Urinary metabolomics reveals glycemic and coffee associated signatures of thyroid function in two population-based cohorts

PLoS One. 2017 Mar 2;12(3):e0173078. doi: 10.1371/journal.pone.0173078. eCollection 2017.


Background: Triiodothyronine (T3) and thyroxine (T4) as the main secretion products of the thyroid affect nearly every human tissue and are involved in a broad range of processes ranging from energy expenditure and lipid metabolism to glucose homeostasis. Metabolomics studies outside the focus of clinical manifest thyroid diseases are rare. The aim of the present investigation was to analyze the cross-sectional and longitudinal associations of urinary metabolites with serum free T4 (FT4) and thyroid-stimulating hormone (TSH).

Methods: Urine Metabolites of participants of the population-based studies Inter99 (n = 5620) and Health2006/Health2008 (n = 3788) were analyzed by 1H-NMR spectroscopy. Linear or mixed linear models were used to detect associations between urine metabolites and thyroid function.

Results: Cross-sectional analyses revealed positive relations of alanine, trigonelline and lactic acid with FT4 and negative relations of dimethylamine, glucose, glycine and lactic acid with log(TSH). In longitudinal analyses, lower levels of alanine, dimethylamine, glycine, lactic acid and N,N-dimethylglycine were linked to a higher decline in FT4 levels over time, whereas higher trigonelline levels were related to a higher FT4 decline. Moreover, the risk of hypothyroidism was higher in subjects with high baseline trigonelline or low lactic acid, alanine or glycine values.

Conclusion: The detected associations mainly emphasize the important role of thyroid hormones in glucose homeostasis. In addition, the predictive character of these metabolites might argue for a potential feedback of the metabolic state on thyroid function. Besides known metabolic consequences of TH, the link to the urine excretion of trigonelline, a marker of coffee consumption, represents a novel finding of this study and given the ubiquitous consumption of coffee requires further research.

MeSH terms

  • Adult
  • Blood Glucose / metabolism*
  • Coffee*
  • Female
  • Humans
  • Male
  • Metabolomics*
  • Middle Aged
  • Proton Magnetic Resonance Spectroscopy
  • Thyroid Function Tests*


  • Blood Glucose
  • Coffee

Grant support

We would like to thank the participants in the Inter99, Health2006 and Health2008 cohort, all members of the Inter99/Health2006/ Health2008 staff at Research Centre for Prevention and Health and The Steering Committee of the Inter99 study. The Inter99 study was supported by The Danish Medical Research Council, The Danish Centre for Evaluation and Health Technology Assessment, Novo Nordisk, Copenhagen County, The Danish Heart Foundation, The Danish Pharmaceutical Association, Augustinus foundation, Ib Henriksens foundation and Beckett foundation. Establishment of the Health2006/Health2008 cohort was financially supported by The Velux Foundation; The Danish Medical Research Council, Danish Agency for Science, Technology and Innovation; The Aase and Ejner Danielsens Foundation; ALK-Abelló A/S (Hørsholm, Denmark), Timber Merchant Vilhelm Bangs Foundation, MEKOS Laboratories (Denmark), and Research Centre for Prevention and Health, the Capital Region of Denmark. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement number 657595. Bruker BioSpin supports the current study in form of metabolite quantification for the NMR measurements, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.