Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Interventions and public health nutrition

Effect of multi-nutrient insufficiency on markers of one carbon metabolism in young women: response to a methionine load

European Journal of Clinical Nutrition volume 70, pages 687–693 (2016)Cite this article

Subjects

Abstract

Background/Objectives:

Multi-nutrient insufficiencies as a consequence of nutritional and economic factors are common in India and other developing countries. We have examined the impact of multi-nutrient insufficiency on markers of one carbon (1C) metabolism in the blood, and response to a methionine load in clinically healthy young women.

Subjects/Methods:

Young women from Pune, India (n=10) and Cleveland, USA (n=13) were studied. Blood samples were obtained in the basal state and following an oral methionine load (50 mg/kg of body weight in orange juice). Plasma concentrations of vitamin B12, folate and B6 were measured in the basal state. The effect of methionine load on the levels of methionine, total homocysteine, cysteine, glutathione and amino acids was examined.

Results:

Indian women were significantly shorter and lighter compared with the American women and had lower plasma concentration of vitamins B12, folate and B6, essential amino acids and glutathione, but higher concentration of total homocysteine. The homocysteine response to methionine load was higher in Indian women. The plasma concentrations of glycine and serine increased in the Indian women after methionine (in juice) load. A significant negative correlation between plasma B6 and homocysteine (r= −0.70), and plasma folate and glycine and serine levels were observed in the Indian group (P<0.05) but not in the American group.

Conclusions:

Multi-nutrient insufficiency in the Indian women caused unique changes in markers of whole body protein and 1C metabolism. These data would be useful in developing nutrient intervention strategies.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Mason JB . Biomarkers of nutrient exposure and status in one-carbon (methyl) metabolism. J Nutr 2003; 133: 941s–947s.

    Article  CAS  Google Scholar 

  2. King WD, Ho V, Dodds L, Perkins SL, Casson RI, Massey TE . Relationships among biomarkers of one-carbon metabolism. Mol Biol Rep 2012; 39: 7805–7812.

    Article  CAS  Google Scholar 

  3. Lamers Y . Indicators and methods for folate, vitamin B-12, and vitamin B-6 status assessment in humans. Curr Opin Clin Nutr Metab Care 2011; 14: 445–454.

    Article  CAS  Google Scholar 

  4. Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G . The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B 12 status. Food Nutr Bull 2008; 29: S67–S73.

    Article  Google Scholar 

  5. Vogiatzoglou A, Oulhaj A, Smith AD, Nurk E, Drevon CA, Ueland PM et al. Determinants of plasma methylmalonic acid in a large population: implications for assessment of vitamin B 12 status. Clin Chem 2009; 55: 2198–2206.

    Article  CAS  Google Scholar 

  6. Bhardwaj A, Kumar D, Raina SK, Bansal P, Bhushan S, Chander V . Rapid assessment for coexistence of vitamin B12 and iron deficiency anemia among adolescent males and females in Northern Himalayan state of India. Anemia 2013; 2013: 959605.

  7. Folate and vitamin B12 deficiencies. Proceedings of a WHO technical consultation held 18-21 October, 2005, in Geneva, Switzerland. Food Nutr Bull 2008; 29: S1–S246.

  8. Sukla KK, Nagar R, Raman R . Vitamin-B12 and folate deficiency, major contributing factors for anemia: A population based study. e-SPEN Journal 2014; 9: e45–e48.

    Article  Google Scholar 

  9. Kalhan SC, Uppal SO, Moorman JL, Bennett C, Gruca LL, Parimi PS et al. Metabolic and genomic response to dietary isocaloric protein restriction in the rat. J Biol Chem 2011; 286: 5266–5277.

    Article  CAS  Google Scholar 

  10. Ingenbleek Y, Hardilliera E, Jung L . Subclinical protein malnutrition is a determinant of hyperhomocysteinemia. Nutrition 2002; 18: 40–46.

    Article  CAS  Google Scholar 

  11. Ingenbleek Y, McCully KS . Vegetrainism produces subclinical malnutrition, hyperhomocysteinemia and atherogenesis. Nutrition 2012; 28: 148–153.

    Article  CAS  Google Scholar 

  12. Chambers JC, Ueland PM, Wright M, Dore CJ, Refsum H, Kooner JS . Investigation of relationship between reduced, oxidized, and protein-bound homocysteine and vascular endothelial function in healthy human subjects. Circ Res 2001; 89: 187–192.

    Article  CAS  Google Scholar 

  13. Chambers JC, Obeid OA, Kooner JS . Physiological increments in plasma homocysteine induce vascular endothelial dysfunction in normal human subjects. Arterioscler Thromb Vasc Biol 1999; 19: 2922–2927.

