Metabolite Profiling Identifies Pathways Associated with Metabolic Risk in Humans
Background—Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes 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 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, 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 glutamine-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-glutamate ratio was associated with lower risk of incident diabetes in FHS (OR 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 to lower 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.
- Received September 13, 2011.
- Accepted March 12, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited