, 12:52 | Cite as

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

  • Ernst Meiss
  • Philipp Werner
  • Clara John
  • Ludger Scheja
  • Nadja Herbach
  • Jörg Heeren
  • Markus Fischer
Original Article


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.


Targeted metabolomics Diabetes Diabetic nephropathy GIPRdn transgenic mice LC–ESI–MS/MS Hydrophilic interaction chromatography 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

11306_2016_958_MOESM1_ESM.xlsx (622 kb)
Supplementary material 1 (XLSX 623 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ernst Meiss
    • 1
  • Philipp Werner
    • 1
  • Clara John
    • 1
    • 2
  • Ludger Scheja
    • 2
  • Nadja Herbach
    • 3
  • Jörg Heeren
    • 2
  • Markus Fischer
    • 1
  1. 1.Department of Food Chemistry, Hamburg School of Food ScienceUniversity of HamburgHamburgGermany
  2. 2.Department of Biochemistry and Molecular Cell BiologyMedical Faculty of Hamburg UniversityHamburgGermany
  3. 3.Institute of Veterinary Pathology, Center for Clinical Veterinary MedicineLudwig-Maximilians-University of MunichMunichGermany

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