@article{0d0effef006f4af6a5c4f8c68922e379,
title = "Metformin effect on nontargeted metabolite profiles in patients with type 2 diabetes and in multiple murine tissues",
abstract = "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.",
author = "Rui, {Wang Sattler} and Jonathan Adam and Stefan Brandmaier and J{\"o}rn Leonhardt and Scheerer, {Markus F.} and Mohney, {Robert P.} and Tao Xu and Jie Bi and Markus Rotter and Martina Troll and Shen Chi and Margit Heier and Christian Herder and Wolfgang Rathmann and Guido Giani and Jerzy Adamski and Thomas Illig and Konstantin Strauch and Yixue Li and Christian Gieger and Annette Peters and Karsten Suhre and Donna Ankerst and Thomas Meitinger and {De Angelis}, {Martin Hrab{\v e}} and Michael Roden and Susanne Neschen and Gabi Kastenm{\"u}ller",
note = "Funding Information: The KORA study was initiated and financed by the Helmholtz Zentrum M{\"u}nchen German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (Bundesministerium f{\"u}r Bildung und Forschung) and by the State of Bavaria. Furthermore, KORA research was supported by the Munich Center of Health Sciences (MC-Health), Ludwig- Maximilians-Universit{\"a}t, as part of LMUinnovativ. Part of this project was supported by European Union Seventh Framework Programme grants HEALTH-2009-2.2.1- 3/242114 (Project OPTiMiSE) and HEALTH-2013-2.4.2-1/602936 (Project CarTarDis). The German Diabetes Center is funded by the German Federal Ministry of Health (Bundesministerium f{\"u}r Gesundheit, Berlin, Germany) and the Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia (D{\"u}sseldorf, Germany). The diabetes part of the KORA F4 study was funded by a grant from the Deutsche Forschungsgemeinschaft (DFG; RA 459/3-1). This study was supported in part by a grant from the Bundesministerium f{\"u}r Bildung und Forschung to the German Center for Diabetes Research (DZD) and by the research consortium {"}Systems Biology of Metabotypes{"} (SysMBo grant 0315494A). K.Su. is supported by Biomedical Research Program funds at Weill Cornell Medical College in Qatar, a program funded by the Qatar Foundation. Publisher Copyright: {\textcopyright}2016 by the American Diabetes Association.",
year = "2016",
month = dec,
day = "1",
doi = "10.2337/db16-0512",
language = "English (US)",
volume = "65",
pages = "3776--3785",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "12",
}