Association between gestational diabetes mellitus and long-term all-cause and cause-specific mortality risks: a prospective cohort study based on metabolomics.
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BACKGROUND: Gestational diabetes mellitus (GDM) is one of the most common metabolic disorders during pregnancy. Women with GDM face an increased risk of type 2 diabetes and cardiovascular disease (CVD) after childbirth, even after accounting for obesity, lifestyle, and socioeconomic factors. However, whether GDM raises long-term all-cause and cause-specific mortality remains uncertain. This study aimed to clarify the long-term links between GDM-related metabolic profiles and mortality using nuclear magnetic resonance (NMR) metabolomics. METHODS: Using data from the UK Biobank (UKB) prospective female cohort, we combined GDM history with NMR metabolomic data to examine associations between GDM-related metabolic signature and all-cause and cause-specific mortality. Cox proportional hazards models were employed to estimate risk, and the added predictive value of these metabolic profiles beyond traditional risk factors was assessed. Sensitivity analyses verified the robustness of the results. RESULTS: Over a median follow-up of 13.5 years, each 1-SD increase in the GDM-related metabolic signature was associated with higher risks of all-cause (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.15–1.19), cardiovascular (1.29, 1.24–1.34), cancer (1.10, 1.07–1.12) and respiratory mortality (1.17, 1.09–1.25). The signature combined lower glutamine, glycine, and histidine, more small, dense, low-density lipoprotein particles, a lower linoleic acid ratio, and disturbed glycolytic intermediates, consistent with insulin resistance, chronic inflammation, and impaired energy metabolism. These associations were robust in sensitivity analyses, and adding the metabolic signature to conventional models improved risk reclassification for cardiovascular mortality (Net Reclassification Improvement [NRI] = 0.24, P < 0.001), with modest changes in time-dependent AUC. CONCLUSIONS: This study provides observational evidence that a GDM-related metabolic signature is associated with increased long-term all-cause and cause-specific mortality in women with a history of GDM. Women with GDM exhibit a systemic metabolic profile characterized by insulin resistance and disruptions in glucose, amino acid, and lipid metabolism, which may explain the association between GDM and mortality. These results shed light on GDM-related metabolic pathways and support metabolomics-based approaches for risk assessment and targeted intervention, underscoring the importance of long-term systemic risk monitoring beyond controlling blood sugar levels.