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The effect of body acid–base state and manipulations on body glucose regulation in human


Long-term exposure to high dietary acid load has been associated with insulin resistance and type 2 diabetes in epidemiological studies. However, it remains unclear whether the acid load of the diet translates to mild metabolic acidosis and whether it is responsible for the impairment in glucose regulation in humans. Previously, in a cross-sectional study we have reported that dietary acid load was not different between healthy individuals with normal weight and those with overweight/obesity, irrespective of insulin sensitivity. However, 4-week high acid load diet increased plasma lactate (a small component of the anion gap) and increased insulin resistance in healthy participants. The change in plasma lactate correlated significantly with the change in insulin resistance. Because cause-and-effect could not be evaluated in these settings, we sought to directly test the effect of an alkalizing treatment preload on postprandial glucose regulation. In a randomized placebo-controlled study with a crossover design, we administered sodium bicarbonate (NaHCO3, 1.68 g) prior to high acid load meal to healthy individuals. We found that while the bicarbonate preload attenuated the post meal decrease in pH observed with placebo, no effect on postprandial glucose regulation (glucose, insulin, and C-peptide) was observed. Following 3-month treatment of nondiabetic individuals with bicarbonate, others have reported no change in insulin resistance markers, consistent with our findings. Together, studies in human suggest that insulin resistance associated with longstanding obesogenic diet may be mediated by mild metabolic acidosis. However, buffering the Western diet with bicarbonate and increasing body pH does not change glucose homeostasis in nondiabetic individuals. Further studies are required to shed light on the role of body acid–base balance and glucose homeostasis in health and disease.

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Fig. 1: Mechanisms proposed to mediate the influence of dietary acid load on type 2 diabetes risk.
Fig. 2: Difference in the degree of insulin resistance and plasma lactate concentrations between lean, overweight/obese insulin-sensitive and insulin-resistant individuals.
Fig. 3: The effect of overfeeding on peripheral insulin resistance and plasma lactate in healthy individuals.
Fig. 4: The effect of sodium bicarbonate versus placebo administered with a high acid load meal on venous blood pH.
Fig. 5: Postprandial glucose regulation following 1.68 g of NaHCO3 or placebo administered with a high acid load meal in healthy individuals.


  1. 1.

    Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377:13–27.

    Article  Google Scholar 

  2. 2.

    Pearson-Stuttard J, Zhou B, Kontis V, Bentham J, Gunter MJ, Ezzati M. Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment. Lancet Diabetes Endocrinol. 2018;6:e6–15.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Johannsen DL, Tchoukalova Y, Tam CS, Covington JD, Xie W, Schwarz JM, et al. Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the “adipose tissue expandability” hypothesis. Diabetes Care. 2014;37:2789–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    Samocha-Bonet D, Campbell LV, Viardot A, Freund J, Tam CS, Greenfield JR, et al. A family history of type 2 diabetes increases risk factors associated with overfeeding. Diabetologia. 2010;53:1700–8.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Magkos F, Fraterrigo G, Yoshino J, Luecking C, Kirbach K, Kelly SC, et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab. 2016;23:591–601.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    Adeva MM, Souto G. Diet-induced metabolic acidosis. Clin Nutr. 2011;30:416–21.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Kiefte-de Jong JC, Li Y, Chen M, Curhan GC, Mattei J, Malik VS, et al. Diet-dependent acid load and type 2 diabetes: pooled results from three prospective cohort studies. Diabetologia. 2017;60:270–9.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Williams RS, Kozan P, Samocha-Bonet D. The role of dietary acid load and mild metabolic acidosis in insulin resistance in humans. Biochimie. 2016;124:171–7.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Remer T, Dimitriou T, Manz F. Dietary potential renal acid load and renal net acid excretion in healthy, free-living children and adolescents. Am J Clin Nutr. 2003;77:1255–60.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Archer E, Hand GA, Blair SN. Validity of U.S. nutritional surveillance: National Health and Nutrition Examination Survey caloric energy intake data, 1971–2010. PLoS ONE. 2013;8:e76632.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    DeFronzo RA, Beckles AD. Glucose intolerance following chronic metabolic acidosis in man. Am J Physiol. 1979;236:E328–34.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Reaich D, Graham KA, Channon SM, Hetherington C, Scrimgeour CM, Wilkinson R, et al. Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with CRF. Am J Physiol. 1995;268:E121–6.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Mandel EI, Curhan GC, Hu FB, Taylor EN. Plasma bicarbonate and risk of type 2 diabetes mellitus. CMAJ. 2012;184:E719–25.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lovejoy J, Newby FD, Gebhart SSP, DiGirolamo M. Insulin resistance in obesity is associated with elevated basal lactate levels and diminished lactate appearance following intravenous glucose and insulin. Metabolism. 1992;41:22–7.

