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Metabolite signatures of diabetes with cardiovascular disease: a pilot investigation



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.


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).


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.


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.


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 etiological pathways underlie diabetes and vascular disease which can be targeted for potential therapeutics or biomarkers discovery.

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Type 2 diabetes


Cardiometabolic risk traits


Asian Indian diabetic heart study/sikh diabetes study


Coronary artery disease


High-performance liquid chromatography/quadrupole time-of-flight tandem spectrometer


Relative standard deviation


The orthogonal partial least squares discriminant


Random forest analysis


Receiver operating characteristic


Area under the curve


Systolic blood pressure


Diastolic blood pressure


Waist to hip ratio


Fasting blood glucose


Homeostasis model assessment for insulin resistance


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Authors thank all the participants of AIDHS/SDS who made this study possible. Technical support provided by Ms. Ruth Hopkin’s is duly acknowledged.


This work was supported by NIH grants -R01DK082766 funded by the National Institute of Health (NIDDK) and NOT-HG-11-009 funded by National Human Genome Research Institute (NHGRI) and Phen × Rising Consortium (NHGRI), and grants from Oklahoma Center for Neuroscience, and Harold Hamm Diabetes Center, and Presbyterian Health Foundation of Oklahoma, funded to DKS. This work was partly supported by the National Research Initiative Grant 2009-55200-05197 from the USDA National Institute for Food and Agriculture, funded to JKPV. This project was also supported partly by Agriculture and Food Research Initiative Competitive Grant No. 2016-67017-24512 from the USDA National Institute of Food and Agriculture, funded to LR.

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Authors and Affiliations



DKS and JKPV conceptualized and designed the project; LR, AR and YL, and JKPV generated metabolome data; LR and BRS performed analysis and assisted in manuscript preparation; ES assisted in clinical characterization and manuscript editing, DKS wrote the manuscript and JKPV assisted in the manuscript preparation.

Corresponding authors

Correspondence to Jairam K. P. Vanamala or Dharambir K. Sanghera.

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Ethical approval

The study was approved by Institutional Review Board of the University of Oklahoma Health Sciences Center (IRB #2911). All participants were recruited by informed consent. The entire research was performed using de-identified data in accordance with the Declaration of Helsinki approved by appropriate ethics committees in India and the US.

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We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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Reddivari, L., Sapkota, B.R., Rudraraju, A. et al. Metabolite signatures of diabetes with cardiovascular disease: a pilot investigation. Metabolomics 13, 154 (2017).

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  • Metabolome
  • Biomarkers
  • Type 2 diabetes
  • Cardiovascular disease
  • Punjabi Indians