INTERNATIONAL FEDERATION OF SPORTS MEDICINE
Effects of Ketone Bodies on Endurance Exercise
Massimiliano Sansone, MD1; Andrea Sansone, MD1; Paolo Borrione, MD2; Francesco Romanelli, MD1;
Luigi Di Luigi, MD3; and Paolo Sgrò, MD, PhD3
Abstract
Priorities for every athlete include improving endurance performance,
optimizing training, nutrition, and recovery. Nutritional strategies are
crucial to support athletes to perform at the highest level, and consid-
ering that muscular and hepatic glycogen stores are limited, alternative
strategies to maximize fat metabolism have been suggested. A keto-
genic diet has been proposed as a possible method of providing meta-
bolic fuel during prolonged periods of exercise. However, clinical trials
and empirical experience have produced contrasting results regarding
the ergogenic value of a ketogenic diet. For this reason, using ketone
esters and/or salts have been proposed to obtain nutritional ketosis
without limiting carbohydrate intake. Exogenous ketones should not
only represent an alternative metabolic fuel source, sparing carbohy-
drates, but they also may increase postexercise glycogen replenishment,
decrease proteolysis, and act as metabolic modulators and signaling
metabolites. While there are some encouraging results showing an in-
crease in endurance performance, contrasting evidence regarding the
efficacy of exogenous ketones for endurance performance is present and
further studies should be performed to make a definitive statement.
Introduction
In the pursuit of excellence, both amateur and profes-
sional athletes are looking for innovative strategies and/or
techniques to improve their performance. In this frame-
work, any gain, both large and small, may represent a pri-
ority considering that the gap separating winners and losers
is seconds. Nutrition, training, recovery, and ergogenic aids
represent the typical areas where athletes and their staff
may find new ways to improve their performance; in par-
ticular, nutrition and supplementation has recently gained
1
Section of Medical Pathophysiology, Food Science and Endocrinology,
Department of Experimental Medicine, Sapienza University of Rome, Rome,
ITALY; 2Unit ofSports Medicine, Department of Movement, Human and
Health Sciences, Università degli Studi di Roma ‘‘Foro Italico’’, Rome,
ITALY; 3Unit of Endocrinology, Department of Movement, Human and
Health Sciences, Università degli Studi di Roma ‘‘Foro Italico’’,
Rome, ITALY
Address for correspondence: Paolo Sgrò, MD, PhD, Unit of Endocrinolo-
gy, Department of Movement, Human and Health Sciences, Università
degli Studi di Roma ‘‘Foro Italico’’, Largo Lauro de Bosis 15, 00135, Rome,
Italy; E-mail: paolo.sgro@uniroma4.it.
1537-890X/1712/444Y453
Current Sports Medicine Reports
Copyright * 2018 by the American College of Sports Medicine
444 Volume 17 & Number 12 & December 2018
Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
the attention of both athletes and sport
scientists alike (1Y3). It is well known
that in endurance exercise performed
at medium and high intensity, carbo-
hydrates represent the main metabolic
substrate (4). Metabolism of fat is of-
ten insufficient to sustain prolonged,
high-intensity exercise. For example,
maximum fat oxidation rate (FatMax)
in endurance athletes ranges from 0.4
to 0.6 gIminj1 reached at 40% to 60%
of maximum oxygen uptake (V̇O2max)
(5), whereas in fat or ketone adapted
ultraendurance athletes performing
specific training sessions, FatMax may
reach 1.2 to 1.3 gIminj1 (6,7). A
FatMax of 0.4 to 0.6 gIminj1 corre-
sponds to ~3.64Y5.46 kcalIminj1,
whereas 1.2Y1.3 gIminj1 corresponds
to ~10.92 to 11.83 kcalIminj1. Run-
ning a marathon at 2:06:36 (h:min:s)
requires an average speed of 20 kmIhj1 which corresponds
to ~22Y23 kcalIminj1 considering a gross efficiency of
~200 mL O2Ikgj1Ikmj1, whereas cycling at 300 W requires
~18 kcalIminj1 considering a gross efficiency of ~22%
(8Y10). It is clear that even the highest FatMax is not
enough to sustain the mechanical power required by some
endurance events. Fat stores are virtually limitless considering
that an a 70-kg endurance athlete with 4% of fat mass may
store roughly 3 kg of fat mass corresponding to ~27000 kcal,
but the inability of fat metabolism to support high intensity
efforts impairs high-end performance representing a significant
limit of fat diets. At the opposite, the oxidation of glucose de-
riving from glycogenolysis is able to sustain high mechanical
power but it also should be considered that muscular and he-
patic glycogen stores are limited and an adapted athlete fol-
lowing a strenuous protocol of carbohydrate loading may store
200Y220 mmol of glycogenIkgj1 d.w. muscle which corre-
sponds to ~500 to 700 g of glycogen (2000Y2800 kcal)
(11,12). This quantity is not enough to end a marathon at
20 kmIhj1 (i.e., 2:06:36 h:min:s) which costs roughly 2800 kcal,
Indeed, the low muscle mass of the best marathon runners is
able to store ~2000 kcal in muscular mass involved in running.
