title: Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes.
abstract: OBJECTIVE
  Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin.
  
  
  METHODS
  We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways.
  
  
  RESULTS
  We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target.
  
  
  CONCLUSIONS
  Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease.
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tao
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany German Center for Diabetes Research, Düsseldorf, Germany.
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
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authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany German Center for Diabetes Research, Neuherberg, Germany.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research, Neuherberg, Germany Department of Environmental Health, Harvard School of Public Health, Boston, MA.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research, Neuherberg, Germany rui.wang-sattler@helmholtz-muenchen.de.
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mesh_terms: D000368:Aged; D008078:Cholesterol, LDL / Q000378:metabolism*; D003430:Cross-Sectional Studies; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D003925:Diabetic Angiopathies / Q000517:prevention & control; D005215:Fasting / Q000097:blood; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005260:Female; D023281:Genomics; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D055432:Metabolomics; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D012307:Risk Factors
chemical_list: D008078:Cholesterol, LDL; D000090943:Delta-5 Fatty Acid Desaturase; D007004:Hypoglycemic Agents; D008687:Metformin; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human; C533241:FADS2 protein, human