title: Effect of metformin therapy on circulating amino acids in a randomized trial: the CAMERA study.
abstract: To investigate whether metformin therapy alters circulating aromatic and branched-chain amino acid concentrations, increased levels amino acid concentrations, increased levels of which have been found to predict Type 2 diabetes.
  
  
  
  In the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) study (NCT00723307), 173 individuals without Type 2 diabetes, but with coronary disease, were randomized to metformin (n=86) or placebo (n=87) for 18 months. Plasma samples, taken every 6 months, were analysed using quantitative nuclear magnetic resonance spectroscopy. Ten metabolites consisting of eight amino acids [three branched-chain (isoleucine, leucine, valine), three aromatic (tyrosine, phenylalanine, histidine) and two other amino acids (alanine, glutamine)], lactate and pyruvate were quantified and analysed using repeated-measures models. On-treatment analyses were conducted to investigate whether amino acid changes were dependent on changes in weight, fat mass or insulin resistance estimated using homeostasis model assessment (HOMA-IR).
  
  
  
  Tyrosine decreased [-6.1 μmol/l (95% CI -8.5, -3.7); P<0.0001], while alanine [42 umol/l (95% CI 25, 59); P<0.0001] increased in the metformin-treated group compared with the placebo-treated group. Decreases in phenylalanine [-2.0 μmol/l (95% CI -3.6, -0.3); P=0.018] and increases in histidine [2.3 μmol/l (95% CI 0.1, 4.6); P=0.045] were also observed in the metformin group, although these changes were less statistically robust. Changes in these four amino acids were not accounted for by changes in weight, fat mass or HOMA-IR values. Levels of branched-chain amino acids, glutamine, pyruvate and lactate were not altered by metformin therapy.
  
  
  
  Metformin therapy results in a sustained and specific pattern of changes in aromatic amino acid and alanine concentrations. These changes are independent of any effects on weight and insulin sensitivity. Any causal link to metformin's unexplained cardiometabolic benefit requires further study.
authors.affiliation: Clinical Trial Service and Epidemiological Studies Unit, University of Oxford, Oxford, UK. david.preiss@ndph.ox.ac.uk.
authors.forename: D
authors.initials: D
authors.lastname: Preiss
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.|Glasgow Polyomics, Joseph Black Building, University of Glasgow, Glasgow, UK.
authors.forename: N
authors.initials: N
authors.lastname: Rankin
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: P
authors.initials: P
authors.lastname: Welsh
authors.affiliation: Diabetes Trials Unit, University of Oxford, Oxford, UK.
authors.forename: R R
authors.initials: RR
authors.lastname: Holman
authors.affiliation: Computational Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
authors.forename: A J
authors.initials: AJ
authors.lastname: Kangas
authors.affiliation: Computational Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Soininen
authors.affiliation: Computational Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Würtz
authors.affiliation: Computational Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.|NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.|Oulu University Hospital, Oulu, Finland.|Computational Medicine, School of Social and Community Medicine and the Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ala-Korpela
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: N
authors.initials: N
authors.lastname: Sattar
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000097:blood*; D000597:Amino Acids, Branched-Chain / Q000097:blood; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos
chemical_list: D000596:Amino Acids; D000597:Amino Acids, Branched-Chain; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010919:Placebos; D008687:Metformin