Aside from running, a 1-d stage in cycling may require ~5 or 6 h
of effort performed at average power output of 270 to 320 W
not considering sudden changes of pace (corresponding to
Effects of Ketone Bodies on Endurance Exercise
4000Y6000 kcal) or an Ironman triathlon (i.e., 3.8 km swim,
180-km time trial and a 42-km run) that elite athletes com-
plete in ~8 h considering 50 min for the swim leg, 4:30 (h:min)
for the bike leg and 2:50 (h:min) for the run leg corre-
sponding to ~8000 kcal. It should be considered that ex-
ogenous carbohydrates supplementation may increase
carbohydrates availability, but exogenous carbohydrates ox-
the spontaneous decarboxylation of acetoacetate (21). In
healthy adults, the liver is capable of producing up to
150Y185 gId j1 of KB (16,21,22). Once produced, KB
cross mitochondrial and cellular membranes and are
transported to peripheral tissue via the bloodstream (i.e.,
brain, heart, muscle) into the cytosol and mitochondria
via the monocarboxylate transporters (MCTs). In mito-
idation rates is limited to 1.8 gIminj1 if the correct blend of
sucrose and fructose is introduced. Furthermore, this high
amount may easily cause gut distress and nausea limiting the
ability of introducing carbohydrates during training and/or
racing (13).
chondria they are converted back to acetyl-CoA via -
ketoacyl-CoA transferase, not present in liver, which uses
succinyl-CoA as the CoA donor, forming succinate and
acetoacetyl-CoA (23). Ketone bodies can be completely
oxidized as a fuel source by skeletal muscle and they have
Ketogenic diets (KD), ketone salts (KS), and/or ketone
esters (KE) have gained the interest of many sports scientists
who suggest that ketone bodies (KB) may represent a near-
endless metabolic substrate able to sustain even the highest
metabolic power required by some endurance events.
Physiology
The word ketone comes from the German word Aketon,
for ‘‘acetone,’’ which is the simplest ketone (14). Ketone
bodies are organic, lipid-derived compounds produced in
the liver during low levels or absence of carbohydrate intake
as seen in starvation, KD, or prolonged fasting to provide a
biochemical fuel source for peripheral tissue (15). The term
‘‘ketone bodies’’ refers to three molecules, acetoacetate
a similar RER to glucose, 1.0 and 0.89 for AcAc and for -
OHB, respectively (16).
After overnight fasting ketonemia ranges from 0.1 to
0.5 mmolILj1, whereas after 5 d or more of fasting ketonemia
may reach 7 to 10 mmolILj1. Four days of KD are able to
raise ketonemia to 1 to 2 mmolILj1; however, plasma KB
concentrations are strictly dependent on carbohydrate in-
take and physical exercise and they may reach 7 to
8 mmolILj1. Physical exercise, in particular if performed in
the fasted state and for a prolonged period, is able to raise
ketonemia to 0.5 to 1 mmolILj1 and in the postexercise
period ketonemia may raise to 1 to 4 mmolILj1 if no car-
bohydrates are ingested (16). Ketone ester ingestion may
raise plasmatic KB concentrations from 1 to 5 mmolILj1
(15). Veech also suggests an increased efficiency of KB in
(AcAc), 3- -hydroxybutyrate (-OHB) and acetone. How- generating metabolic energy compared with glucose and
ever, only AcAc and acetone are ‘‘ketones’’ containing a car- fatty acids. Indeed, KB could increase the hydraulic effi-
bonyl group with two hydrocarbon atoms. -OHB is a KB, ciency of heart by 28% compared with glucose in animal
but is not a ketone since one of its hydrocarbon atoms is re- models as observed by Sato et al. (16,22,24,25). A possible
placed by a hydroxyl group. The two most abundant KB are explanation may be represented by the ability of KB me-
AcAc and -OHB, but only AcAc is produced in the liver and tabolism to induce changes in mitochondrial electron
can be subsequently enzymatically converted to -OHB or
spontaneously degraded to acetone which is the less abun-
dant KB (16).
