Skip to main content
SpringerLink
Log in

Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid–base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. P. Frings-Meuthen, J. Buehlmeier, N. Baecker, P. Stehle, R. Fimmers, F. May, G. Kluge, M. Heer, High sodium chloride intake exacerbates immobilization-induced bone resorption and protein losses. J. Appl. Physiol. 111, 537–542 (2011)

    Article  CAS  PubMed  Google Scholar 

  2. E. Wynn, S.A. Lanham-New, M.A. Krieg, D.R. Whittamore, P. Burckhardt, Low estimates of dietary acid load are positively associated with bone ultrasound in women older than 75 years of age with a lifetime fracture. J. Nutr. 138, 1349–1354 (2008)

    CAS  PubMed  Google Scholar 

  3. P. Frings-Meuthen, N. Baecker, M. Heer, Low-grade metabolic acidosis may be the cause of sodium chloride-induced exaggerated bone resorption. J. Bone Miner. Res. 23, 517–524 (2008)

    Article  CAS  PubMed  Google Scholar 

  4. U. Alexy, T. Remer, F. Manz, C.M. Neu, E. Schoenau, Long-term protein intake and dietary potential renal acid load are associated with bone modeling and remodeling at the proximal radius in healthy children. Am. J. Clin. Nutr. 82, 1107–1114 (2005)

    CAS  PubMed  Google Scholar 

  5. H.M. Macdonald, S.A. New, W.D. Fraser, M.K. Campbell, D.M. Reid, Low dietary potassium intakes and high dietary estimates of net endogenous acid production are associated with low bone mineral density in premenopausal women and increased markers of bone resorption in postmenopausal women. Am. J. Clin. Nutr. 81, 923–933 (2005)

    CAS  PubMed  Google Scholar 

  6. S. Berkemeyer, T. Remer, Anthropometrics provide a better estimate of urinary organic acid anion excretion than a dietary mineral intake-based estimate in children, adolescents, and young adults. J. Nutr. 136, 1203–1208 (2006)

    CAS  PubMed  Google Scholar 

  7. T. Remer, F. Manz, Estimation of the renal net acid excretion by adults consuming diets containing variable amounts of protein. Am. J. Clin. Nutr. 59, 1356–1361 (1994)

    CAS  PubMed  Google Scholar 

  8. M. Heer, P. Frings-Meuthen, J. Titze, M. Boschmann, S. Frisch, N. Baecker, L. Beck, Increasing sodium intake from a previous low or high intake affects water, electrolyte and acid-base balance differently. Br. J. Nutr. 101, 1286–1294 (2009)

    Article  CAS  PubMed  Google Scholar 

  9. L.A. Frassetto, R.C. Morris Jr, A. Sebastian, Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet. Am. J. Physiol Renal Physiol. 293, F521–F525 (2007)

    Article  CAS  PubMed  Google Scholar 

  10. L.L. Hamm, P.M. Ambuhl, R.J. Alpern, Role of glucocorticoids in acidosis. Am. J. Kidney Dis. 34, 960–965 (1999)

    Article  CAS  PubMed  Google Scholar 

  11. T. Remer, K. Pietrzik, F. Manz, Short-term impact of a lactovegetarian diet on adrenocortical activity and adrenal androgens. J. Clin. Endocrinol. Metab. 83, 2132–2137 (1998)

    CAS  PubMed  Google Scholar 

  12. M.F. McCarty, Acid-base balance may influence risk for insulin resistance syndrome by modulating cortisol output. Med. Hypotheses 64, 380–384 (2005)

    Article  CAS  PubMed  Google Scholar 

  13. M. Maurer, W. Riesen, J. Muser, H.N. Hulter, R. Krapf, Neutralization of western diet inhibits bone resorption independently of K intake and reduces cortisol secretion in humans. Am. J. Physiol Renal Physiol. 284, F32–F40 (2003)

    Article  CAS  PubMed  Google Scholar 

  14. L. Shi, A. Sanchez-Guijo, M.F. Hartmann, E. Schonau, J. Esche, S.A. Wudy, T. Remer, Higher glucocorticoid secretion in the physiological range is associated with lower bone strength at the proximal radius in healthy children: importance of protein intake adjustment. J. Bone Miner. Res. 30, 240–248 (2015)

