MRC Lifecourse Epidemiology Unit & NIHR Southampton Biomedical Research Centre,
University of Southampton and University Hospital Southampton NHS Foundation Trust,
Southampton, UK
Children born to mothers with gestational diabetes mellitus (GDM) have an increased risk of obesity and metabolic disease in adulthood. There is now evidence suggesting that maternal GDM induces stable modifications of the offspring’s epigenome, resulting in persistent changes in gene expression and programming long-term effects on appetite and metabolism.
Long-Term Effects of Maternal GDM on the Offspring
Alongside the perinatal implications of GDM, infants born to women with GDM are at an increased risk of adiposity and are more likely to develop type 2 diabetes later in life [1–3]. Among siblings, the risk of diabetes is higher in those born after the mother was diagnosed with diabetes, indicating that this risk is related to intra-uterine exposure to hyperglycaemia [3]. Concurrent with the rising prevalence of maternal obesity, the increasing incidence of GDM may now be playing an important role in a worsening intergenerational cycle of metabolic disease [4]. While research suggests that the risks of perinatal complications rise steeply above particular thresholds of maternal glycaemia, both the HAPO study and more recent mother-offspring cohorts show a continuous relation between higher levels of maternal dysglycaemia in pregnancy and greater offspring adiposity [1, 5].
Epigenetic Processes
Epigenetic processes include DNA methylation, post-translational modification of histones, and non-coding RNAs. DNA methylation occurring predominantly at cytosines in cytosine- guanine (CpG) dinucleotides is the most widely studied [4]. These processes induce heritable changes in gene expression without a change in nucleotide sequence and play an essential role in cell differentiation, determining when and where a gene is expressed. Increasing evidence suggests that epigenetic changes induced by the early-life environment make a major contribution to later phenotype [6]. We found that perinatal methylation of a CpG site in the promoter region of the nuclear receptor RXRA was strongly related to childhood adiposity in two independent cohorts, explaining >25% of the variance in childhood fat mass [7]. Similarly, methylation of specific CpG loci in the promoter of PGC1α [8] at age 5 years predicted later adiposity at age 14 years, strongly supporting the hypothesis that developmentally induced epigenetic marks may be valuable predictors of later adiposity, independent of potential confounding influences.
Research to systematically determine the contribution of epigenetic processes in providing the “memory” of how GDM influences obesity and metabolic disease is at an early stage, but evidence from animal models and initial clinical studies point to an important influence (Fig. 1). In humans, methylation changes have been observed in cord blood and placenta in GDM offspring compared to unexposed controls [9, 10]. Current research is now extending these observations to address other epigenetic processes, such as non-coding RNAs, to utilize genome-scale techniques, and to replicate and validate observations in larger cohorts. Epigenetic studies may soon lead to the identification of biomarkers with utility in trials of nutritional and lifestyle interventions to prevent GDM and normalize maternal glucose concentrations during pregnancy, thereby hastening the development of measures to reduce the risk of overweight and obesity in the offspring.
Fig 1. Gestational diabetes, epigenetic processes, and offspring metabolic programming. Transplacental facilitated diffusion of glucose is such that maternal hyperglycaemia results in fetal hyperglycaemia; this is thought to alter epigenetic processes during development, changing DNA “packaging” in ways that alter gene expression and metabolism across the life course and thereby increasing the risk of obesity and type 2 diabetes later in life.
References
HAPO Study Cooperative Research Group: Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations with neonatal anthropometrics. Diabetes 2009;58:453–459.
Tam WH, Ma RC, Yang X, Li AM, Ko GT, Kong AP, Lao TT, Chan MH, Lam CW, Chan JC: Glucose intolerance and cardiometabolic risk in adolescents exposed to maternal gestational diabetes: a 15-year follow-up study. Diabetes Care 2010;33:1382–1384.
Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, Roumain J, Bennett PH, Knowler WC: Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000;49:2208–2211.
Low FM, Gluckman PD, Godfrey KM: Early life development and epigenetic mechanisms: mediators of metabolic programming and obesity risk. In Kussmann M, Stover P (eds): Nutrigenomics and Proteomics in Health and Disease. Oxford, Wiley, in press.
Aris IM, Soh SE, Tint MT, Liang S, Chinnadurai A, Saw SM, Rajadurai VS, Kwek K, Meaney MJ, Godfrey KM, Gluckman PD, Yap FK, Chong YS, Lee YS: Effect of maternal glycemia on neonatal adiposity in a multiethnic Asian birth cohort. J Clin Endocrinol Metab 2014;99:240–247.
Godfrey KM, Costello PM, Lillycrop KA: The developmental environment, epigenetic biomarkers and long-term health. J Dev Orig Health Dis 2015;6:399–406.
Godfrey KM, Sheppard A, Gluckman PD, et al: Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 2011;60:1528–1534.
Clarke-Harris R, Wilkin TJ, Hosking J, et al: PGC1alpha promoter methylation in blood at 5–7 years predicts adiposity from 9 to 14 years (EarlyBird 50). Diabetes 2014;63:2528–2537.
El Hajj N, Pliushch G, Schneider E, Dittrich M, Müller T, Korenkov M, Aretz M, Zechner U, Lehnen H, Haaf T: Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus. Diabetes 2013;62:1320–1328.
Finer S, Mathews C, Lowe R, et al: Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring. Hum Mol Genetics 2015;24:3021–3029.
