title: Metabolite profiling identifies pathways associated with metabolic risk in humans.
abstract: BACKGROUND
  Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood.
  
  
  RESULTS
  To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmö Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; P<0.001), glutamate (0.05 to 0.14; P<0.001), and the glutamine-to-glutamate ratio (-0.05 to -0.20; P<0.001) in the discovery sample (FHS); similar associations were observed in the replication sample (MDC). High glutamine-to-glutamate ratio was associated with lower risk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (P<0.05).
  
  
  CONCLUSIONS
  Biochemical profiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice.
authors.affiliation: Cardiology Division, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Rhee
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: McCabe
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Shen
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Palma
authors.forename: Lee D
authors.initials: LD
authors.lastname: Roberts
authors.forename: Andre
authors.initials: A
authors.lastname: Dejam
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Souza
authors.forename: Amy A
authors.initials: AA
authors.lastname: Deik
authors.forename: Martin
authors.initials: M
authors.lastname: Magnusson
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
mesh_terms: D000368:Aged; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D050171:Dyslipidemias / Q000378:metabolism; D005260:Female; D005973:Glutamine / Q000008:administration & dosage; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009711:Nucleotides / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D012306:Risk; D055105:Waist Circumference
chemical_list: D000596:Amino Acids; D009711:Nucleotides; D005973:Glutamine