Sex-specific signatures of fetal programming for gestational diabetes mellitus in umbilical cord: A cohort study from Tanzania

BACKGROUND: Gestational diabetes mellitus (GDM) is defined as glucose intolerance first recognized during pregnancy. Offspring of GDM mothers have an increased risk of developing type 2 diabetes (T2D), obesity, and other metabolic disorders later in life. METHODS: We analyzed metabolic, genetic, epigenetic, and transcriptional profiles in umbilical cord blood (UCB) from male and female offspring of GDM mothers versus normoglycemic controls in Tanzania. We constructed polygenic and methylation risk scores for T2D and GDM to assess whether diabetes-related susceptibility is detectable at birth. We identified differentially expressed genes (DEGs) and corresponding epigenome-wide alterations in GDM-exposed UCB. We then integrated genetic (PGS), epigenetic (MRS), and transcriptomic (DEG) data to identify convergent molecular signatures of GDM exposure. We examined their associations with neonatal anthropometry and cord insulin levels to infer potential effects on early growth. We further assessed DEG relevance by examining expression in human fetal and adult islets and by reviewing mouse-knockout data to explore possible roles in β-cell development or function. RESULTS: Offspring of GDM mothers showed sex-specific differences in neonatal anthropometry, particularly among females, who exhibited greater adiposity and growth measures. Female offspring also displayed higher PGS for T2D, especially β-cell dysfunction, and a MRS for GDM/T2D associated with elevated cord insulin. We identified 36 DEGs in GDM-exposed UCB overall, with a striking sex-specific pattern (273 DEGs in females vs. 4 in males). Several DEGs and associated DNA methylation (DNAm) sites correlated with neonatal anthropometry, particularly in females, indicating putative fetal programming signatures. These signals showed convergence across genetic risk, DNA methylation, and gene expression layers. The expression of SESN3, HMBS, NUTM2D, and MAN2A2 associated with insulin levels. MAN2A2 expression also associated with birth weight and length in female offspring. The SLC4A1 gene showed fetal pancreas-specific expression and co-expression with key pancreatic developmental genes, suggesting a role in pancreatic development. CONCLUSIONS: We identified integrated multi-omic signatures of GDM exposure in offspring at birth, with markedly stronger effects in females. These genes and pathways may contribute to fetal metabolic programming in this understudied Tanzanian population, offering new insights into biological mechanisms that may influence early development. TRIAL REGISTRATION: ClinicalTrials.gov NCT02191683 Registered 2 July 2014.