    Article  CAS  Google Scholar 

  15. 15.

    Crawford SO, Hoogeveen RC, Brancati FL, Astor BC, Ballantyne CM, Schmidt MI, et al. Association of blood lactate with type 2 diabetes: the atherosclerosis risk in Communities Carotid MRI Study. Int J Epidemiol. 2010;39:1647–55.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Juraschek SP, Selvin E, Miller ER, Brancati FL, Young JH. Plasma lactate and diabetes risk in 8045 participants of the atherosclerosis risk in communities study. Ann Epidemiol. 2013;23:791–6.e794.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Farwell WR, Taylor EN. Serum bicarbonate, anion gap and insulin resistance in the National Health and Nutrition Examination Survey. Diabet Med. 2008;25:798–804.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Samocha-Bonet D, Dixit VD, Kahn CR, Leibel RL, Lin X, Nieuwdorp M, et al. Metabolically healthy and unhealthy obese-the 2013 Stock Conference report. Obes Rev. 2014;15:697–708.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    Williams RS, Heilbronn LK, Chen DL, Coster AC, Greenfield JR, Samocha-Bonet D, et al. Dietary acid load, metabolic acidosis and insulin resistance—lessons from cross-sectional and overfeeding studies in humans. Clin Nutr. 2016;35:1084–90.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Tam CS, Viardot A, Clement K, Tordjman J, Tonks K, Greenfield JR, et al. Short-term overfeeding may induce peripheral insulin resistance without altering subcutaneous adipose tissue macrophages in humans. Diabetes. 2010;59:2164–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Samocha-Bonet D, Campbell LV, Mori TA, Croft KD, Greenfield JR, Turner N, et al. Overfeeding reduces insulin sensitivity and increases oxidative stress, without altering markers of mitochondrial content and function in humans. PLoS ONE. 2012;7:e36320.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. 22.

    Brons C, Jensen CB, Storgaard H, Hiscock NJ, White A, Appel JS, et al. Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J Physiol. 2009;587(Pt 10):2387–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. 23.

    Erdmann J, Kallabis B, Oppel U, Sypchenko O, Wagenpfeil S, Schusdziarra V. Development of hyperinsulinemia and insulin resistance during the early stage of weight gain. Am J Physiol Endocrinol Metab. 2008;294:E568–75.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Souto G, Donapetry C, Calvino J, Adeva MM. Metabolic acidosis-induced insulin resistance and cardiovascular risk. Metab Syndr Relat Disord. 2011;9:247–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Berkemeyer S. Acid-base balance and weight gain: are there crucial links via protein and organic acids in understanding obesity? Med Hypotheses. 2009;73:347–56.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Fenton TR, Huang T. Systematic review of the association between dietary acid load, alkaline water and cancer. BMJ Open. 2016;6:e010438.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kozan P, Blythe JC, Greenfield JR, Samocha-Bonet D. The effect of buffering high acid load meal with sodium bicarbonate on postprandial glucose metabolism in humans—a randomized placebo-controlled study. Nutrients. 2017;9.

  28. 28.

    Harris SS, Dawson-Hughes B. No effect of bicarbonate treatment on insulin sensitivity and glucose control in non-diabetic older adults. Endocrine. 2010;38:221–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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We thank our study participants and the members of the Clinical Insulin Resistance group at the Garvan Institute of Medical Research.


The clinical studies performed in Samocha-Bonet’s laboratory were funded by Diabetes Australia Research Program and the Garvan Research Foundation, Sydney, Australia. This article is published as part of a supplement sponsored by NuOmix-Research k.s. The conference was financially supported by Protina Pharmazeutische GmbH, Germany and Sirius Pharma, Germany, and organized by NuOmix-Research k.s. Neither company had any role in writing of the paper.

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DS-B conceived some of the clinical studies reported in the review, presented the findings at the 3rd International Acid–Base Symposium, and wrote the report. EC contributed to writing and reviewed the report.

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Correspondence to Dorit Samocha-Bonet.

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Chalmers, E., Samocha-Bonet, D. The effect of body acid–base state and manipulations on body glucose regulation in human. Eur J Clin Nutr 74, 20–26 (2020).

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