Metabolic footprint of diabetes: a multiplatform metabolomics study in an epidemiological setting

Karsten Suhre, Christa Meisinger, Angela Döring, Elisabeth Altmaier, Petra Belcredi, Christian Gieger, David Chang, Michael V Milburn, Walter E Gall, Klaus M Weinberger, Hans-Werner Mewes, Martin Hrabé de Angelis, H-Erich Wichmann, Florian Kronenberg, Jerzy Adamski, Thomas Illig, Karsten Suhre, Christa Meisinger, Angela Döring, Elisabeth Altmaier, Petra Belcredi, Christian Gieger, David Chang, Michael V Milburn, Walter E Gall, Klaus M Weinberger, Hans-Werner Mewes, Martin Hrabé de Angelis, H-Erich Wichmann, Florian Kronenberg, Jerzy Adamski, Thomas Illig

Abstract

Background: Metabolomics is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in a biological fluid. However, no single analytic technique covers the entire spectrum of the human metabolome. Here we present results from a multiplatform study, in which we investigate what kind of results can presently be obtained in the field of diabetes research when combining metabolomics data collected on a complementary set of analytical platforms in the framework of an epidemiological study.

Methodology/principal findings: 40 individuals with self-reported diabetes and 60 controls (male, over 54 years) were randomly selected from the participants of the population-based KORA (Cooperative Health Research in the Region of Augsburg) study, representing an extensively phenotyped sample of the general German population. Concentrations of over 420 unique small molecules were determined in overnight-fasting blood using three different techniques, covering nuclear magnetic resonance and tandem mass spectrometry. Known biomarkers of diabetes could be replicated by this multiple metabolomic platform approach, including sugar metabolites (1,5-anhydroglucoitol), ketone bodies (3-hydroxybutyrate), and branched chain amino acids. In some cases, diabetes-related medication can be detected (pioglitazone, salicylic acid).

Conclusions/significance: Our study depicts the promising potential of metabolomics in diabetes research by identification of a series of known and also novel, deregulated metabolites that associate with diabetes. Key observations include perturbations of metabolic pathways linked to kidney dysfunction (3-indoxyl sulfate), lipid metabolism (glycerophospholipids, free fatty acids), and interaction with the gut microflora (bile acids). Our study suggests that metabolic markers hold the potential to detect diabetes-related complications already under sub-clinical conditions in the general population.

Conflict of interest statement

Competing Interests: This study was conducted under the direction of the Helmholtz Zentrum Munich - German Research Center for Environmental Health, independently of Biocrates, Chenomx and Metabolon, who provided the metabolomics measurements on a fee-for-service basis. HMGU researchers did not receive any financial advantages (e.g., consultancy fees) from any of these companies. Co-authorship has been offered to the following members of these companies solely for the value of their scientific input in the interpretation of the data, which was provided free of charge: David Chang, Chenomx Inc.; Michael V. Milburn and Walter E. Gall, Metabolon Inc.; Klaus M. Weinberger, Biocrates Life Sciences AG. This participation of authors from industry does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. Moreover, none of the results presented in this work are presently under consideration for IP protection.

Figures

Figure 1. Venn diagram showing the number…
Figure 1. Venn diagram showing the number of metabolites common to all three platforms, to two platforms and metabolites detected specifically by one platform.
The identity of the individual metabolites that are measured on each platform is provided in Table S2. Note that the metabolites metabolites that are quantified uniquely on the Biocrates platform carry specific information on the lipid side-chain composition of the different phospholipid classes (sometimes also referred to as lipidomics). The Metabolon platform, in contrast, provides a wider non-targeted, but semi-quantitative coverage of the general metabolome. NMR presently allows quantifying only a smaller set of metabolites, but this at a much higher degree of reproducibility, faster, and without specific sample preparation.
Figure 2. 1,5-AG and glucose (measured on…
Figure 2. 1,5-AG and glucose (measured on Metabolon platform).
Lower 1,5-AG concentrations at higher glucose levels in participants with diabetes when compared to the control group display the current role of 1,5-AG as a marker for glycemic control in patients with diabetes.
Figure 3. A systemic view of metabolic…
Figure 3. A systemic view of metabolic markers that associate with diabetes in this study.
The coverage of the metabolome's diversity allows the detection of systemic metabolic imbalances, thereby providing a disease specific picture of human physiology.

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