Ketogenesis represents the process in which fatty acids
are converted into AcAc in mitochondria of perivenous he-
patocytes in the presence of different factors. Low levels of
insulin, high levels of glucagon and epinephrine stimulate
the release of fatty acids from adipose tissue which are
transport system increasing increasing the energy of the
transport chain redox span between site I and site II. This
results in an increased energy release by the electron travel-
ing across that span by means of the reduction of nico-
tinamide adenine dinucleotide (NAD+) and the oxidation of
the Coenzyme Q (CoQ) couple and in an increase in redox
energy of respiratory chain (26). As a consequence, the en-
ergy of the protons ejected from the mitochondria at the
converted to acetyl CoA by -oxidation in the liver. During energy-conserving sites increases causing a corresponding
periods of low carbohydrate intake, glycolysis produces increase in the energy of adenosine triphosphate (ATP) hy-
small amounts of pyruvate and consequently low quantities drolysis (27). Such increase in ATP hydrolysis may be re-
of oxaloacetate are produced in the mitochondria via py- lated to the intrinsec higher heat of -OHB combustion than
ruvate carboxylase (17). Even a low-medium protein intake pyruvate; indeed the combustion in a bomb calorimeter of
below 1.7 gIkgj1Idj1 is necessary to induce ketogenesis; -OHB is able to produce 31% more calories per C2 unit
indeed high amount of protein stimulates gluconeogenesis than pyruvate. The greater enthalpy generated by -OHB
increasing glucose availability and suppressing ketogenesis
(18). On average, 1.6 g of amino acids is required to syn-
thesize 1 g of glucose (19). Moreover, low intracellular
glucose causes oxaloacetate to be preferentially utilized in
the process of gluconeogenesis, instead of condensing with
acetyl CoA. The high ratio acetyl CoA/oxaloacetate diverts
acetyl CoA to KB formation (20). Subsequently, acetyl
CoA is converted to acetoacetyl CoA. Acetoacetyl CoA is
derives from the fact that -OHB is more reduced than py-
ruvate showing a higher ratio of hydrogen:carbon present in
each molecule (22). Furthermore, KB metabolism may
generate energy more efficiently even if compared with
palmitate which is more reduced than KB. Indeed, three
aspects should be considered: 1) the redox potential of the
CoQ couple is not oxidized as it is during KB metabolism,
but rather reduced, decreasing energy available for ATP
transformed into hydroxymethylglutaryl (HMG) CoA synthesis; 2) during  oxidation, there is a significant loss of
by mitochondrial HMG CoA synthase. HMG CoA is efficiency in producing ATP because half of the reducing
then cleaved to liberate AcAc in a step mediated by HMG equivalents enter at a flavoprotein site with an lower po-
CoA lyase. The reduction of AcAc to -OHB is catalyzed by tential compared with NAD couple reducing the redox span
3-HB dehydrogenase (HBD), and acetone is formed by between NAD+ couple and CoQ couple; 3) elevation of free

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fatty acids increases uncoupling proteins generating heat
production (22). Translating these aspects into skeletal
muscle metabolism, the better efficieny of KB should be
defined by the ability to generate more power for the same
oxygen consumption requiring less oxygen per mole of car-
bon during their oxidation (28). Indeed, endurance perfor-
mance may be considered as a product of three physiological
variables: V̇O2max, lactate threshold and efficiency. V̇O2max
is determined by cardiac output, muscular blood flow, ox-
ygen carrying blood capacity and mitochondrial volume
density; therefore, peripheral oxygen availability potentially
represents a limiting factor for endurance performance
(29,30). The better efficiency showed by KB in energy
production compared with glucose should facilitate a higher-
power output at the same V̇O2, increasing maximal per-
formance; at the same time, this efficiency should decrease
V̇O2 at the same power output and therefore increasing
submaximal performance (i.e., time to exhaustion). Nev-
ertheless, this aspect deserves to be evaluated in depth with
further studies. It also should be considered that KB rep-
resent an alternative fuel source to glucose allowing the
athlete to spare glucose and preserve glycogen stores for
high intensity efforts, such as the final climb of a cycling
stage or the last 10 km of a marathon. A decreased reliance
on carbohydrates also may be helpful to support the high
volume of training considering both the limited human
glycogen stores and the slow process of muscular glycogen
replenishment.
