Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

Abstract

Context: 3,5-Diiodo-<smlcap>L</smlcap>-thyronine (3,5-T₂) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by a high-fat diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T₂ and glucose but not lipid metabolism. Objective: The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T₂ concentrations in healthy individuals. Study Design and Methods: Urine metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by ¹H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T₂ concentrations. Results: Serum 3,5-T₂ concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T₂ concentrations doubled owing to a 1-standard deviation (SD) decrease in urine trigonelline levels, or increased by 29-50% in relation to a 1-SD decrease in urine pyroglutamate, acetone and hippurate levels. Conclusion: Our findings in humans confirmed the metabolic effects of circulating 3,5-T₂ on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T₂ exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones.

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

“…Of special interest was, similar to the previous studies, the lack of a clear association with serum T4 and/or T3 concentrations (44,45). In a follow-up study of the same cohort, 3,5-T2 serum concentrations were analyzed with respect to urine metabolites analyzed by 1 H-NMR spectroscopy (45)(46)(47)(48). Again, very few individuals had remarkably elevated 3,5-T2 serum concentrations that might be suggestive of underlying disease, although health status could not be traced back due to the population-based study using anonymized sera.…”

“…This observation is the first one to link a THM to coffee consumption, and so far, no clearcut hypothesis has been tested to challenge a potential causal relationship (45,46). However, indirect evidence might support the assumption that hepatic accumulation of 3,5-T2 (see below) may alter hepatic (and/or renal) metabolism of components consumed with (caffeinated and decaffeinated) coffee and thus even might provide a link between beneficial antisteatotic effects ascribed to 3,5-T2 and also to coffee consumption (44)(45)(46)(47)(48) (Figure 4). Table 2 summarizes the observations made in various pathophysiological states with respect to altered 3,5-T2 concentration in human serum, as determined by the monoclonal antibody-based CLIA.…”

Empowering thyroid hormone research in human subjects using OMICs technologies

“…Population-based study (Inter99 (N = 5620) and Health06/08 (N = 3788)); prediction of changes in TSH/ HPT axis but anticipated relations with anthropometric parameters or blood lipids could not be detected (Pietzner et al 2015c). However, application of urine metabolomics among 715 euthyroid subjects enabled us to partially confirm observations from animal models with respect to the oxidation of FAs (acetone as proxy for β-oxidation) and oxidative stress or detoxification of xenobiotics (pyroglutamate as intermediate in the γ-glutamyl cycle) (Pietzner et al 2015b). Importantly, only minor overlap with the classical markers of thyroid function became obvious, comprising trigonelline (FT 4 ) and hippurate (TSH).…”

“…Apart from the comprehensive characterization of classical TH effects, urine metabolomics was particularly useful to exploit a possible endogenous fate of the putative T 3 -metabolite 3,5-T 2 as its endogenous relevance in humans is still a matter of debate (Pietzner et al 2015b). A first population-based study provided only vague evidence in relation 3,5-T 2 to glucose metabolism or the Table 2 Summary of metabolomics studies in humans done so far.…”

Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites

“…Serum levels of 3,5-T2 have been reported to be around 0.24 nM in euthyroid humans ( 23 ), and they seem not to differ in thyroid dysfunction states ( 11 ). However, a study reported reduced free T3 levels together with elevated 3,5-T2 levels in patients with postoperative atrial fibrillation ( 24 ).…”