Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues.
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 from multiple murine tissues corroborated and complemented the findings from the human cohort.
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Jonathan
J
Adam
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Stefan
S
Brandmaier
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Jörn
J
Leonhardt
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Markus F
MF
Scheerer
Metabolon, Inc., Durham, NC.
Robert P
RP
Mohney
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Tao
T
Xu
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Jie
J
Bi
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Markus
M
Rotter
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Martina
M
Troll
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Shen
S
Chi
Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Margit
M
Heier
German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
Christian
C
Herder
German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
Wolfgang
W
Rathmann
Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
Guido
G
Giani
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany.
Jerzy
J
Adamski
Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.|Institute for Human Genetics, Hannover Medical School, Hannover, Germany.
Thomas
T
Illig
Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, München, Germany.
Konstantin
K
Strauch
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Yixue
Y
Li
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Christian
C
Gieger
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Department of Environmental Health, Harvard School of Public Health, Boston, MA.
Annette
A
Peters
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.|Faculty of Biology, Ludwig-Maximilians-Universität, Planegg-Martinsried, Germany.|Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar (WCMC-Q), Education City-Qatar Foundation, Doha, Qatar.
Karsten
K
Suhre
Lehrstuhl für Mathematische Modelle Biologischer Systeme, Technische Universität München, Garching, Germany.
Donna
D
Ankerst
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, München, Germany.
Thomas
T
Meitinger
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany.
Martin
M
Hrabĕ de Angelis
German Center for Diabetes Research (DZD), Neuherberg, Germany.|ShanghaiTech University, Shanghai, China.|Department of Endocrinology and Diabetology, Medical Faculty, Düsseldorf, Düsseldorf, Germany.
Michael
M
Roden
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Susanne
S
Neschen
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Gabi
G
Kastenmüller
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany rui.wang-sattler@helmholtz-muenchen.de.|Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Rui
R
Wang-Sattler
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002956:Citrulline / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D005215:Fasting / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D008137:Longitudinal Studies; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism
D007004:Hypoglycemic Agents; D002956:Citrulline; D008687:Metformin