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Metabolite targeting: development of a comprehensive targeted metabolomics platform for the assessment of diabetes and its complications

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Abstract

Biomarker studies for metabolic disorders like diabetes mellitus (DM) are an important approach towards a better understanding of the underlying pathophysiological mechanisms of diseases (Roberts and Gerszten in Cell Metab 18:43–50, 2013; Wilson et al. in Proteome Res 4:591–598, 2005). Furthermore, screening of potential metabolic biomarkers opens the opportunity of early diagnosis as well as therapy and drug monitoring of metabolic disorders (Rhee et al. in J Clin Invest 10:1–10, 2011; Wang et al. in Nat Med 17:448–458, 2011; Wenk in Nat Rev Drug Discov 4:594–610, 2005). The aim of the present study was to develop methods for the quantitative determination of 74 potential metabolite biomarkers for DM and diabetic nephropathy (DN) in serum. Several studies have shown that the concentrations of many polar metabolites like amino or organic acids are changed in subjects suffering from diabetes (Wang et al. in Nat Med 17:448–458, 2011; Yuan et al. in J Chromatogr B 813:53–58, 2007). Analyzing polar analytes presents a challenge in liquid chromatography (LC) coupled with ESI–MS/MS (Gika et al. in J Sep Sci 31:1598–1608, 2008; Spagou et al. in J Sep Sci 33:716–727, 2010). Considering those reasons we decided to develop a specific HILIC–ESI–QqQ–MS/MS-method for quantitative determination of these polar metabolites. A subsequent method validation was carried out for both HILIC and RP chromatography with respect to the guidelines of the Food and Drug Administration (FDA in Food and Drug Administration: Guidance for industry, bioanalytical method validation, 2001). The HILIC and RP LC–MS methods were successfully validated. Furthermore, the HILIC method presented here was applied to serum samples of GIPRdn transgenic mice, a diabetic strain developing DN, and non transgenic littermate controls. Significant, diabetes-associated changes were observed for the concentrations of 21 out of 62 metabolites. The new methods described here accurately quantify 74 metabolites known to be regulated in diabetes, allowing for direct comparison between studies and laboratories. Thus, these methods may be highly adoptable in clinical research, providing a starting point for early diagnosis and metabolic screening.

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    Authors and Affiliations

    1. Department of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146, Hamburg, Germany

      Ernst Meiss, Philipp Werner, Clara John & Markus Fischer

    2. Department of Biochemistry and Molecular Cell Biology, Medical Faculty of Hamburg University, Martinistraße 52, 20246, Hamburg, Germany

      Clara John, Ludger Scheja & Jörg Heeren

    3. Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University of Munich, Veterinärstraße 13, 80539, Munich, Germany

      Nadja Herbach

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    1. Ernst Meiss
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    Ernst Meiss, Philipp Werner, and Clara John have contributed equally to this work.

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    Meiss, E., Werner, P., John, C. et al. Metabolite targeting: development of a comprehensive targeted metabolomics platform for the assessment of diabetes and its complications. Metabolomics 12, 52 (2016). https://doi.org/10.1007/s11306-016-0958-0

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