title: Untargeted metabolic profiling identifies altered serum metabolites of type 2 diabetes mellitus in a prospective, nested case control study.
abstract: BACKGROUND
  Application of metabolite profiling could expand the etiological knowledge of type 2 diabetes mellitus (T2D). However, few prospective studies apply broad untargeted metabolite profiling to reveal the comprehensive metabolic alterations preceding the onset of T2D.
  
  
  METHODS
  We applied untargeted metabolite profiling in serum samples obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 300 individuals who developed T2D after a median follow-up time of 6 years and 300 matched controls. For that purpose, we used ultraperformance LC-MS with a protocol specifically designed for large-scale metabolomics studies with regard to robustness and repeatability. After multivariate classification to select metabolites with the strongest contribution to disease classification, we applied multivariable-adjusted conditional logistic regression to assess the association of these metabolites with T2D.
  
  
  RESULTS
  Among several alterations in lipid metabolism, there was an inverse association with T2D for metabolites chemically annotated as lysophosphatidylcholine(dm16:0) and phosphatidylcholine(O-20:0/O-20:0). Hexose sugars were positively associated with T2D, whereas higher concentrations of a sugar alcohol and a deoxyhexose sugar reduced the odds of diabetes by approximately 60% and 70%, respectively. Furthermore, there was suggestive evidence for a positive association of the circulating purine nucleotide isopentenyladenosine-5'-monophosphate with incident T2D.
  
  
  CONCLUSIONS
  This study constitutes one of the largest metabolite profiling approaches of T2D biomarkers in a prospective study population. The findings might help generate new hypotheses about diabetes etiology and develop further targeted studies of a smaller number of potentially important metabolites.
authors.affiliation: Department of Epidemiology and drogan@dife.de.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Drogan
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, and Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; School of Chemistry and Manchester Centre for Integrative Systems Biology, University of Manchester, Manchester, UK; School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK;
authors.forename: Warwick B
authors.initials: WB
authors.lastname: Dunn
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, and Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; School of Chemistry and Manchester Centre for Integrative Systems Biology, University of Manchester, Manchester, UK;
authors.forename: Wanchang
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Epidemiology and.
authors.forename: Brian
authors.initials: B
authors.lastname: Buijsse
authors.affiliation: Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany;
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Schulze
authors.affiliation: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK;
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, and Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; School of Chemistry and Manchester Centre for Integrative Systems Biology, University of Manchester, Manchester, UK;
authors.forename: Marie
authors.initials: M
authors.lastname: Brown
authors.affiliation: Department of Epidemiology and.
authors.forename: Anna
authors.initials: A
authors.lastname: Floegel
authors.affiliation: Department of Epidemiology and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dietrich
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden;
authors.forename: Olov
authors.initials: O
authors.lastname: Rolandsson
authors.affiliation: School of Chemistry and Manchester Centre for Integrative Systems Biology, University of Manchester, Manchester, UK; Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK;
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: School of Chemistry and Manchester Centre for Integrative Systems Biology, University of Manchester, Manchester, UK;
authors.forename: Royston
authors.initials: R
authors.lastname: Goodacre
authors.affiliation: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK;
authors.forename: Nita G
authors.initials: NG
authors.lastname: Forouhi
authors.affiliation: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK;
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sharp
authors.affiliation: Department of Endocrinology, Diabetes and Nutrition, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Spranger
authors.affiliation: Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK;
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: Department of Epidemiology and.
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D015415:Biomarkers