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

Abstract

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.

Fig 1. Study design.

A) Flow diagram of analyses strategies. B) Graphical chart of cross-sectional and longitudinal analyses.

Fig 2. Cross-sectional association between urine metabolome and thyroid function.

A) Corrected p-values (false discovery rate (FDR)) of the cross-sectional associations of metabolites levels (right side) or ppm (left side) with free thyroxine (FT4) or thyrotropin (TSH) in Inter99 and Health2006/08. Multivariable linear regression models were adjusted for age, sex, body-mass-index, HbA1c, low-density lipoprotein cholesterol and systolic blood pressure. B) Median levels of alanine, lactate, N,N-dimethylglycine or trigonelline by tertiles of FT4 in Inter99 and Health2006/08. C): Median levels of glycine, lactate, dimethylamine or glucose by tertiles of log(TSH) in Inter99 and Health2006/08.

Fig 3. Longitudinal association between urine metabolome and thyroid function.

A) Corrected p-values (false discovery rate (FDR)) of the longitudinal associations of urine metabolites levels (right side) or ppm (left side) with changes in free thyroxine (FT4) or thyrotropin (TSH) in Inter99. Models were performed in all subjects (x-axis) and *only in subjects with noticeable change assessed by the reference change value (RCV). Multivariable mixed linear models were adjusted for age, sex, body-mass-index, HbA1c, low-density lipoprotein cholesterol and systolic blood pressure (for more details see method section). Estimated mean value with 95% confidence limits for changes in free thyroxine (B: ΔFT4) or thyrotropin (C: Δlog(TSH)) by quartiles of selected urinary metabolite concentrations in Inter99 calculated by mixed linear models. DMA = dimethylamine. DMG = dimethylglycine.