    Article  CAS  PubMed  Google Scholar 

  15. D. Krupp, L. Shi, C. Maser-Gluth, M. Pietzarka, T. Remer, 11beta Hydroxysteroid dehydrogenase type 2 and dietary acid load are independently associated with blood pressure in healthy children and adolescents. Am. J. Clin. Nutr. 97, 612–620 (2013)

    Article  CAS  PubMed  Google Scholar 

  16. D. Krupp, L. Shi, T. Remer, Longitudinal relationships between diet-dependent renal acid load and blood pressure development in healthy children. Kidney Int. 85, 204–210 (2014)

    Article  CAS  PubMed  Google Scholar 

  17. K. Murakami, S. Sasaki, Y. Takahashi, K. Uenishi, Association between dietary acid-base load and cardiometabolic risk factors in young Japanese women. Br. J. Nutr. 100, 642–651 (2008)

    Article  CAS  PubMed  Google Scholar 

  18. J. Buehlmeier, P. Frings-Meuthen, T. Remer, C. Maser-Gluth, P. Stehle, G. Biolo, M. Heer, Alkaline salts to counteract bone resorption and protein wasting induced by high salt intake: results of a randomized controlled trial. J. Clin. Endocrinol. Metab. 97, 4789–4797 (2012)

    Article  CAS  PubMed  Google Scholar 

  19. A. Pavy-Le Traon, M. Heer, M.V. Narici, J. Rittweger, J. Vernikos, From space to earth: advances in human physiology from 20 years of bed rest studies (1986-2006). Eur. J. Appl. Physiol 101, 143–194 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. L.A. Frassetto, S.A. Lanham-New, H.M. Macdonald, T. Remer, A. Sebastian, K.L. Tucker, F.A. Tylavsky, Standardizing terminology for estimating the diet-dependent net acid load to the metabolic system. J. Nutr. 137, 1491–1492 (2007)

    CAS  PubMed  Google Scholar 

  21. C. Luthy, C. Moser, O. Oetliker, Acid-base determination of urine in 3 steps. Med. Lab (Stuttg) 30, 174–181 (1977)

    CAS  Google Scholar 

  22. T. Remer, G. Montenegro-Bethancourt, L. Shi, Long-term urine biobanking: storage stability of clinical chemical parameters under moderate freezing conditions without use of preservatives. Clin. Biochem. 47, 307–311 (2014)

    Article  CAS  PubMed  Google Scholar 

  23. P. Vecsei, B. Penke, R. Katzy, L. Baek, Radioimmunological determination of plasma cortisol. Experientia 28, 1104–1105 (1972)

    Article  CAS  PubMed  Google Scholar 

  24. T. Remer, C. Maser-Gluth, S.A. Wudy, Glucocorticoid measurements in health and disease–metabolic implications and the potential of 24-h urine analyses. Mini. Rev. Med. Chem. 8, 153–170 (2008)

    Article  CAS  PubMed  Google Scholar 

  25. P.M. Stewart, Z.S. Krozowski, 11 beta-hydroxysteroid dehydrogenase. Vitam. Horm. 57, 249–324 (1999)

    Article  CAS  PubMed  Google Scholar 

  26. S. Zhang, J. Paul, M. Nantha-Aree, N. Buckley, U. Shahzad, J. Cheng, J. DeBeer, M. Winemaker, D. Wismer, D. Punthakee, V. Avram, L. Thabane, Empirical comparison of four baseline covariate adjustment methods in analysis of continuous outcomes in randomized controlled trials. Clin. Epidemiol. 6, 227–235 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  27. T. Remer, F. Manz, Potential renal acid load of foods and its influence on urine pH. J. Am. Diet. Assoc. 95, 791–797 (1995)

    Article  CAS  PubMed  Google Scholar 

  28. S.L. Gluck, Acid-base. Lancet 352, 474–479 (1998)

    Article  CAS  PubMed  Google Scholar 

  29. S. Berkemeyer, J. Vormann, A.L. Gunther, R. Rylander, L.A. Frassetto, T. Remer, Renal net acid excretion capacity is comparable in prepubescence, adolescence, and young adulthood but falls with aging. J. Am. Geriatr. Soc. 56, 1442–1448 (2008)

    Article  PubMed  Google Scholar 

  30. S. Lewicka, M. Nowicki, P. Vecsei, Effect of sodium restriction on urinary excretion of cortisol and its metabolites in humans. Steroids 63, 401–405 (1998)

