Exploratory metabolomics of nascent metabolic syndrome

Metabolic syndrome (MetS) is a disorder defined by having three of five features: increased waist circumference (WC), hypertriglyceridemia, decreased high-density lipoprotein-cholesterol, hypertension and an elevated blood glucose (BG). Metabolic Syndrome ( MetS) affects 35% of American adults and significantly increases risk for Atherosclerotic cardiovascular disease (ASCVD) and type-2 diabetes (T2DM). An understanding of the metabolome will help elucidate the pathogenesis of MetS and lead to better management. We hypothesize that the metabolites, gamma-aminobutyric acid (GABA), d-pyroglutamic acid (PGA) and N-acetyl-d-tryptophan (NAT) will be altered in nascent MetS patients without the confounding of ASCVD or T2DM. We also correlated these metabolites with biomarkers of inflammation.

This was an exploratory study of 30 patients with nascent MetS and 20 matched controls undertaken in 2018. Metabolites were evaluated from patient's frozen early morning urine samples and were correlated with biomarkers of inflammation and adipokines. They were assayed by the NIH Western Metabolomics Center using liquid chromatography/mass spectrometry and standardized to urinary creatinine. All patients had normal hepatic and renal function.

GABA and PGA levels were significantly increased in MetS patients compared to controls: 2.8-fold and 2.9-fold median increases respectively with p < 0.0001 and p = 0.004, possibly deriving from glutamate. NAT was significantly decreased by 90% in MetS patients compared to controls, p < 0.001. GABA correlates significantly with cardio-metabolic (CM) features including WC, blood pressure systolic (BP-S) while NAT correlated inversely with WC, BP-S, blood glucose (BG) and triglycerides (TG). GABA correlated positively with chemerin, leptin, Fetuin A and endotoxin. NAT correlated inversely with WC, BP-S, BG, TG, high sensitivity C - reactive protein (hsCRP), toll-like receptor-4 (TLR-4), lipopolysaccharide binding protein (LBP), chemerin and retinol binding protein-4 (RBP-4).

We make the novel observation of increased GABA and PGA with decreased NAT in patients with MetS. While GABA and PGA correlates positively with CM features and biomediators of inflammation, the metabolite NAT correlated inversely. Thus, GABA and PGA could contribute to the pro-inflammatory state of MetS while NAT could mitigate this pro-inflammatory response.