Hyperketonemia from Endogenous Origin

After an overnight fast endogenous ketone body production amounts to ~0.25 mmol/min (or ~35 g/24 h) resulting in relatively low circulating ketone body concentrations (~0.1–0.5 mmol/L) [22–24]. However, with prolonged fasting/starvation (~5 days), the rate of ketone body production reaches levels of ~1–2 mmol/min (or 140–280 g/24 h) [23, 24], corresponding to a plasma concentration of ~7–10 mmol/L. Beyond 5 days without food, plasma ketone body concentrations plateau and rarely exceed ~10 mmol/L [22]. This upper limit of ketonemia has been suggested to be the result of an inherent feedback mechanism by which ketone bodies inhibit their own production via exerting an insulinotropic [25–27] and anti-lipolytic effect [28] (for a review on this topic, see Balasse and Féry [22] and Balasse [29]). Outside of prolonged fasting/starvation a ketogenic diet can increase circulating ketone body concentrations to ~1–2 mmol/L after 2–4 days [30, 31]. Typical ketogenic diets are characterized by high fat (~80 % of daily energy intake), low carbohydrate (~20–50 g/day or ~5 % of daily energy intake), and moderate to relatively low protein intake (~15 % of daily energy intake) [9, 32]. However, the level of ketonemia induced via a ketogenic diet is largely dependent on the amount of carbohydrate ingested and can reach ~7–8 mmol/L following sustained periods of severe carbohydrate intake restriction (i.e., keto adaptation) [9].

Next to dietary interventions, prolonged physical exercise performed in the fasted state also stimulates ketogenesis during exercise [33–35] and results in post-exercise hyperketonemia [22, 34–38]. For example, ketone body concentrations can reach ~0.5–1.0 mmol/L in response to 2 h of exercise performed in an overnight fasted state [33] and can subsequently increase to ~1–4 mmol/L during early post-exercise recovery [22, 34–38]. The extent of exercise-induced hyperketonemia during and after exercise is influenced by the intensity and duration of the exercise performed as well as the nutritional status [22, 35, 38, 39]. For example, carbohydrate intake in close temporal proximity to exercise strongly attenuates the exercise induced increase in plasma ketone body concentrations [22, 35, 38–41]. Interestingly, well-trained individuals demonstrate an attenuated rise in plasma ketone body concentrations during and after exercise when compared to untrained individuals [34, 36, 37]. This has been attributed to a training mediated attenuation in the post-exercise increase in free fatty acid (FFA) concentrations [34, 36], and/or to increased activity of the enzymes involved in ketone body utilization [42, 43].

Evaluating ketone body kinetics in an overnight fasted state [44–46] or in response to prolonged fasting/starvation [33, 47–49] is of little practical relevance to endurance athletes seeking to apply optimal fueling strategies for competition. Furthermore, although ketogenic diets have been proposed to benefit various types of athletes [9, 10, 32], induction of nutritional ketosis via a ketogenic diet is dependent upon the depletion of hepatic and muscle glycogen reserves, thereby increasing circulating FFA and endogenous ketone body production [50]. However, a high fat, low carbohydrate ketogenic diet may reduce the capacity to utilize carbohydrate [51], thereby compromising exercise training intensity [8] and limiting exercise performance [52–54], particularly during moderate to high-intensity exercise activities, such as marathon running and hill climbs, sprints, and accelerations during a cycling race [55]. Therefore, orally ingested ketone body supplements may represent a more practical alternative to increase circulating ketone body concentrations in athletes [11, 15] since they do not require adherence to a high fat, low carbohydrate ketogenic diet to induce ketosis.

Hyperketonemia from Exogenous Origin

Since the 1960s, studies examining the effects of exogenously provided ketone bodies have utilized ketone body salts administered either intravenously [47, 56–61] or orally [37]. Currently commercially available ketone body supplements (salts) provide ~8–12 g of β-OHB and ~1 g of sodium per serving, and serve as a means to rapidly increase circulating ketone body availability. Recently, ketone esters [i.e., (R)-3-hydroxybutyl (R)-3-hydroxybutyrate] have emerged as a more practical and applicable way to increase the availability of blood ketone bodies [15, 62–64]. Following ingestion, ketone esters [i.e., ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate] are cleaved in the gut and absorbed via the gut epithelium and monocarboxylate transporters into the circulation, or undergo first-pass metabolism in the liver to ketone bodies [11]. In comparison to starvation and/or a ketogenic diet which can take days to elicit a robust increase in ketone body concentrations, ingestion of ketone body supplements can rapidly increase plasma ketone body concentrations, reaching peak levels within 1–2 h [15, 62]. Plasma ketone body concentrations may increase to ~3 mmol/L 1 h after ingestion of ~400 mg of the ketone ester per kg body weight [31, 45, 46] or alternatively reach similar concentrations 10 min after ingesting ~600 mg/kg body weight, eventually resulting in plasma ketone body concentrations of ~6 mmol/L 45 min after ingestion [47].

Although ketone body supplements may induce a state of hyperketonemia, the ketone body concentrations achieved following ingestion appear to be influenced by concomitant food intake [41]. In this regard, recent data published in abstract form [41] reported that postprandial ketone body concentrations following ingestion of a ketone ester supplement (395 mg/kg body weight) were strongly influenced by baseline nutritional status. Specifically, an attenuated increase in peak plasma β-OHB concentrations (fed: 2.1 ± 0.2 mmol/L vs. fasted: 3.1 ± 0.1 mmol/L), and a 60 % reduction in β-OHB area under the curve was demonstrated when the ketone esters were ingested after consumption of a mixed meal when compared to consumption under fasted (post-absorptive) conditions [41]. These findings suggest that co-ingestion of ketone esters with other nutrients may impact gastric emptying and/or tissue uptake of the ingested ketone bodies. This finding may have implications regarding the effectiveness of ketone ester supplementation in athletes, who ingest large amounts of carbohydrate during a competitive event and adapt their nutrient intake during competition according to their specific nutritional needs [65]. Alternatively, whether ketone body supplementation impacts or compromises the intake of other important substrates, such as carbohydrate, may be an important consideration for endurance athletes who often struggle to ingest adequate amounts of carbohydrate during competition [66]. Finally, an additional consideration is how ketone body intake during exercise is tolerated by athletes. Normal healthy subjects, consuming 714 mg/kg of a milk-based ketone ester drink three times a day, were reported to experience feelings of discomfort, including abdominal distention and headaches [15]. However, it should be noted that the milk-based test drink volume amounted to 1.1 L per serving, making it difficult to differentiate between the effects of the ketone esters per se and simply the volume of the drinks that were ingested [15].