Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans

TLDR

Metabolic risk factors cluster in individuals prone to diabetes and cardiovascular disease, yet the underlying biological mechanisms remain poorly understood. The study sought to identify cardiometabolic risk pathways by measuring 45 plasma metabolites with LC‑MS in the Framingham Heart Study and Malmö Diet and Cancer Study. Significant metabolite associations were examined in experimental cardiovascular and metabolic disease models. Metabolic risk factors were linked to multiple metabolites, especially glutamine and glutamate, with higher glutamine‑to‑glutamate ratios associated with lower diabetes risk and improved glucose tolerance and blood pressure in mice.

Abstract

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.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).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.