directly modify the epigenome by DNA methylation [77,78]. Notably, epigenetic modifications can be transmitted throughout generations, and the transgenerational effects might become manifest only several years later [79,80].…”

Section: General Aspects Of Edcsmentioning

confidence: 99%

Bisphenol A and Phthalates in Diet: An Emerging Link with Pregnancy Complications

et al. 2020

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Endocrine-disrupting chemicals (EDCs) are exogenous substances that are able to interfere with hormone action, likely contributing to the development of several endocrine and metabolic diseases. Among them, Bisphenol A (BPA) and phthalates contaminate food and water and have been largely studied as obesogenic agents. They might contribute to weight gain, insulin resistance and pancreatic β-cell dysfunction in pregnancy, potentially playing a role in the development of pregnancy complications, such as gestational diabetes mellitus (GDM), and adverse outcomes. Pregnancy and childhood are sensitive windows of susceptibility, and, although with not univocal results, preclinical and clinical studies have suggested that exposure to BPA and phthalates at these stages of life might have an impact on the development of metabolic diseases even many years later. The molecular mechanisms underlying this association are largely unknown, but adipocyte and pancreatic β-cell dysfunction are suspected to be involved. Remarkably, transgenerational damage has been observed, which might be explained by epigenetic changes. Further research is needed to address knowledge gaps and to provide preventive measure to limit health risks connected with exposure to EDCs.

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“…Women with GDM have increased risks of metabolic syndrome, 2 type 2 diabetes mellitus 3 and cardiovascular disease later in life 4 . Children born to women with GDM have an increased risk of high birthweight and long‐term metabolic disease, indicating transmission of risk through generations due to genetic, epigenetic and environmental influence 5 . The incidence of GDM in Europe varies by country and population but has increased over the last decades, 6 contributing to a considerable increase in national medical costs 7 .…”

Section: Introductionmentioning

confidence: 99%

Interpregnancy weight change and recurrence of gestational diabetes mellitus: a population‐based cohort study

Sørbye

Cnattingius

Skjærven

et al. 2020

BJOG

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Objective To estimate recurrence risk of gestational diabetes mellitus (GDM) by interpregnancy weight change. Design Population‐based cohort study. Setting and population Data from the Swedish (1992–2010) and the Norwegian (2006–2014) Medical Birth Registries on 2763 women with GDM in first pregnancy, registered with their first two singleton births and available information on height and weight. Methods Interpregnancy weight change (BMI in second pregnancy minus BMI in first pregnancy) was categorised in six groups by BMI units. Relative risks (RRs) of GDM recurrence were obtained by general linear models for the binary family and adjusted for confounders. Analyses were stratified by BMI in first pregnancy (<25 and ≥25 kg/m2). Main outcome measure GDM in second pregnancy. Results Among overweight/obese women (BMI ≥25), recurrence risk of GDM decreased in women who reduced their BMI by 1–2 units (relative risk [RR] 0.80, 95% CI 0.65–0.99) and >2 units (RR 0.72, 95% CI 0.59–0.89) and increased if BMI increased by ≥4 units (RR 1.26, 95% CI 1.05–1.51) compared wth women with stable BMI (−1 to 1 units). In normal weight women (BMI <25), risk of GDM recurrence increased if BMI increased by 2–4 units (RR 1.32, 95% CI 1.08–1.60) and ≥4 units (RR 1.61, 95% CI 1.28–2.02) compared with women with stable BMI. Conclusion Interpregnancy weight loss reduced risk of GDM recurrence in overweight/obese women. Weight gain between pregnancies increased recurrence risk for GDM in both normal and overweight/obese women. Our findings highlight the importance of weight management in the interconception window in women with a history of GDM. Tweetable abstract Interpregnancy weight loss reduces recurrence of gestational diabetes mellitus in overweight/obese women.

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Diabetes in pregnancy and epigenetic mechanisms—how the first 9 months from conception might affect the child's epigenome and later risk of disease

Cited by 57 publications

References 91 publications

Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns

Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns

Bisphenol A and Phthalates in Diet: An Emerging Link with Pregnancy Complications

Interpregnancy weight change and recurrence of gestational diabetes mellitus: a population‐based cohort study

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