GESTATIONAL DIABETES MELLITUS AND MATERNAL EPIGENETIC AGE ACCELERATION DURING PREGNANCY

Abstract

Gestational diabetes mellitus (GDM) affects 10–20% of pregnancies globally and carries a seven- to ten-fold increased lifetime risk of type 2 diabetes. Pregnancy accelerates biological aging at the molecular level, yet whether GDM further amplifies this signal and whether metformin reduces it remains unknown. DNA methylation-based epigenetic clocks offer a quantitative tool to measure this acceleration beyond conventional glycemic biomarkers. This study aimed to determine whether GDM is associated with increased epigenetic age acceleration (EAA) during pregnancy compared to non-GDM controls, and whether metformin-treated women show a reduction in EAA relative to untreated or lifestyle-managed GDM cases. A retrospective longitudinal analysis was conducted using DNA methylation data from two independent Qatari cohorts, the Qatar Birth Cohort (QBiC) and the Women's Wellness and Research Center cohort (WWRC). EAA was estimated using seven clocks: Horvath, Hannum, PhenoAge, GrimAge, GrimAge2, DNAmFitAge, and DunedinPACE, alongside PC-based refinements, computed as residuals adjusting for chronological age, BMI, and batch. Trajectories were examined across first to third trimester (T1–T3) and second to third trimester (T2–T3) gestational windows across four groups: non-GDM controls, untreated GDM patients, lifestyle-managed GDM patients, and metformin-treated GDM patients.GDM cases showed consistently higher EAA than controls across both cohorts. In the treatment-stratified analyses, the untreated GDM group showed the highest PhenoAge EAA increase, while the metformin group showed a decline, ending with a lower EAA at the third trimester. GrimAge, GrimAge2, and DunedinPACE were the most robust and reproducible signals across the two cohorts. These findings indicate that GDM is associated with accelerated maternal epigenetic aging during pregnancy. Metformin may reduce this epigenetic age acceleration, suggesting a potential epigenetic benefit of metformin treatment beyond glycemic control in GDM management.

Date of Award	2026
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences