Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Oct 30;8:848.
doi: 10.3389/fphys.2017.00848. eCollection 2017.

On the Metabolism of Exogenous Ketones in Humans

Affiliations
Free PMC article

On the Metabolism of Exogenous Ketones in Humans

Brianna J Stubbs et al. Front Physiol. .
Free PMC article

Abstract

Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3-1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.

Keywords: (R)-3-hydroxybutyl (R)-3-hydroxybutyrate; d-β-hydroxybutyrate; exogenous ketones; ketone ester; ketone salt; ketones.

Figures

Figure 1
Figure 1
Blood, breath, and urine ketone kinetics following mole-matched ketone ester (KE) and ketone salt (KS) drinks, at two amounts, in 15 subjects at rest. Values are means ± SEM. (A) Blood d-βHB. (B) Tmax of blood d-βHB. (C) AUC of blood d-βHB. (D) Isotopic abundance (%) of d- and l-chiral centers in pure liquid KE and KS. (E) Blood d-βHB and l-βHB concentrations in subjects (n = 5) consuming 3.2 mmol.kg−1 of βHB in KS drinks. (F) d-βHB and l-βHB concentrations in urine samples from subjects (n = 10) consuming 3.2 mmol.kg−1 of βHB in KS drinks. (G) Blood d- and l-βHB after 4, 8, and 24 h in subjects (n = 5) consuming 3.2 mmol.kg−1 of βHB in KS drinks. (H) Breath acetone over 24 h in subjects (n = 5) consuming 3.2 mmol.kg−1 of βHB in KE and KS drinks (ppm = parts per million). (I) Urine d-βHB excreted over 4 h after KE and KS drinks (n = 15). (J) Urine pH 4 h after drink, dotted line indicates baseline. p < 0.05 KE vs. equivalent amount of KS, *p < 0.05 difference between 1.6 vs. 3.2 mmol.kg−1 of βHB, §p < 0.05 difference between amounts of d- and l-βHB, p < 0.05 difference between baseline and post-drink level.
Figure 2
Figure 2
Concentrations of plasma non-esterified fatty acids, triacylglycerol, glucose, and insulin following equimolar ketone ester and ketone salt drinks, at two amounts, in subjects (n = 15) at rest. Values are means ± SEM. (A) Plasma FFA. (B) Plasma TG. (C) Plasma glucose. (D) Plasma insulin at baseline and after 30 and 60 min. EH, ketone ester high; EL, ketone ester low; SH, ketone salt high; SL, ketone salt low. *p < 0.05 difference from baseline value.
Figure 3
Figure 3
Blood d-βHB, pH, bicarbonate (HCO3-) and electrolytes measured in arterialized blood samples from resting subjects (n = 7) following a ketone ester or salt drink containing 3.2 mmol.kg−1 of βHB. Shaded areas represent the normal range. Values are means ± SEM. (A) Venous blood d-βHB. (B) Arterialized blood pH. (C) Blood bicarbonate. (D) Blood potassium. (E) Blood sodium. (F) Blood chloride. p < 0.05 difference between KE and KS, *p < 0.05 difference from baseline value.
Figure 4
Figure 4
Blood, urine, plasma, and breath ketone concentrations following mole-matched ketone ester or isocaloric dextrose drinks in fed and fasted subjects (n = 16) at rest. Data from both of the two study visits in each condition (fed and fasted) completed by an individual are included in the analysis. Values are means ± SEM. (A) Blood d-βHB. (B) AUC of blood d-βHB. (C) Urine d-βHB excretion. (D) Plasma acetoacetate (AcAc). (E) Measured breath acetone (ppm = parts per million). (F,G) Mean d-βHB Cmax and difference between βHB Cmax over two visits when subjects separately consumed two ketone ester drinks in both the fed (F) and fasted (G) state. X axis = mean d-βHB Cmax of the 2 visits (mM), Y axis = difference between d-βHB Cmax in each visit. 95% confidence limits are shown as dotted lines. Significance denoted by: *p < 0.05 fed vs. fasted.
Figure 5
Figure 5
Plasma substrate concentrations following mole-matched ketone ester or isocaloric dextrose drinks in fed or fasted subjects (n = 16) at rest. Values are means ± SEM. (A) Plasma FFA. (B) Plasma TG. (C) Plasma glucose. (D) Plasma insulin. Significance denoted: *p < 0.05 vs. baseline, p < 0.05 ketone vs. control.
Figure 6
Figure 6
Blood d-βHB following 3 ketone ester drinks consumed following a fast, by subjects (n = 12), or with NG ketone ester feeding (n = 4); both methods maintained blood d-βHB concentrations above 1 mM (dotted line) for 9 h. Values are means ± SEM.

Similar articles

See all similar articles

Cited by 31 articles

See all "Cited by" articles

References

    1. Ari C., Kovács Z., Juhasz G., Murdun C., Goldhagen C. R., Koutnik A. P. (2016). Exogenous Ketone supplements reduce anxiety-related behavior in Sprague–Dawley and Wistar Albino Glaxo/Rijswijk Rats. Front. Mol. Neurosci. 9:137. 10.3389/fnmol.2016.00137 - DOI - PMC - PubMed
    1. Balasse E. O. (1979). Kinetics of ketone body metabolism in fasting humans. Metab. Clin. Exp. 28, 41–50. 10.1016/0026-0495(79)90166-5 - DOI - PubMed
    1. Balasse E. O., Fery F. (1989). Ketone-body production and disposal - effects of fasting, diabetes, and exercise. Diabetes Metab. Rev. 5, 247–270. 10.1002/dmr.5610050304 - DOI - PubMed
    1. Balasse E., Ooms H. A. (1968). Changes in the concentrations of glucose, free fatty acids, insulin and ketone bodies in the blood during sodium hydroxybutyrate infusions in man. Diabetologia 4, 133–135. 10.1007/BF01219433 - DOI - PubMed
    1. Bates D. M. M., Bolker B. M., Walker S. (2015). _lme4: linear mixed-effects models using Eigen and S4_. R package version 1.1-8, J. Stat. Softw. 67, 1–48. 10.18637/jss.v067.i01 - DOI
Feedback