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Circulation DOI:10.1161/CIRCULATIONAHA.111.067827

Metabolite profiling identifies pathways associated with metabolic risk in humans.

Publication TypeJournal Article
Year of Publication2012
AuthorsCheng, S, Rhee, EP, Larson, MG, Lewis, GD, McCabe, EL, Shen, D, Palma, MJ, Roberts, LD, Dejam, A, Souza, AL, Deik, AA, Magnusson, M, Fox, CS, O'Donnell, CJ, Vasan, RS, Melander, O, Clish, CB, Gerszten, RE, Wang, TJ
Date Published2012 May 08
KeywordsAged, Amino Acids, Animals, Body Mass Index, Cardiovascular Diseases, Diabetes Mellitus, Dyslipidemias, Female, Glutamine, Humans, Hypertension, Insulin Resistance, Male, Metabolic Networks and Pathways, Metabolome, Mice, Mice, Inbred C57BL, Middle Aged, Nucleotides, Obesity, Risk, Waist Circumference

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.

METHODS AND 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

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.


Alternate JournalCirculation
PubMed ID22496159
PubMed Central IDPMC3376658
Grant ListN01-HC-25195 / HC / NHLBI NIH HHS / United States
R01-DK-HL081572 / DK / NIDDK NIH HHS / United States
R01 DK081572 / DK / NIDDK NIH HHS / United States
R01 HL081572 / HL / NHLBI NIH HHS / United States
K23 HL091106 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
K99 HL107642 / HL / NHLBI NIH HHS / United States