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Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans

Cheng, Susan; Rhee, Eugene P.; Larson, Martin G.; Lewis, Gregory D.; McCabe, Elizabeth L.; Shen, Dongxiao; Palma, Melinda J.; Roberts, Lee D.; Dejam, Andre and Souza, Amanda L., et al. (2012) In Circulation 125(18). p.132-2222
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. 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 Malmo 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... (More)
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 Malmo 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-toglutamate 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. (Circulation. 2012;125:2222-2231.) (Less)
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publication status
published
subject
keywords
epidemiology, metabolic syndrome, metabolomics, risk factors
in
Circulation
volume
125
issue
18
pages
132 - 2222
publisher
Lippincott Williams and Wilkins
external identifiers
  • wos:000306962600015
  • scopus:84860756406
ISSN
1524-4539
DOI
10.1161/CIRCULATIONAHA.111.067827
language
English
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yes
id
6bf893af-4bcf-4dc5-a030-013063a5c050 (old id 3135810)
date added to LUP
2012-11-01 10:31:08
date last changed
2017-11-19 03:56:12
@article{6bf893af-4bcf-4dc5-a030-013063a5c050,
  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. 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 Malmo 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&lt;0.001), glutamate (0.05 to 0.14; P&lt;0.001), and the glutamine-toglutamate ratio (-0.05 to -0.20; P&lt;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. (Circulation. 2012;125:2222-2231.)},
  author       = {Cheng, Susan and Rhee, Eugene P. and Larson, Martin G. and Lewis, Gregory D. and McCabe, Elizabeth L. and Shen, Dongxiao and Palma, Melinda J. and Roberts, Lee D. and Dejam, Andre and Souza, Amanda L. and Deik, Amy A. and Magnusson, Martin and Fox, Caroline S. and O'Donnell, Christopher J. and Vasan, Ramachandran S. and Melander, Olle and Clish, Clary B. and Gerszten, Robert E. and Wang, Thomas J.},
  issn         = {1524-4539},
  keyword      = {epidemiology,metabolic syndrome,metabolomics,risk factors},
  language     = {eng},
  number       = {18},
  pages        = {132--2222},
  publisher    = {Lippincott Williams and Wilkins},
  series       = {Circulation},
  title        = {Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans},
  url          = {http://dx.doi.org/10.1161/CIRCULATIONAHA.111.067827},
  volume       = {125},
  year         = {2012},
}