Metabolite signatures of diabetes with cardiovascular disease: a pilot investigation

Introduction Type 2 diabetes (T2D) is an independent risk factor in the development of cardiovascular disease. However, there are significant limitations in the detection of the metabolic disturbances in hyperglycemia that lead to vascular dysfunction. Objectives The goals of the study were: (i) to identify circulating metabolites discriminating T2D and normoglycemia, and (ii) to assess phenotypic correlations of identified metabolites with other cardiometabolic risk traits (CMTs). Methods We have generated global and targeted metabolomic profiles using AB Sciex TripleTOF 5600 and Thermo Scientific Q Exactive Plus using serum samples of patients and healthy controls from a Punjabi population from India. Results In global profiling, we identified eight unknown molecules that currently do not match to any spectra in public databases. Additionally, serum levels of pyroglutamate, imidazole-4-acetate, tyramine-O-sulphate and 2,3-diphosphoglycerate were significantly elevated (2-5 fold) and betaine-aldehyde was reduced (fourfold) in patients. In targeted screening of amino acids and sugars, increased concentrations of serine, inositol, and threonine strongly correlated with T2D in both genders, while N-acetyl-l-alanine was reduced (58 fold) in men and glutamine was increased (fourfold) in women. Using random forest and ROC (AUC) analyses, we further cross-validated the predictive abilities of these molecules. Inositol, serine and threonine were among the top informative biomarkers in both genders while N-acetyl-l-alanine was highly confined to men. Conclusions Our study has identified several metabolites whose concentrations were altered in T2D. Although further study is needed in larger datasets, the identified metabolites (unknown or known) point towards shared etiologicalpathways underlie diabetes and vascular disease which can be targeted for potential therapeutics or biomarkers discovery.