Metformin effect on nontargeted metabolite profiles in patients with type 2 diabetes and in multiple murine tissues

Wang Sattler Rui, Jonathan Adam, Stefan Brandmaier, Jörn Leonhardt, Markus F. Scheerer, Robert P. Mohney, Tao Xu, Jie Bi, Markus Rotter, Martina Troll, Shen Chi, Margit Heier, Christian Herder, Wolfgang Rathmann, Guido Giani, Jerzy Adamski, Thomas Illig, Konstantin Strauch, Yixue Li, Christian GiegerAnnette Peters, Karsten Suhre, Donna Ankerst, Thomas Meitinger, Martin Hrabě De Angelis, Michael Roden, Susanne Neschen, Gabi Kastenmüller

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim was to investigate the pleiotropic effect of metformin using a nontargeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA (Cooperative Health Research in the Region of Augsburg) follow-up survey 4 cohort. To compare T2D patients treated with metformin (mt-T2D, n = 74) and those without antidiabetes medication (NDT-T2D, n = 115), we used multivariable linear regression models in a cross-sectional study. We applied a generalized estimating equation to confirm the initial findings in longitudinal samples of 683 KORA participants. In a translational approach, we used murine plasma, liver, skeletal muscle, and epididymal adipose tissue samples from metformin-Treated db/db mice to further corroborate our findings from the human study. We identified two metabolites significantly (P < 1.42E-04) associated with metformin treatment. Citrulline showed lower relative concentrations and an unknown metabolite X-21365 showed higher relative concentrations in human serum when comparing mt-T2D with NDT-T2D. Citrulline was confirmed to be significantly (P < 2.96E-04) decreased at 7-year follow-up in patients who started metformin treatment. In mice, we validated significantly (P < 4.52E-07) lower citrulline values in plasma, skeletal muscle, and adipose tissue of metformin-Treated animals but not in their liver. The lowered values of citrulline we observed by using a nontargeted approach most likely resulted from the pleiotropic effect of metformin on the interlocked urea and nitric oxide cycle. The translational data derived frommultiplemurine tissues corroborated and complemented the findings from the human cohort.

Original languageEnglish (US)
Pages (from-to)3776-3785
Number of pages10
Issue number12
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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