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Diabetes. 2016 Dec;65(12):3776-3785. Epub 2016 Sep 12.

Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues.

Author information

1
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
2
Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
3
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
4
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
5
German Center for Diabetes Research (DZD), Neuherberg, Germany.
6
Metabolon, Inc., Durham, NC.
7
Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
8
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
9
Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
10
Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Neuherberg, Germany.
11
Institute of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany.
12
Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
13
Institute for Human Genetics, Hannover Medical School, Hannover, Germany.
14
Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
15
Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, München, Germany.
16
Department of Environmental Health, Harvard School of Public Health, Boston, MA.
17
Faculty of Biology, Ludwig-Maximilians-Universität, Planegg-Martinsried, Germany.
18
Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar (WCMC-Q), Education City-Qatar Foundation, Doha, Qatar.
19
Lehrstuhl für Mathematische Modelle Biologischer Systeme, Technische Universität München, Garching, Germany.
20
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
21
Institute of Human Genetics, Technische Universität München, München, Germany.
22
ShanghaiTech University, Shanghai, China.
23
Department of Endocrinology and Diabetology, Medical Faculty, Düsseldorf, Düsseldorf, Germany.
24
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany rui.wang-sattler@helmholtz-muenchen.de.

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 from multiple murine tissues corroborated and complemented the findings from the human cohort.

PMID:
27621107
DOI:
10.2337/db16-0512
[Indexed for MEDLINE]
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