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Bioinformatics Analysis of Targeted Metabolomics—Uncovering Old and New Tales of Diabetic Mice under Medication

Institute of Bioinformatics and Systems Biology (E.A., H.-W.M., K.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Biocrates Life Sciences AG (S.L.R., A.G., K.M.W.), A-6020 Innsbruck, Austria; Department of Genome-oriented Bioinformatics (H.-W.M.), Life and Food Science Center Weihenstephan, Technische Universität München, D-85354 Freising, Germany; and Faculty of Biology (K.S.), Ludwig-Maximilians-Universität, D-82152 Planegg-Martinsried, Germany

Address all correspondence and requests for reprints to: Professor Dr. Karsten Suhre, Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany. E-mail: karsten.suhre{at}helmholtz-muenchen.de.

Metabolomics is a powerful tool for identifying both known and new disease-related perturbations in metabolic pathways. In preclinical drug testing, it has a high potential for early identification of drug off-target effects. Recent advances in high-precision high-throughput mass spectrometry have brought the metabolomic field to a point where quantitative, targeted, metabolomic measurements with ready-to-use kits allow for the automated in-house screening for hundreds of different metabolites in large sets of biological samples. Today, the field of metabolomics is, arguably, at a point where transcriptomics was about 5 yr ago. This being so, the field has a strong need for adapted bioinformatics tools and methods. In this paper we describe a systematic analysis of a targeted quantitative characterization of more than 800 metabolites in blood plasma samples from healthy and diabetic mice under rosiglitazone treatment. We show that known and new metabolic phenotypes of diabetes and medication can be recovered in a statistically objective manner. We find that concentrations of methylglutaryl carnitine are oppositely impacted by rosiglitazone treatment of both healthy and diabetic mice. Analyzing ratios between metabolite concentrations dramatically reduces the noise in the data set, allowing for the discovery of new potential biomarkers of diabetes, such as the N-hydroxyacyloylsphingosyl-phosphocholines SM(OH)28:0 and SM(OH)26:0. Using a hierarchical clustering technique on partial ² values, we identify functionally related groups of metabolites, indicating a diabetes-related shift from lysophosphatidylcholine to phosphatidylcholine levels. The bioinformatics data analysis approach introduced here can be readily generalized to other drug testing scenarios and other medical disorders.