    Article  CAS  PubMed  Google Scholar 

  31. G. Wambach, C. Bleienheuft, G. Bonner, Sodium loading raises urinary cortisol in man. J. Endocrinol. Invest. 9, 257–259 (1986)

    Article  CAS  PubMed  Google Scholar 

  32. P.J. Nolan, M.A. Knepper, R.K. Packer, Inhibition of IMCD 11 beta-hydroxysteroid dehydrogenase type 2 by low pH and acute acid loading. J. Am. Soc. Nephrol. 8, 530–534 (1997)

    CAS  PubMed  Google Scholar 

  33. A. Thompson, M.A. Bailey, A.E. Michael, R.J. Unwin, Effects of changes in dietary intake of sodium and potassium and of metabolic acidosis on 11beta-hydroxysteroid dehydrogenase activities in rat kidney. Exp. Nephrol. 8, 44–51 (2000)

    Article  CAS  PubMed  Google Scholar 

  34. J. Murotsuki, R. Gagnon, X. Pu, K. Yang, Chronic hypoxemia selectively down-regulates 11beta-hydroxysteroid dehydrogenase type 2 gene expression in the fetal sheep kidney. Biol. Reprod. 58, 234–239 (1998)

    Article  CAS  PubMed  Google Scholar 

  35. J.J. Hermans, M.A. Fischer, P.M. Schiffers, H.A. Struijker-Boudier, High dietary potassium chloride intake augments rat renal mineralocorticoid receptor selectivity via 11beta-hydroxysteroid dehydrogenase. Biochim. Biophys. Acta 1472, 537–549 (1999)

    Article  CAS  PubMed  Google Scholar 

  36. N. Goraya, J. Simoni, C.H. Jo, D.E. Wesson, A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin. J. Am. Soc. Nephrol. 8, 371–381 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. I.J. Brown, I. Tzoulaki, V. Candeias, P. Elliott, Salt intakes around the world: implications for public health. Int. J. Epidemiol. 38, 791–813 (2009)

    Article  PubMed  Google Scholar 

  38. M. Heer, A. Boerger, N. Kamps, C. Mika, C. Korr, C. Drummer, Nutrient supply during recent European missions. Pflugers Arch. 441, R8–14 (2000)

    Article  CAS  PubMed  Google Scholar 

  39. Joint WHO/FAO Expert Consultation on Diet, nutrition and the prevention of chronic diseases 916, 1–149 (2003)

  40. F. Prodam, R. Ricotti, V. Agarla, S. Parlamento, G. Genoni, C. Balossini, G.E. Walker, G. Aimaretti, G. Bona, S. Bellone, High-end normal adrenocorticotropic hormone and cortisol levels are associated with specific cardiovascular risk factors in pediatric obesity: a cross-sectional study. BMC Med. 11, 44 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. A.A. Ferrando, C.A. Stuart, M. Sheffield-Moore, R.R. Wolfe, Inactivity amplifies the catabolic response of skeletal muscle to cortisol. J. Clin. Endocrinol. Metab. 84, 3515–3521 (1999)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the volunteers, who gave time and effort to ensure the success of the projects, the staff of the Institute of Aerospace Medicine for their collaboration in conducting the studies, and the staff of the Department of Pharmacology for excellent biochemical analysis.

Author information

Author notes

    Authors and Affiliations

    1. Institute of Aerospace Medicine, German Aerospace Center (DLR), Linder Hoehe, 51147, Cologne, Germany

      Judith Buehlmeier, Petra Frings-Meuthen & Martina Heer

    2. Institute of Nutrition and Food Science, University of Bonn, Endenicher Straße 11-13, 53115, Bonn, Germany

      Judith Buehlmeier & Martina Heer

    3. Department of Nutritional Epidemiology, DONALD Study Center at the Research Institute of Child Nutrition, University of Bonn, Heinstück 11, 44225, Dortmund, Germany

      Thomas Remer

    4. Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany

      Christiane Maser-Gluth

    Authors
    1. Judith Buehlmeier
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Thomas Remer
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Petra Frings-Meuthen
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Christiane Maser-Gluth
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Martina Heer
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Judith Buehlmeier.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Judith Buehlmeier and Thomas Remer have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Buehlmeier, J., Remer, T., Frings-Meuthen, P. et al. Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials. Endocrine 52, 139–147 (2016). https://doi.org/10.1007/s12020-015-0730-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12020-015-0730-7

    Keywords

    Search

    Navigation