Ketogenic Diet
Ketogenic diet represents the most intuitive way to obtain
biological ketosis forcing the body to produce KB by greatly
reducing carbohydrate intake. Ketogenic diet is generally
characterized by a total carbohydrate intake of less than
50 gIdj1 and a moderate protein intake of approximately
1.5 gIkgj1Idj1 to induce ketogenesis (31,32). Ketogenic
diet has been representing an effective treatment for refrac-
tory epilepsy in children since the early 20th century (33).
The exact mechanism responsible for anticonvulsant prop-
erties is unclear; postulated hypotheses include reduced
glucose utilization/glycolysis, reprogrammed transport, in-
direct impact on ATP-sensitive potassium channel or aden-
osine A1 receptor, alteration of sodium channel isoform
expression, or effects on circulating hormones including
leptin (34,35). An interesting hypothesis suggests that rais-
ing resting membrane potential may inhibit the synchronous
neuronal discharge characteristic of epilepsy (22).
A number of variations of the Hopkins KD also has been
considered as a treatment for weight loss, cancer che-
motherapy adjuvant, Acyl CoA dehydrogenase deficiency,
neurodegenerative diseases, and muscle wasting (22). A well-
formulated KD also may increase omega-3 daily amount if
correct fat sources are chosen, with consequent decrease of
inflammation and of insulin resistance and increase of
FatMax and of muscular anabolic response to stimuli
representing a therapeutic aid for diabetes and sarcopenia
(36,37). A well-known method to induce hyperketonemia
also is represented by repeated ingestion of medium-chain
triglyceride (MCTG); 20 to 30 gIdj1 of MCTG may be a
proper quantity to increase ketonemia to 0.29 mmolILj1 (38).
The first studies regarding the effects of KD on endurance
446 Volume 17 & Number 12 & December 2018
Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
performance were performed almost forty years ago by
Phynney et al. considering the typical diet of Inuit observed
by western scientists during expeditions in Arctic (39Y41). In
particular, Phynney et al. observed that KD preserved time to
exhaustion performed at 65% of V̇O2max in highly trained
athletes while respiratory quotient decreased to 0.72 indi-
cating that fat metabolism was the sole substrate used by the
athletes. It is worth noting that increasing reliance on fat
oxidation and, consequently, on oxidative processes, may
promote an adaptive response to oxidative stress induced by
mitochondrial reactive oxygen species; this response is called
mitohormesis, and it may enhance mitochondrial function
(31). Other studies have investigated the effects of KD on
different populations and also the impact of KD in athletes of
different sports have been studied (42Y48). Nevertheless,
when evaluating the outcome of these studies it should be
considered that the metabolic demands of top level endurance
exercise are complicated because they also include high in-
tensity efforts performed at or above anaerobic threshold,
and the evidence observed in sedentary and/or active subjects
cannot be translated to elite athletes performing endurance
exercise including high-intensity efforts (16). Indeed, endur-
ance exercises requiring short bursts of high intensity efforts
above anaerobic threshold and/or prolonged periods of time
spent at intensity of anaerobic threshold may be impaired
by KD. High levels of ketonemia may impair glycolysis
limiting the functionality of fast twich fibers. Otherwise,
ultra endurance performance and other endurance activi-
ties performed at low-medium intensity may be positvely af-
fected by KD.
The main concern of KD may be represented by the need to
train and race in the presence of scarce levels of carbohydrate.
