DNA Methylation Biomarkers Predict Offspring Metabolic Risk From Mothers With Hyperglycemia in Pregnancy

Gestational diabetes mellitus affects almost 18 million pregnancies worldwide, increasing by >70% in the past 20 years. DNA methylation has been associated with maternal hyperglycemia and type 2 diabetes risk in offspring. This study hypothesized that hyperglycemia during pregnancy influences DNA methylation changes at birth that mediate metabolic risk in offspring. Cord blood samples (n = 112) were obtained from women with normal (n = 43), impaired (n = 31), and low (n = 38) glucose tolerance enrolled in the Hong Kong field center of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Differentially methylated regions (DMRs) were identified using methylation sequencing and evaluated for their association with offspring metabolic dysfunction. Receiver operating characteristic curve analysis assessed the predictive value of DMRs for the classification of maternal glycemic status. These DMRs were assessed in human β-cells and pancreatic ductal epithelial cells in response to hyperglycemic stimuli. Methylation sequencing identified 19 methylation biomarkers in cord blood associated with maternal hyperglycemia, which correlated with offspring metabolic abnormalities. Incorporating the 19 DMRs improved the prediction of offspring β-cell dysfunction at 7, 11, and 18 years of age from area under the curve (AUC) scores ranging from 0.53 to 0.68 using clinical factors alone to AUC scores ranging from 0.71 to 0.95. Validation in human cell models confirmed that hyperglycemia influences methylation-dependent gene expression. This study demonstrates that DNA methylation biomarkers in cord blood predict offspring metabolic dysfunction, highlighting their potential as early indicators of diabetes risk. The findings align with methylation-mediated regulation in human pancreatic cells. ARTICLE HIGHLIGHTS Maternal hyperglycemia is linked to 19 cord blood DNA methylation biomarkers that predict offspring metabolic dysfunction. These methylation changes, associated with maternal glycemic status, improved the prediction of β-cell dysfunction at 7, 11, and 18 years of age compared with clinical factors alone. Validation in human β-cells and pancreatic ductal epithelial cells confirmed that hyperglycemia influences methylation-dependent gene expression. These findings highlight the role of epigenetic modifications at birth as early indicators of diabetes risk, suggesting that in utero hyperglycemic exposure may mediate long-term metabolic outcomes in offspring.