    Article  CAS  Google Scholar 

  14. Sassi S, Cosmi B, Palareti G, Legnani C, Grossi G, Musolesi S et al. Influence of age, sex and vitamin status on fasting and post-methionine load plasma homocysteine levels. Haematologica 2002; 87: 957–964.

    CAS  PubMed  Google Scholar 

  15. De JR, Griffioen PH, van Zelst B, Brouns RM, Visser W, Lindemans J . Evaluation of a shorter methionine loading test. Clin Chem Lab Med 2004; 42: 1027–1031.

    Google Scholar 

  16. Kalhan SC, Gruca LL, Parimi PS, O’Brien A, Dierker L, Burkett E . Serine metabolism in human pregnancy. Am J Physiol Endocrinol Metab 2003; 284: E733–E740.

    Article  CAS  Google Scholar 

  17. Garcia AJ, Apitz-Castro R . Plasma total homocysteine quantification: an improvement of the classical high-performance liquid chromatographic method with fluorescence detection of the thiol-SBD derivatives. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 779: 359–363.

    Article  CAS  Google Scholar 

  18. Lammarre SG, MacMillan L, Morrow GP, Randell E, Pongnopparat T, Brosnan M et al. An isotope-dilution, GC-MS assay for formate and its application to human and animal metabolism. Amino acids 2014; 46: 1885–1891.

    Article  Google Scholar 

  19. Kelleher BP, Broin SD . Microbiological assay for vitamin B12 performed in 96-well microtitre plates. J Clin Pathol 1991; 44: 13.

    Article  Google Scholar 

  20. Tamura T, Freeberg LE, Cornwell PE . Inhibition by EDTA of Growth of Lactobacillus casei in the folate microbiologic assay and its reversal by added manganese or Iron. Clin Chem 1990; 36: 11.

    Google Scholar 

  21. Bergstrom J, Furst P, Vinnars E . Effect of a test meal, without and with protein, on muscle and plasma free amino acids. Clin Sci 1990; 79: 331–337.

    Article  CAS  Google Scholar 

  22. Rao S, Yajnik CS, Kanade, Fall CH, Margetts BM, Jackson AA et al. Intake of micronutrient-rich foods in rural Indian mothers is associated with the size of their babies at birth: Pune Maternal Nutrition Study. J Nutr 2001; 131: 1217–1224.

    Article  CAS  Google Scholar 

  23. Hermann W, Schorr H, Obeid R, Geisel J . Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr 2003; 78: 131–136.

    Article  Google Scholar 

  24. Antony AC . Vegetarianism and B-12 (cobalamin) deficiency. Am J Clin Nutr 2003; 78: 3–6.

    Article  CAS  Google Scholar 

  25. Pawlak R, Lester SE, Babatunde T . The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: a review of literature. Eur J Clin Nutr 2014; 68: 541–548.

    Article  CAS  Google Scholar 

  26. Quinlivan EP, Gregory JF . Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr 2003; 77: 221–225.

    Article  CAS  Google Scholar 

  27. Gaine PC, Pikosky MA, Martin WF, Bolster DR, Maresh CM, Rodriguez NR . Level of dietary protein impacts whole body protein turnover in trained males at rest. Metabolism 2006; 55: 501–507.

    Article  CAS  Google Scholar 

  28. Lariviere F, Kupranycz DA, Chiasson J-L, Hoffer. J . Plasma leucine kinetics and urinary nitrogen excretion in intensively treated diabetes mellitus. Am J Physiol 1992; 263: E173–E179.

    CAS  PubMed  Google Scholar 

  29. Sketcher RD, James WP . Branched-chain amino acid oxidation in relation to catabolic enzyme activities in rats given a protein-free diet at different stages of development. Br J Nutr 1974; 32: 615–623.

    Article  CAS  Google Scholar 

  30. Adibi S . Influence of dietary deprivation on plasma concentration of free amino acids of man. J Appl Physiol 1968; 25: 52–57.

    Article  CAS  Google Scholar 

  31. Adibi SA, Modesto TA, Morse EL, Amin PM . Amino acid levels in plasma, liver, and skeletal muscle during protein deprivation. Am J Physiol 1973; 225: 408–414.

    Article  CAS  Google Scholar 

  32. Nagao K, Bannai M, Seki S, Mori M, Takahashi M . Adaptational modification of serine and threonine metabolism in the liver to essential amino acid deficiency in rats. Amino Acids 2009; 36: 555–562.

