Impact on offspring methylation patterns of maternal gestational diabetes mellitus and intrauterine growth restraint suggest common genes and pathways linked to subsequent type 2 diabetes risk

Abstract

Size at birth, postnatal weight gain, and adult risk for type 2 diabetes may reflect environmental exposures during developmental plasticity and may be mediated by epigenetics. Both low birth weight (BW), as a marker of fetal growth restraint, and high birth weight (BW), especially after gestational diabetes mellitus (GDM), have been linked to increased risk of adult type 2 diabetes. We assessed DNA methylation patterns using a bead chip in cord blood samples from infants of mothers with GDM (group 1) and infants with prenatal growth restraint indicated by rapid postnatal catch-up growth (group 2), compared with infants with normal postnatal growth (group 3). Seventy-five CpG loci were differentially methylated in groups 1 and 2 compared with the controls (group 3), representing 72 genes, many relevant to growth and diabetes. In replication studies using similar methodology, many of these differentially methylated regions were associated with levels of maternal glucose exposure below that defined by GDM [the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study] or were identified as changes observed after randomized periconceptional nutritional supplementation in a Gambian cohort characterized by maternal deprivation. These Key Words: fetal programming ⅐ epigenetics ⅐ maternal environmentFetal exposure to a diabetic environment in utero is associated with an increased risk of impaired glucose tolerance and defective insulin secretory response in adults, independent of genetic predisposition to type 2 diabetes (1). In addition, maternal low birth weight (BW) is associated with an increased risk of gestational diabetes mellitus (GDM) in these women (2). In fact, an excess in maternal transmission of diabetes is consistent with an epigenetic effect of hyperglycemia in pregnancy acting in concert with genetic factors to produce diabetes in the next generation. The first manifestation in female offspring is often GDM in their own pregnancies, which illustrates how diabetes transmission can be perpetuated over generations (3).

Maternal diabetes modulates dental epithelial stem cells proliferation and self-renewal in offspring through apurinic/apyrimidinicendonuclease 1-mediated DNA methylation

“…A number of studies have shown that the maternal environment, in particular hyperglycaemia during pregnancy, can alter foetal development, affecting organ formation and increasing the risk of diseases such as neural tube defects, cardiovascular disease, obesity, diabetes, and cancer in the offspring via epigenetic mechanisms313233343536373839. In the present study, we established a maternal gestational diabetes rat model to determine its effects on tooth development in offspring and to study the mechanisms associated with these effects.…”

Differential adipokine DNA methylation and gene expression in subcutaneous adipose tissue from adult offspring of women with diabetes in pregnancy

“…Targeted and global epigenetic changes, including changes in methylation of genes encoding adipokines, have been reported in placenta (a central organ in the flux of nutrition from mother to fetus, important for mediating the impact of maternal GDM) and cord blood from newborn offspring in response to prenatal exposure to maternal obesity, hyperglycemia, and GDM [16–27], but the extent to which these changes persist into adulthood is unknown. Studies of the association between maternal glycemia or BMI and offspring adipokine methylation have rendered contradictory results, showing decreased LEP and ADIPOQ methylation on the fetal side of the placenta with increasing maternal blood glucose concentrations [17, 18] or increased placental LEP DNA methylation with exposure to gestational diabetes mellitus (GDM) and maternal obesity [23].…”

Sex-specific associations of low birth weight with adult-onset diabetes and measures of glucose homeostasis: Brazilian Longitudinal Study of Adult Health

“…Additionally, several studies have demonstrated alteration of DNA methylation patterns in offspring of diabetic mothers1520, but to the best of our knowledge, we are the first to show that maternal diabetes may modify the association between intrauterine growth restriction and adult-onset diabetes in a sex-specific manner. DNA methylation of loci associated with insulin resistance and type 2 diabetes in infants born to mothers with gestational diabetes and in infants born with growth restriction demonstrates large changes in methylation but surprisingly little overlap in specific methylated loci by sex47. The fact that we only found that low birth weight men with maternal history of diabetes have increased risk of diabetes suggest factors leading to low birth weight in men other than maternal diabetes are not sufficient to confer diabetes risk.…”