Metabolomic and proteomic signatures of gestational diabetes predicting long-term risk of type 2 diabetes: a prospective cohort study in the UK Biobank

Background Women who develop gestational diabetes mellitus (GDM) during pregnancy have up to a 20-fold increased risk of progressing to type 2 diabetes mellitus (T2DM) later in life. Despite this elevated risk, efforts to accurately predict which women with GDM will develop T2DM remain largely unsuccessful. Methods Using data from women in the UK Biobank, comprehensive metabolomic (n = 197,263; 685 with GDM) and proteomic (n = 17,895; 62 with GDM) profiling was performed. We derived GDM-associated metabolomic and proteomic signatures using metabolomic and proteomic features as predictors and GDM as a binary outcome in generalized linear models with elastic net regularization. In prospective analyses, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between the GDM-associated metabolomic and proteomic signatures and incident T2DM. Results Distinct metabolomic signatures associated with prior GDM were identified, characterized by higher levels of alanine, glucose–lactate, lactate, isoleucine, and leucine, and lower levels of creatinine, glycine, glutamine, citrate, 3-hydroxybutyrate and docosahexaenoic acid. Proteomic profiling revealed lower concentrations of proteins involved in cholesterol metabolism, integrin and cytokine signaling, and higher concentrations of proteins involved in inositol phosphate metabolism and phosphatidylinositol signaling. Higher scores for the GDM-associated metabolomic and proteomic signatures were significantly associated with incident T2DM (HR per SD 1.82, 95% CI 1.73–1.91; and 1.27, 95% CI 1.10–1.47, respectively). Conclusions We identified distinct molecular signatures of GDM that were detectable years after pregnancy and predictive of T2DM risk. These findings may improve long-term risk stratification and inform early prevention strategies for T2DM.