On the Metabolism of Exogenous Ketones in Humans
- Ketone Ester (KE) drinks elevated blood βHB to a greater extent (>50%) than Ketone Salt (KS) drinks, while KS drinks increased blood levels of L-βHB, which was metabolized more slowly.
- Both drinks had similar effects on FFA, TG, glucose and electrolyte concentrations, although only KE significantly decreased blood pH below normal range.
- Consumption of a meal prior to KE intake decreased total blood βHB, but did not affect blood acetoacetate or breath acetone levels. Decreased gut βHB uptake is probably the cause of lower blood βHB following meal consumption.
- Either three KE drinks or nasogastric feeding effectively maintained ketosis over 1mM for 9h.
Nutritional or endogenous ketosis is a metabolic state resulting from prolonged fasting, exercise or when consuming a ketogenic diet (KD) low in carbohydrates, adequate protein and high fat. In contrast, when acute ketosis is achieved by consumption of ketone supplements, it is referred to as exogenous ketosis. In both cases, blood levels of β-hydroxybutyrate (βHB) is elevated above 0.5 mmol/L. Despite the increasing scientific support for the health benefits of KD, compliance to such a strict diet can be challenging. Therefore, there is interest in developing and understanding the potential of exogenous ketones, formulated with βHB in the form of salts or esters. Ketone esters (KE) may avoid the problems associated with increased mineral consumption in ketone salt (KS) drinks, but KE are not yet commercially available due to unmaskable bitter taste, limited human studies and manufacturing cost.
In a recent publication by Stubbs and collaborators,1 published in Frontiers in Physiology, the authors investigated the effects of KE (R-3-hydroxybutyl-R-1,3-hydroxybutyrate) and KS (KetoForce, containing sodium and potassium βHB salts) on blood levels of βHB and metabolites in addition to the ketosis-inducing efficacy of KE following meal ingestion. They also investigated if nasogastric infusion could be used for KE administration, given that some patients may require feeding in this manner.
Study 1: Effect of KE and KS drinks on blood ketone bodies and substrates
On a first study, the authors compared the effects of low and high doses of KE and KS drinks on blood βHB and substrates in 15 participants (BMI: 22.7 ± 2.2; 22.7 ± 2.1 years old). Both drinks elevated ketone levels in a dose dependent manner for up to 2h (high dose KS) and 3h (high dose KE), with greater increase following KE drink. A relevant observation is that βHB is a chiral molecule (contains an asymmetric carbon center) that has two mirror image isoforms, D- or L-βHB. The isoform measured by handheld meters is the D-enantiomer and when samples were further analyzed by gas-chromatography – mass spectrometry, the authors found that levels of combined D- and L- βHB were similar for both KE and KS drinks. In addition, L- βHB remained elevated for at least 8h following intake, suggesting a lower rate of metabolism. However, the biological function of L- βHB in humans remains unclear. All drinks (KE, KS and both doses) acutely decreased blood levels of free fatty acids (FFA), triglycerides (TG) and glucose with return to baseline levels 4h following ingestion. Finally, both drinks decreased potassium and increased sodium and chloride concentrations (however, only KE increased chloride levels beyond normal range values).
Study 2: Effect of meal consumption on blood βHB and substrate changes following KE drinks
A second study investigated the effect of meal consumption on blood βHB and substrate levels followed by intake of KE drink in 16 participants (BMI: 22.5 ± 2.5; 27.4 ± 6.5 years old). Consumption of a meal high in carbohydrates and calories decreased peak βHB (by approximately 1mmol/L) but did not prevent the decrease in blood levels of fatty acids, triglycerides and glucose induced by KE drink.
Study 3: Effect of repeated intake of KE on blood βHB levels
As repeated consumption of exogenous ketones would be required to maintain ketosis, the authors investigated the effects of KE drinks consumed in series (every 3h) and of continuous intragastric infusion. Repeated consumption of KE drink sustained elevated blood βHB levels, despite rise and fall in between intakes. Additionally, total blood levels of βHB were similar between groups who consumed KE drinks every 3h or were given KE via a nasogastric tube continuously throughout the same 9h period.
In conclusion, exogenous ketones, in either salt or ester forms, increased blood βHB levels in healthy adults, although elevation of L- βHB lasts longer after racemic (containing both D- and L-βHB isoforms) KS consumption. Both KE and KS drinks mildly and acutely affected blood and urinary acid base balance and reduced blood glucose and lipids without inhibiting insulin secretion. The KE consistently increased blood βHB although ketosis was decreased when intake was preceded by a meal. We cannot, however, infer how meal consumption would affect βHB levels induced by KS intake as KS drinks were not included in this experiment. Finally, sustained ketosis was achieved when KE drinks were consumed in succession (every 3h) or using continuous infusion via nasogastric tube.
Nutritional ketosis, achieved by restriction of dietary carbohydrate, results in lower blood glucose and elevated FFA and the co-existence of low FFA and high βHB is a unique state induced by exogenous ketosis. This is likely due to negative feedback mechanisms exerted by ketone bodies on their own synthesis by reduction of hepatic FFA supply. Similarly, decreased blood glucose following consumption of exogenous ketones appears to occur through limiting hepatic gluconeogenesis and improved insulin sensitivity. At this point, however, the effects of exogenous ketones on insulin secretion are still unclear. One clinical use of KD is to improve blood glucose control, yet the elevated blood FFA may be implicated in increased risk of cardiovascular disease. Therefore, the ability of exogenous ketones to decrease blood glucose without elevating blood FFA could deliver the desired glucose reducing effect while decreasing a potential risk.
Recent studies suggest that ketone bodies themselves may underlie the health benefits associated with KD, as their role as intracellular signaling molecules continues to be unraveled. In this scenario, increasing levels of ketone bodies could improve health outcomes regardless of strict restriction of carbohydrates. It is appropriate to emphasize, however, that the effects of chronic consumption of exogenous ketones still require further investigation.
- Stubbs BJ, Cox PJ, Evans RD, et al. On the metabolism of exogenous ketones in humans. Front. Physiol. 2017;8:848.