Metabolite profiling identifies pathways associated with metabolic risk in humans

Area of Science:

• Metabolomics
• Cardiovascular Disease Research
• Diabetes Mellitus Research

Background:

• Metabolic risk factors cluster in individuals prone to diabetes and cardiovascular disease.
• Underlying biological mechanisms for these clusters are poorly understood.

Purpose of the Study:

• To identify metabolic pathways associated with cardiometabolic risk.
• To investigate the relationship between plasma metabolites and cardiometabolic risk factors.

Main Methods:

• Liquid chromatography/mass spectrometry to measure 45 plasma metabolites.
• Analysis in the Framingham Heart Study (FHS) and Malmö Diet and Cancer Study (MDC).
• Interrogation of findings in experimental models of cardiovascular and metabolic disease.

Main Results:

• Metabolic risk factors associated with branched-chain amino acids, hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites.
• Insulin resistance strongly linked to glutamine, glutamate, and the glutamine-to-glutamate ratio.
• High glutamine-to-glutamate ratio associated with lower incident diabetes risk in FHS.
• Glutamine administration in mice improved glucose tolerance and decreased blood pressure.

Conclusions:

• Biochemical profiling identified novel circulating metabolites associated with metabolic traits.
• Excess glutamine relative to glutamate, from exogenous administration, reduced metabolic risk in mice.