Identification of urine metabolites associated with 5-year changes in biomarkers of glucose homoeostasis

Aim: Metabolomics provides information on pathogenetic mechanisms and targets for interventions, and may improve risk stratification. During the last decade, metabolomics studies were used to gain deeper insight into the pathogenesis of diabetes mellitus. However, longitudinal metabolomics studies of possible subclinical states of disturbed glucose metabolism are limited. Therefore, the aim of this study was to analyze the associations between baseline urinary metabolites and 5-year changes in continuous markers of glucose homoeostasis, including fasting glucose, HbA_1c and homoeostasis model assessment of insulin resistance (HOMA-IR) index values. Methods: Urine metabolites in 3986 participants at both baseline and 5-year follow-up of the population-based Inter99 study were analyzed by ¹H-NMR spectroscopy. Linear regression and analyses of covariance models were used to detect associations between urine metabolites and 5-year changes in markers of glucose homoeostasis. Results: Higher baseline levels of urinary alanine, betaine, N,N-dimethylglycine (DMG), creatinine and trimethylamine were associated with an increase in HbA_1c from baseline to follow-up. In contrast, formic acid and trigonelline levels were associated with a decrease in HbA_1c over time. Analyses of 5-year changes in fasting glucose and HOMA-IR index showed similar findings, with high baseline levels of lactic acid, beta-d-glucose, creatinine, alanine and 1-methylnicotinamide associated with increases in both parameters. Conclusion: Several urine metabolites were found to be associated with detrimental longitudinal changes in biomarkers of glucose homoeostasis. The identified metabolites point to mechanisms involving betaine and coffee metabolism as well as the possible influence of the gut microbiome.