This aspect requires a keto-adaptation of at least 2 to 4 wk
during which athletes may show signs of weakness, asthenia,
lethargy, drowsiness and poor performance (18,49,50). De-
spite no standard definition exists to define the ideal range of
carbohydrate intake to achieve ketosis because of individual
variability, a carbohydrate daily intake of 0.5 gIkgj1Idj1 or
G50 gIdj1 may represent an accurate assessment (14). Daily
protein intake should range from 1.76 to 2.2 gIkgj1 lean mass
per day or 1.2Y1.7 gIkgj1 body weight per day, and the
remaining calories should come from fat, covering 70% to
80% of daily energy intake (31,32). It should be taken into
account that a high daily intake of proteins may inhibit keto-
genesis by stimulating gluconeogenesis (49). Furthermore, very
low calorie KD may require to be supplemented by sodium
and potassium to maintain daily intakes for sodium at 3 to
5 gIdj1 and for potassium at 2 to 3 gIdj1 (18). Indeed,
blood insulin levels tend to decrease in KD causing an
increase in renal sodium excretion (45,51). Consequent-
ly, it can be supposed that the adrenal cortex increases the
compensatory secretion of aldosterone augmenting sodi-
um reabsorption and potassium excretion. A study by
McSwiney et al. showed promising results demonstrating
that after 12 wk of KD (%carbohydrate:protein:fat =
6:17:77, 41.1 T 13.3 g carbohydratesIdj1, 3022.3 T 911.1
kcalIdj1), amateur athletes lost significant fat mass com-
pared with athletes following an high carbohydrate diet
(HCD) (%carbohydrate:protein:fat = 65:14:20, 2643.6 T
358.0 kcalIdj1). Body fat mass significantly decreased in
the KD group, with a loss of 4.6 kg compared with 0.5 kg in
Effects of Ketone Bodies on Endurance Exercise
the HCD group and they showed significant improvements
in relative critical power in 3 min all-out cycling test (pre,
8.3 T 2.2 wIkgj1 vs post, 9.7 T 2.3 wIkgj1) and relative
peak power during single 6-s sprint cycling test (pre, 13.7 T
1.4 wIkgj1 vs post, 14.5 T 1.1 wIkgj1) compared with
baseline (49). Also, relative critical power in 3 min all-out
cycling test (HCD, 8.4 T 2.2 wIkgj1 vs KD, 9.7 T 2.3 wIkgj1)
and relative peak power during single 6-s sprint cycling test
(HCD, 13.8 T 2.2 wIkgj1 vs KD, 14.5 T 1.1 wIkgj1) were
significantly higher in the KD group compared with the Hc
group at the end of the treatment.
Absolute critical power in 3-min all-out cycling test and
absolute power during single 6-s sprint cycling test did not
differ significantly between the groups (49). Moreover, the
KD group showed a marked but not significant decrease in
time required to complete 100-km cycling test (HC, 168.44 T
9.14 minIsj1vs KD, 161.53 T 8.44 minIsj1), and a signifi-
cantly inferior RER, indicating a greater reliance of fat
metabolism compared with the high carbohydrate group
(49). In evaluating this marked but not significant im-
provement in 100-km cycling test in the KD group, it should
be considered the response of two subjects suggests a large
individual variation in response to a KD. Indeed, these two
subjects showed an improvement of ~12 min compared
with an average improvement of 5 min in the KD group.
Similarly, Zinn et al. showed a significant higher FatMax
(pre, 0.6 T 0.1 gIminj1 vs post, 0.8 T 0.1 gIminj1), a sig-
nificant increase in exercise intensity relative to V̇O2max at
which peak absolute FatMax occurred (pre, 48.2% T 8.7%
vs post, 63.2% T 5.7% V̇O2max) and a significant reduction
in body weight (j4.0 T 3.1 kg) following KD. Nevertheless,
the incremental cycle test showed a significant decrease in
time to exhaustion (j2 T 0.7 min), and a marked but not
significant reduction in peak power (j18 T 16.4 W), in
V̇O2max (j1.69 T 3.4 mLO2Ikgj1Iminj1), and ventilatory
threshold (j6 T 44.5 W) following KD. However, it should
be considered that only five amateur athletes were involved in
this study and they were provided with a daily macronu-
trient prescription of G50 g total carbohydrate, 1.5 gIkgj1
protein and ad libitum fat (50). Similar results were ob-
served in 42 healthy, nontrained subjects (V̇O2max: 36.7 T
8.5 mLIO2j1Ikgj1Iminj1) following KD for 6 wk. Subjects
were asked to follow a KD according to their personal
preferences but were advised to eat ad libitum but limit their
carbohydrate intake to a maximum of 20 to 40 gIdj1 to
derive at least 75%, 15% to 20%, and 5% to 10% of total
energy from fats, protein, and carbohydrates, respectively.
