Novel amino acid and fatty acid signatures linked to type 2 diabetes risk after gestational diabetes mellitus.

BACKGROUND

Women with gestational diabetes mellitus (GDM) history carry increased risks of type 2 diabetes compared to women without GDM history. This study aims to identify the dysregulated metabolic pathways and metabolite signatures during pregnancy that predict the risk of developing type 2 diabetes post-GDM.

METHODS

101 Hispanic women with GDM diagnoses were followed from the 3rd trimester of index pregnancy to 12 years post-delivery. Oral and intravenous glucose tolerance tests were performed every 12–15 months until development of type 2 diabetes, lost-to-follow-up or the end of the study. Type 2 diabetes incidence was identified as a fasting glucose concentration ≥ 126 mg/dL or 2-hour glucose ≥ 200 mg/dL. In this study, archived plasma samples from the 3rd trimester of pregnancy were assayed for untargeted metabolomics using mass-spectrometry to explore metabolic signatures of diabetes development. Metabolome-wide association analysis was performed to assess the association of metabolomic features with type 2 diabetes incidence using Cox proportional hazards models adjusted for age at delivery, along with post-delivery body mass index, additional pregnancy, and self-reported daily calorie intake at each follow-up visit as time-varying covariates, followed by Mummichog pathway enrichment analysis.

RESULTS

Among the 101 women, 52 developed diabetes in 12 years. Metabolomics analysis suggested that nine amino acid and fatty acid metabolic pathways were associated with the risk of developing type 2 diabetes in GDM women (p-values of pathway enrichment tests < 0.05). Higher plasma levels of agmatine, hydroxyproline/5-aminolevulinate, along with lower plasma levels of threonine/homoserine, 25-hydroxycholesterol, FA12:0 (laurate), FA20:0 (arachidic acid), FA20:3 (homolinoleic acid), FA18:3 n-3 or n-6 (linolenic acid) in 3rd trimester were associated with a 12%–60% higher hazard of developing type 2 diabetes during the up to 12 years’ post-delivery period (all p-values < 0.05).

CONCLUSION

Levels of amino acid and fatty acid metabolomic signatures in pregnancy may help identify individuals at an elevated risk of developing type 2 diabetes after GDM-complicated pregnancy, highlighting opportunities for earlier, more targeted prevention that require confirmation in larger, prospective studies.