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Omics Phenotyping of Endocrine Disease in the General Population

Periodic Reporting for period 1 - OPEDGP (Omics Phenotyping of Endocrine Disease in the General Population)

Reporting period: 2015-08-01 to 2017-07-31

Background and objectives:
Endocrine diseases, such as diabetes and thyroid diseases, are common in the general population and poses a significant burden to individual and society. During the last decade metabolomics, as one of the ‘omics’ techniques including genomics, transcriptomics or proteomics, gains more and more popularity in the field of biomarker discovery and represents a promising tool to identify new diagnostic tool and disease-related pathways and biomarkers of disease risk and prognosis. Metabolomics deals with the investigation of the metabolome comprising the entirety of all small-molecule, so-called metabolites, in any biological sample. Metabolomics is mostly used as hypothesis-free approach because it gives an overview over the metabolic state of an organism (sample) at a given time point. In the present project we used nuclear magnetic resonance spectroscopy (NMR) based metabolomics approach to reveal new markers of endocrine diseases in large population-based studies with longitudinal follow-up. We focused on the urinary metabolome due to the non-invasive nature of the biofluid and the promising implementation in screening tools.

The key thyroid hormones, triiodothyronine (T3) and thyroxine (T4), are central components of the hypothalamic-pituitary-thyroid axis and are under control of the pituitary gland released thyroid-stimulating hormone (TSH). TSH and free T4 (FT4) are accepted biomarkers for the diagnosis and follow-up of disorders in thyroid function. We found that significant associations of different amino acids, glucose and trigonelline with changes in thyroid function. Trigonelline was, beside the relation with continuous changes in thyroid function, also associated with an increased risk of hypothyroidism. Trigonelline is known as a metabolite in the niacin metabolism and a bioactive compound in coffee suggesting coffee playing a role in thyroid function.
We also investigated the association of baseline urine metabolites with 5-year changes in continuous markers of glucose homoeostasis including fasting glucose, glycated haemoglobin (HbA1c) and homoeostasis model assessment of insulin resistance (HOMA-IR). Several urinary metabolites like alanine, betaine, 1-methylnicotinamide, trimethylamine and trigonelline, were associated with detrimental longitudinal changes in biomarkers of glucose homoeostasis (see figure 1 attached as image). These findings support the hypothesis that the betaine metabolism is involved in the mechanisms of diabetes. The increased betaine excretion might be an early marker of tubular impairment. Beside betaine, the detected metabolites revealed links to the coffee metabolism and the possible influence of the gut microbiome. Urine seems to be a promising tool to screen for individuals who are likely to be affected by longitudinal alterations in glucose homoeostasis.

We found evidence that urinary metabolites can be used as biomarkers of endocrine diseases (thyroid disease and diabetes) and changes in biomarkers of endocrine function even in a general population setting. These findings may improve our understanding of disease mechanisms and lead to better prediction of disease.
1. NMR data preprocessing
NMR datasets from the included studies were processed including the following preprocessing steps: the removal of the water signal, outlier detection, bucketing, peak alignment of the NMR spectra and normalization.
2. Statistical-epidemiological analyses of cross-sectional and longitudinal associations between the urine metabolome and thyroid function as well as incident thyroid diseases (WP1+ WP2)
3. Analyses of longitudinal association between the urine metabolome and glucose homoeostasis (WP2)
4. Discovery of genetic determinants of urine metabolites (WP3)
In collaboration with the The Novo Nordisk Foundation Center for Basic Metabolic Research, a genome-wide association (GWA) study regarding the seventeen quantified urine metabolites and their ratios were performed. The analyses confirmed mainly findings of a large previous study.
5. Dissemination/communication of results
Presently, two original peer reviewed articles have been published (OPEN ACCESS). The research fellow has participated in and presented data at several international congresses.
The advantage of the presented project is the use of the urinary metabolome due to its non-invasive nature and its possible simple implication in screening programs. Furthermore, the presented studies were in relation to the corresponding research field the first studies which investigated continuous changes in insulin sensitivity as well as thyroid function and therefore also considered subclinical alterations and were not limited to manifest diseases. In regards to the development of screening tools it is of particular interest to identify subjects who are on the way to developing diseases and therefore the investigation of consecutive changes in metabolic status are crucial. In light of metabolomics studies the applied approaches are mainly hypotheses-free, therefore further research is needed to clarify the usefulness of the detected metabolites.
Nevertheless, the finding of trigonelline as metabolite associated with changes in markers of glucose homoeostasis as well as thyroid function represents a most interesting finding in the project. The effect of coffee consumption on various diseases or metabolic alterations is focus of a controversial discussion. Older studies mainly showed adverse effects, whereas newer evidence suggest possible positive health effects on different diseases including diabetes mellitus or liver diseases. However the research field is influenced by potential pitfalls like the consideration of the coffee composition (e.g. caffeinated or decaffeinated coffee as well as different additives) or the various preparation method (filter coffee or Turkish coffee) which makes it hard to drawn a generalized conclusion. Therefore, the further investigation of the impact of coffee consumption on metabolic alteration and diseases seems of particular interest and might forms the basis for interventional and experimental studies.