<b>DNA Methylation Biomarkers Predict Offspring Metabolic Risk from Mothers with Hyperglycaemia in Pregnancy</b>

<p dir="ltr">Gestational diabetes mellitus (GDM) affects almost 18 million pregnancies worldwide, increasing by more than 70% in the last 20 years. DNA methylation has been associated with maternal hyperglycaemia and type 2 diabetes (T2D) risk in offspring. This study hypothesizes that hyperglycaemia 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 Centre of the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study. Differentially methylated regions (DMRs) were identified using methylation sequencing (methyl-seq) and evaluated for their association with offspring metabolic dysfunction. Receiver operating characteristic (ROC) curve analysis assessed the predictive value of DMRs for the classification of maternal glycaemic status. These DMRs were assessed in human b-cells and pancreatic ductal epithelial cells, in response to hyperglycaemic stimuli. Methyl-seq identified 19 methylation biomarkers in cord blood associated with maternal hyperglycaemia, which correlated with offspring metabolic abnormalities. Incorporating the 19 DMRs improved the prediction of offspring <a href="" target="_blank">b cell dysfunction </a>at 7, 11 and 18 years of age, from AUC 0.53-0.68 using clinical factors alone, to AUC scores ranging from 0.71-0.95. Validation in human cell models confirmed that hyperglycaemia 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.</p>