Preliminary evidence of effects of potassium chloride on a metabolomic path to diabetes and cardiovascular disease

Abstract

Introduction

Low potassium intake can affect cardiovascular disease (CVD) risk and cardiometabolic risk factors.

Objective

We hypothesize that potassium chloride (KCl) supplementation can improve cardiovascular risk metabolomic profile.

Methods

In this secondary analysis of a pilot randomized clinical trial (RCT) of 26 participants with prediabetes randomized to KCl or placebo, we performed targeted mass-spectrometry-based metabolomic profiling on baseline and 12-week (end-of-study) plasma samples. Principal component analysis (PCA) was used to reduce the many correlated metabolites into fewer, independent factors that retain most of the information in the original data.

Results

Those taking KCl had significant reductions (corresponding to lower cardiovascular risk) in the branched-chain amino acids (BCAA) factor (P = 0.004) and in valine levels (P = 0.02); and non-significant reductions in short-chain acylcarnitines (SCA) factor (P = 0.11).

Conclusions

KCl supplementation may improve circulating BCAA levels, which may reflect improvements in overall cardiometabolic risk profile.

Clinical Trials Registry

Clinicaltrials.gov identifier: NCT02236598; https://clinicaltrials.gov/ct2/show/NCT02236598.

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Data availability

De-identified data described in the manuscript, code book, and analytic code will be made available upon review of requests.

Abbreviations

A1c:

Hemoglobin A1c

BCAA:

Branched-chain amino acids

CVD:

Cardiovascular disease

IQR:

Interquartile range

KCl:

Potassium chloride

LCA:

Long-chain acylcarnitines

OGTT:

Oral glucose tolerance test

PCA:

Principal component analysis

SCA:

Short-chain acylcarnitines

References

  1. Abdulla, H., Smith, K., Atherton, P. J., & Idris, I. (2016). Role of insulin in the regulation of human skeletal muscle protein synthesis and breakdown: A systematic review and meta-analysis. Diabetologia,59, 44–55.

    CAS  Article  Google Scholar 

  2. Aburto, N. J., Hanson, S., Gutierrez, H., Hooper, L., Elliott, P., & Cappuccio, F. P. (2013). Effect of increased potassium intake on cardiovascular risk factors and disease: Systematic review and meta-analyses. BMJ,346, f1378.

    Article  Google Scholar 

  3. Chatterjee, R., Slentz, C., Davenport, C. A., Johnson, J., Lin, P. H., Muehlbauer, M., et al. (2017). Effects of potassium supplements on glucose metabolism in African Americans with prediabetes: A pilot trial. American Journal of Clinical Nutrition,106, 1431–1438.

    CAS  Article  Google Scholar 

  4. Chatterjee, R., Yeh, H. C., Shafi, T., Selvin, E., Anderson, C., Pankow, J. S., et al. (2010). Serum and dietary potassium and risk of incident type 2 diabetes mellitus: The Atherosclerosis Risk in Communities (ARIC) Study. Archives of Internal Medicine,170, 1745–1751.

    CAS  Article  Google Scholar 

  5. Filippini, T., Violi, F., D'Amico, R., & Vinceti, M. (2017). The effect of potassium supplementation on blood pressure in hypertensive subjects: A systematic review and meta-analysis. International Journal of Cardiology,230, 127–135.

    Article  Google Scholar 

  6. Guasch-Ferre, M., Hruby, A., Toledo, E., Clish, C. B., Martinez-Gonzalez, M. A., Salas-Salvado, J., et al. (2016a). Metabolomics in prediabetes and diabetes: A systematic review and meta-analysis. Diabetes Care,39, 833–846.

    CAS  Article  Google Scholar 

  7. Guasch-Ferre, M., Hu, F. B., Ruiz-Canela, M., Bullo, M., Toledo, E., Wang, D. D., et al. (2017). Plasma metabolites from choline pathway and risk of cardiovascular disease in the PREDIMED (prevention with mediterranean diet) study. Journal of the American Heart Association,6, e006524.

    Article  Google Scholar 

  8. Guasch-Ferre, M., Zheng, Y., Ruiz-Canela, M., Hruby, A., Martinez-Gonzalez, M. A., Clish, C. B., et al. (2016b). Plasma acylcarnitines and risk of cardiovascular disease: Effect of Mediterranean diet interventions. American Journal of Clinical Nutrition,103, 1408–1416.

    CAS  Article  Google Scholar 

  9. Kalhan, S. C. (2009). Fatty acids, insulin resistance, and protein metabolism. Journal of Clinical Endocrinology and Metabolism,94, 2725–2727.

    CAS  Article  Google Scholar 

  10. Kraus, W. E., Granger, C. B., Sketch, M. H., Jr., Donahue, M. P., Ginsburg, G. S., Hauser, E. R., et al. (2015). A guide for a cardiovascular genomics biorepository: The CATHGEN experience. Journal of Cardiovascular Translational Research,8, 449–457.

    Article  Google Scholar 

  11. Mente, A., O'Donnell, M. J., Rangarajan, S., McQueen, M. J., Poirier, P., Wielgosz, A., et al. (2014). Association of urinary sodium and potassium excretion with blood pressure. New England Journal of Medicine,371, 601–611.

    Article  Google Scholar 

  12. Newgard, C. B., An, J., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Lien, L. F., et al. (2009). A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metabolism,9, 311–326.