7-dy food records showed that the subjects consumed on
average a KD 2224 T 584 kcal with 71.6%, 20.9%, and
7.7% of total energy intake from fat, protein, and carbohy-
drate, respectively. A significant reduction in body weight
(j2.0 T 1.9 kg) and RER at rest (pre, 0.86 vs post, 0.79) was
observed, but, at the same time, absolute power (pre, 241 T
57 vs post, 231 T 57 W) and V̇O2max (pre, 2.55 T 0.68 LIminj1 vs
post, 2.49 T 0.69 LIminj1) decreased during maximal in-
cremental cycling test (52). Zajac et al. reported similar
outcomes in eight off-road cyclists with a training
experience of at least 5 years and a minimal V̇O 2max of
55 mLIkgj1Iminj1 after KD for 4 wk and HCD for other
weeks in crossover design. The HCD included 50% carbo-
hydrates, 30% fats, and 20% protein, while the KD was
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composed of 70% fat, 15% protein, and 15% carbohy-
drates. In these subjects a significant reduction in fat mass
(HCD, 14.88 T 3.78 kg vs KD, 11.02 T 3.66 kg) and RER at
rest (HCD, 0.88 T 0.04 vs KD, 0.76 T 0.01) and during
submaximal cycling test (HCD, 0.84 T 0.03 vs KD, 0.79 T
0.02, at 90 min) was observed. Nevertheless, incremental
cycling test showed that power at V̇O2max (HCD 362 T
16.09 vs KD 350 T 14.60 W) and power expressed at lactate
threshold (257 T 10.60 vs KD 246 T 9.50 W) decreased
significantly in the KD group compared with the HCD
group. Otherwise, relative V̇O2max (HCD 56.02 T 3.50 vs
KD 59.40 T 3.10 mLIkg j1 Imin j1 , and relative V̇O 2 at
lactate threshold (43.5 T 1.8 mLIkg j1 Imin j1 vs 47.8 T
2.1 mLIkg j1 Imin j1 ) significantly increased in the KD
group compared with HCD group. This evidence may be
explained by the significant weight loss observed in the KD
group (53). It is worth mentioning the study performed by
Burke et al. for 3 wk on 21 world class walkers divided into
three groups according to three different dietary ap-
proaches: HCD (8.6 gIkgj1 carbohydrates, 2.1 gIkgj1 pro-
tein, 1.2 gIkgj1 fat), periodized carbohydrates diet (PHCD)
(8.3 gIkgj1 carbohydrates, 2.2 gIkgj1 protein, 1.2 gIkgj1
fat), low carbohydrated high fat diet (LCHF) (G50 gIdj1
carbohydrates, 2.2 gIkgj1 protein, 4.7 gIkgj1 fat). Athletes’
performance was evalauted through an incremental walking
test, a 10-km race and a 25-km standardized long walk. In
the KD group FatMax improved significantly from the
pretreatmen value of 0.62 T 0.32 gImj1 to posttreatment of
1.57 T 0.37 gImj1, whereas in the HCD and PHCD groups
no change was observed in FatMax. Moreover, oxygen cost
of race walking increased significantly in the KD group in-
dicating an impairment in walking economy. The HCD and
PHCD groups improved significantly 10 km race perfor-
mance, showing 6.6% and 5.3% improvements in perfor-
mance following the 3-wk diet and training intervention,
respectively. In the KD group, 10-km race performance
showed an impairment by 1.6%.
These outcomes provide insufficient evidence supporting
ergogenic properties of KD on endurance performance;
however, KD may be beneficial for athletes representing an
aid for weight loss and for supporting training sessions
performed at low-moderate intensity for long periods of
time. High-volume low-intensity trainings are typical of the
early season in the classical periodization of annual training
schedule (54,55). Indeed, stressing fat metabolism repre-
sents a priority of this period and KD may be helpful to
increase FatMax in presence of low-moderate intensity with
a synergic effect. Moreover, high volume of training re-
quires an adequate caloric intake that may be difficult to
obtain with high carbohydrate diet and it may detrimental
for increasing fat oxidation considering the hyperinsulinism
induced by high intake of carbohydrates. KD may represent
a good option to support high energetic demand and, at the
same time, to maximize fat oxidation. The ability of KD to
support low-medium intensity efforts in ultra-endurance
events without stressful carbohydrate-loading prior the
event and exogenous carbohydrates supplementation dur-
ing the event also may be helpful to avoid gastrointestinal
upset and logistic problems.