    Article  CAS  Google Scholar 

  33. Noguchi Y, Shikata N, Furuhata Y, Kimura T, Takahashi M . Characterization of dietary protein-dependent anibo acid metabolism by linking free amino acids with transcriptional profiles through analysis of correlation. Physiol Genomics 2008; 34: 315–326.

    Article  CAS  Google Scholar 

  34. Gibson NR, Jahoor F, Ware L, Jackson AA . Endogenous glycine and tyrosine production is maintained in adults consuming a marginal-protein diet. Am J Clin Nutr 2002; 75: 511–518.

    Article  CAS  Google Scholar 

  35. Sheikh K, Camejo G, Lanne B, Halvarsson T, Landergren MR, Oakes. ND . Beyond lipids, pharmacological PPARa activation has important effects on amino acid metabolism as studied in the rat. Am J Physiol Endocrinol Metab 2007; 292: E1157–E1185.

    Article  CAS  Google Scholar 

  36. Motil KJ, Matthews DE, Bier DM, Burke JF, Munro HN, Young VR . Whole-body leucine and lysine metabolism: response to dietary protein intake in young men. Am J Physiol 1981; 240: E712–E721.

    CAS  PubMed  Google Scholar 

  37. Kalhan SC, Hanson RW . Resurgence of serine: an often neglected but indispensable amino acid. J Biol Chem 2012; 287: 19786–19791.

    Article  CAS  Google Scholar 

  38. Lamarre SG, Molloy AM, Reinke SN, Sykes BD, Brosnan ME, Brosnan JT . Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration. Am J Physiol Endocrinol Metab 2012; 302: E61–E67.

    Article  CAS  Google Scholar 

  39. Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr 2001; 74: 233–241.

    Article  CAS  Google Scholar 

  40. Lu SC . Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J 13: 1169–1183.

  41. Finkelstein JD, Martin JJ . Methionine metabolism in mammals. Adaptation to methionine excess. J Biol Chem 1986; 261: 1582–1587.

    CAS  PubMed  Google Scholar 

  42. Selhub J, Miller JW . The pathogenesis of homocysteinemia: interruption of the coordinate regulation by s-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr 1992; 55: 131–138.

    Article  CAS  Google Scholar 

  43. Grillo MA, Colombatto S . S-adenosylmethionine and its products. Amino Acids 2008; 34: 187–193.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the study participants for taking part in this study. We thank Dr KJ Coyaji, Medical Director of the KEM Hospital and Dr VS Padbidri, Director Research for providing research facilities. We thank Mrs PC Yajnik for administrative support. This work was supported in part by the National Institutes of Health grants, R21 HD073880 (to SCK), a Clinical and Translational Science Award RR024989 to Case Western Reserve University and Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to prevention strategies in South Asian peoples (GIFTS), FP7-HEALTH-2011-two-stage/EC-GA no 278917.

Author information

Authors and Affiliations

  1. Kamalnayan Bajaj Diabetology Research Centre, King Edward Memorial Hospital Research Centre, Pune, India

    P Katre, S Joshi, D S Bhat, M Deshmukh, N Gurav, S Pandit, H Lubree, K Kalyanaraman, S S Naik & C S Yajnik

  2. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    S Marczewski, C Bennett, L Gruca & S C Kalhan

Authors
  1. P Katre
    View author publications

    Search author on:PubMed Google Scholar

  2. S Joshi
    View author publications

    Search author on:PubMed Google Scholar

  3. D S Bhat
    View author publications

    Search author on:PubMed Google Scholar

  4. M Deshmukh
    View author publications

    Search author on:PubMed Google Scholar

  5. N Gurav
    View author publications

    Search author on:PubMed Google Scholar

  6. S Pandit
    View author publications

    Search author on:PubMed Google Scholar

  7. H Lubree
    View author publications

    Search author on:PubMed Google Scholar

  8. S Marczewski
    View author publications

    Search author on:PubMed Google Scholar

  9. C Bennett
    View author publications

    Search author on:PubMed Google Scholar

  10. L Gruca
    View author publications

    Search author on:PubMed Google Scholar

  11. K Kalyanaraman
    View author publications

    Search author on:PubMed Google Scholar

  12. S S Naik
    View author publications

    Search author on:PubMed Google Scholar

  13. C S Yajnik
    View author publications

    Search author on:PubMed Google Scholar

  14. S C Kalhan
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to C S Yajnik or S C Kalhan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Katre, P., Joshi, S., Bhat, D. et al. Effect of multi-nutrient insufficiency on markers of one carbon metabolism in young women: response to a methionine load. Eur J Clin Nutr 70, 687–693 (2016). https://doi.org/10.1038/ejcn.2015.155

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/ejcn.2015.155

This article is cited by

Search

Advanced search

Quick links