    CAS  Article  Google Scholar 

  13. O'Donnell, M., Mente, A., Rangarajan, S., McQueen, M. J., Wang, X., Liu, L., et al. (2014). Urinary sodium and potassium excretion, mortality, and cardiovascular events. New England Journal of Medicine,371, 612–623.

    Article  Google Scholar 

  14. Peng, Y., Zhong, G. C., Mi, Q., Li, K., Wang, A., Li, L., et al. (2017). Potassium measurements and risk of type 2 diabetes: A dose-response meta-analysis of prospective cohort studies. Oncotarget,8, 100603–100613.

    Article  Google Scholar 

  15. Rebholz, C. M., Lichtenstein, A. H., Zheng, Z., Appel, L. J., & Coresh, J. (2018). Serum untargeted metabolomic profile of the dietary approaches to stop hypertension (DASH) dietary pattern. American Journal of Clinical Nutrition,108, 243–255.

    Article  Google Scholar 

  16. Ruiz-Canela, M., Guasch-Ferre, M., Toledo, E., Clish, C. B., Razquin, C., Liang, L., et al. (2018). Plasma branched chain/aromatic amino acids, enriched Mediterranean diet and risk of type 2 diabetes: Case-cohort study within the PREDIMED Trial. Diabetologia,61, 1560–1571.

    CAS  Article  Google Scholar 

  17. Ruiz-Canela, M., Hruby, A., Clish, C. B., Liang, L., Martinez-Gonzalez, M. A., & Hu, F. B. (2017). Comprehensive metabolomic profiling and incident cardiovascular disease: A systematic review. Journal of the American Heart Association,6, e005705.

    Article  Google Scholar 

  18. Shah, S. H., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Crosslin, D. R., Haynes, C., et al. (2010a). Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. Circulation: Cardiovascular Genetics,3, 207–214.

    CAS  Google Scholar 

  19. Shah, S. H., Crosslin, D. R., Haynes, C. S., Nelson, S., Turer, C. B., & Stevens, R. D., et al. (2012). Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia,55, 321–330.

    CAS  Article  Google Scholar 

  20. Shah, S. H., Granger, C. B., Hauser, E. R., Kraus, W. E., Sun, J. L., Pieper, K., et al. (2010b). Reclassification of cardiovascular risk using integrated clinical and molecular biosignatures: Design of and rationale for the Measurement to Understand the Reclassification of Disease of Cabarrus and Kannapolis (MURDOCK) Horizon 1 Cardiovascular Disease Study. American Heart Journal,160, 371–379.e2.

    Article  Google Scholar 

  21. Shah, S. H., Hauser, E. R., Bain, J. R., Muehlbauer, M. J., Haynes, C., & Stevens, R. D., et al. (2009). High heritability of metabolomic profiles in families burdened with premature cardiovascular disease. Molecular Systems Biology,5, 258.

    Article  Google Scholar 

  22. Tobias, D. K., Lawler, P. R., Harada, P. H., Demler, O. V., Ridker, P. M., Manson, J. E., et al. (2018). Circulating branched-chain amino acids and incident cardiovascular disease in a prospective cohort of US women. Circulation: Genomic and Precision Medicine,11, e002157.

    CAS  Google Scholar 

  23. Walford, G. A., Ma, Y., Clish, C., Florez, J. C., Wang, T. J., Gerszten, R. E., et al. (2016). Metabolite profiles of diabetes incidence and intervention response in the diabetes prevention program. Diabetes,65, 1424–1433.

    CAS  Article  Google Scholar 

  24. Wang, H., Anstrom, K., Ilkayeva, O., Muehlbauer, M. J., Bain, J. R., & Mcnulty, S., et al. (2017). Sildenafil treatment in heart failure with preserved ejection fraction: Targeted metabolomic profiling in the RELAX Trial. JAMA Cardiology,2, 896–901.

    Article  Google Scholar 

  25. White, P. J., & Newgard, C. B. (2019). Branched-chain amino acids in disease. Science,363, 582–583.

    CAS  Article  Google Scholar 

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Acknowledgements

We thank the participants who were very much invested in and supportive of the trial and the biorepository, which allowed for this study.

Funding

National Institutes of Health/Clinical and Translational Science Award at Duke UL1TR002553 (CAD). National Institutes of Health/Duke Clinical and Translational Science award KL2TR001115-02 (RC); National Institutes of Health/Clinical and Translational Core for the Duke O’Brien Center for Kidney Research, award 1P30DK096493-03 (RC). National Institutes of Health R01-HL127009 (Sha).

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RC, LPS, DD, PHL, DE, SHS designed research (project conception, development of overall research plan, and study oversight); RC, CAD, CS, JJ, OI, LK conducted research (hands-on conduct of the experiments and data collection); OI, LK provided essential reagents or provided essential materials (applies to authors who contributed by providing animals, constructs, databases, etc., necessary for the research); CAD, LK analyzed data or performed statistical analysis; RC, CAD, LK, PHL, CS, JJ, OI, LPS, DD, DE, SHS wrote paper (only authors who made a major contribution); RC, SHS had primary responsibility for final content.

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Correspondence to Ranee Chatterjee.

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Chatterjee, R., Davenport, C.A., Kwee, L. et al. Preliminary evidence of effects of potassium chloride on a metabolomic path to diabetes and cardiovascular disease. Metabolomics 16, 75 (2020). https://doi.org/10.1007/s11306-020-01696-w

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Keywords

  • Potassium chloride
  • Potassium supplements
  • Prediabetes
  • Metabolites
  • Branched-chain amino acids
  • Cardiovascular disease risk