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Metabolite signatures of diabetes with cardiovascular disease: a pilot investigation

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Abstract

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

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Abbreviations

T2D:

Type 2 diabetes

CMTs:

Cardiometabolic risk traits

AIDHS/SDS:

Asian Indian diabetic heart study/sikh diabetes study

CAD:

Coronary artery disease

HPLC/Q-TOF:

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

RSD:

Relative standard deviation

OPLS-DA:

The orthogonal partial least squares discriminant

RF:

Random forest analysis

ROC:

Receiver operating characteristic

AUC:

Area under the curve

SYSBP:

Systolic blood pressure

DYSBP:

Diastolic blood pressure

WHRATIO:

Waist to hip ratio

FBG:

Fasting blood glucose

HOMA-IR:

Homeostasis model assessment for insulin resistance

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Acknowledgements

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

Funding

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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Author notes

  1. Lavanya Reddivari and Bishwa R. Sapkota have contributed equally to this work.

Authors and Affiliations

  1. Department of Plant Science, Penn State University, University Park, PA, USA

    Lavanya Reddivari & Apoorva Rudraraju

  2. Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm 317 BMSB, Oklahoma City, OK, USA

    Bishwa R. Sapkota, Christopher Aston & Dharambir K. Sanghera

  3. Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Bishwa R. Sapkota & Dharambir K. Sanghera

  4. Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Bishwa R. Sapkota, Evgeny Sidorov & Dharambir K. Sanghera

  5. Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Evgeny Sidorov

  6. Department of Food Science, Penn State University, University Park, PA, USA

    Yundi Liang & Jairam K. P. Vanamala

  7. Center for Molecular Immunology and Infectious Diseases, Penn State University, University Park, PA, USA

    Jairam K. P. Vanamala

  8. Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Dharambir K. Sanghera

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  1. Lavanya Reddivari
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  2. Bishwa R. Sapkota
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  8. Dharambir K. Sanghera
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Contributions

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.

Conflict of interest

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). https://doi.org/10.1007/s11306-017-1278-8

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