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Context: 3,5-Diiodo-<smlcap>L</smlcap>-thyronine (3,5-T<sub>2</sub>) 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-T<sub>2</sub> 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-T<sub>2</sub> 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 <sup>1</sup>H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T<sub>2</sub> concentrations. Results: Serum 3,5-T<sub>2</sub> concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T<sub>2</sub> 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-T<sub>2</sub> 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-T<sub>2</sub> exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones.
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German Rheumatism Research Center, Berlin, Germany
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Institute for Clinical Chemistry, Interdisciplinary University Laboratory, University Medicine Göttingen, Göttingen, Germany
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Background: Variability of measurements in medical research can be due to different sources. Quantification of measurement errors facilitates probabilistic sensitivity analyses in future research to minimize potential bias in epidemiological studies. We aimed to investigate the variation of thyroid-related outcomes derived from ultrasound (US) and laboratory analyses in a repeated measurements study. Subjects and Methods: Twenty-five volunteers (13 females, 12 males) aged 22–70 years were examined once a month over 1 year. US measurements included thyroid volume, goiter, and thyroid nodules. Laboratory measurements included urinary iodine concentrations and serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and thyroglobulin. Variations in continuous thyroid markers were assessed as coefficient of variation (CV) defined as mean of the individual CVs with bootstrapped confidence intervals and as intraclass correlation coefficients (ICCs). Variations in dichotomous thyroid markers were assessed by Cohen’s kappa. Results: CV was highest for urinary iodine concentrations (56.9%), followed by TSH (27.2%), thyroglobulin (18.2%), thyroid volume (10.5%), fT3 (8.1%), and fT4 (6.3%). The ICC was lowest for urinary iodine concentrations (0.42), followed by fT3 (0.55), TSH (0.64), fT4 (0.72), thyroid volume (0.87), and thyroglobulin (0.90). Cohen’s kappa values for the presence of goiter or thyroid nodules were 0.64 and 0.70, respectively. Conclusion: Our study provides measures of variation for thyroid outcomes, which can be used for probabilistic sensitivity analyses of epidemiological data. The low intraindividual variation of serum thyroglobulin in comparison to urinary iodine concentrations emphasizes the potential of thyroglobulin as marker for the iodine status of populations.
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German Centre for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany
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German Centre for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany
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Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
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Charité – Universitätsmedizin Berlin, BCRT – Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
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Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
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Objective
Thyroid dysfunction is associated with relevant disturbances in glucose metabolism. Moreover, thyroid function undergoes important changes with ageing. The objective of this study was to investigate the association of thyroid function with insulin resistance with particular consideration of possible age-related effect modifications.
Design
A sample of 4193 participants from two independent epidemiological studies, the Study of Health in Pomerania-TREND-0 and the Berlin Aging Study II, was included in this cross-sectional analysis.
Methods
Insulin resistance was estimated by homeostasis model of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI). Associations of thyroid biomarkers (thyroid-stimulating hormone, free thyroxine, and free triiodothyronine (fT3)) with parameters of glucose metabolism were analysed by regression models adjusted for age, sex, smoking status, and study site.
Results
A higher fT3 was significantly associated with higher fasting glucose and higher fasting and 2-h postload insulin levels, a higher HOMA-IR, and lower ISI. A higher fT3 was also associated with a higher risk for impaired fasting glucose (RR 1.09, 95 CI 1.02; 1.18; P = 0.017). Many of these associations between thyroid markers and parameters of glucose metabolism were significant in young and middle-aged participants but not in older individuals.
Conclusions
The main finding of this study was a consistent association of fT3 with almost all markers of insulin resistance. However, this effect seems to be wearing off in higher age highlighting a potential age-related modification of the interaction between thyroid function and glucose metabolism. Further studies are needed to clarify causal relationships.
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DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
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Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Germany
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Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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Objective
Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters
Methods
Uptake of 1 nM of iodothyronines or sulfated iodothyronines in COS1 cells expressing SLC22 proteins was performed.
Results
We first tested 25 mouse (m) SLC22 proteins for TH uptake and found that the majority of the organic anion transporter (OAT) clade were capable of 3,3’,5-triiodothyronine and/or thyroxine (T4) transport. Based on phylogenetic tree analysis of the mouse and human (h) SLC22 family, we selected eight hSLC22s that grouped with the newly identified mouse TH transporters. Of these, four tested positive for uptake of one or more substrates, particularly hSLC22A11 showed robust (3-fold over control) uptake of T4. Uptake of sulfated iodothyronines was strongly (up to 17-fold) induced by some SLC22s, most notably SLC22A8, hSLC22A9, mSLC22A27 and mSLC22A29. Finally, the zebrafish orthologues of SLC22A6/8 drOatx and drSlc22a6l also transported almost all (sulfated) iodothyronines tested. The OAT inhibitors lesinurad and probenecid inhibited most SLC22 proteins.
Conclusions
Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology.