In some specific cases and sports, KD may be used to
facilitate weight loss in a short period of time without
Current Sports Medicine Reports 447
 Table.

448
Summary of the effects of KE or KS administration on maximal cycling performance.
Authors Subjects Intervention Exercise Outcome Ketonemia

Cox et al. a) 6 male endurance a) KE: ((R)-3-hydroxybutyl a) 45 min of cycling a) Estimated 3-b-hydroxybutyrate -OHB: a) 2 mmolILj1
(2016) athletes (R)-3-hydroxybutyrate KE exercise 40% and 75% ( -OHB) oxidation accounts for at 40% V̇O2max
b) 10 male endurance (573 mgIkgj1 body weight) of maximum oxygen 16%Y18% of total oxygen 4 mmolILj1 at 75%
athletes b) 573 mgIkgj1 KE prior to uptake (V̇O2max) consumption during exerciseb) V̇O2maxb)
c) 8 endurance the start of exercise and b) 3 experimental trials average blood lactate 3.5 T 0.3 mmolILj1c)
athletes (6 male and 191 mgIkgj1 KE 45 min of 1 h of constant load concentration: 2Y3 mM (~50%) 2Y2.5 mmolILj1
2 female) into each 1-h trialc) cycling at 75% of V̇O2max lower than carbohydrate (CHO) during all-out TT
573 mgIkgj1 c) 1 h steady-state cycling group, and lower than fat (FAT)
KE + glucose test at 75% V̇O2max followed group at 30 and 45 minb)
by a blinded 30 min cycling Significant lower glycemia after
time trial (TT) for maximum KE than either FAT or CHO intake
distance within 5 min of exercisec) 2%

Volume 17 & Number 12 & December 2018

improvement in 30-min cycling TT
Leckey et al. 10 male professional 2 doses of 250 mgIkgj1 Simulation of the 2017 Bergen 2% impairment in 31 km cycling Serum acetoacetate
(2017) cyclists (V̇O2max, ketone diester 1,3-butanediol World Championship TT TT (3.7% decrease in (AcAc) concentration:
71.4 T 5.6 mLIkgj1Iminj1, acetoacetate diester, 50 and course (31.7 km) power output) 0.5 mmolILj1 Serum
5.3 T 0.3 LIminj1) 30 min before the start of TT  -OHB concentration:
0.4 mmolILj1
Evans et al. 19 cyclist (12 male -OHB salts: 0.38 gIkgj1 Submaximal incremental cycling Lower plasma glucose Peak plasma -OHB
(2018) and 7 female) Male V̇O2max: dissolved in 3.8 mLIkgj1 test of 6 steps (at power concentrations and higher concentration:
j1 j1
65.5 T 5.6 mL O2Ikg Imin plain water. Each bolus outputs corresponding to RER during submaximal 0.44 T 0.15 mmolILj1
Female V̇O2max: serving provided approximately 30%, 40%, 50%, cycling trial
54.9 T 3.6 mLIkgj1Iminj1 È18.5 g -OHB 60%, 70%, and 80%V̇O2max,
with each step lasting 8 min
Rodger et al. 12 elite cyclists (V̇O2max; 11.7 g of  -OHB salt 90 min cycling test at 80% of ~2% higher average 4 min Plasma -OHB
(2017) 68.0 T 6.7 mLIminj1Ikgj1) ingested 20 min prior to their second ventilatory maximal cycling power concentration:
the trial and halfway point threshold (VT) prior to a paced output (9 W) 0.63 mmolILj1
(45 min) during the 90-min 4 min maximal cycling test Moderate increase in mean RER
submaximal cycling test during submaximal and
maximal test
O’Malley 10 males (V̇O2max: 0.3 gIkgj1 -OHB KS Submaximal cycling exercise at ~7% lower average TT power Plasma -OHB
et al. (2017) 45 T 10 mLIkgj1Iminj1) 30%, 60%, and 90% VT output (j16 W) in ketone concentration:
followed by a 150-kJ group. Increased time to ~1Y1.2 mmolILj1
cycling TT complete TT in ketone group
(711 T 137 s vs (665 T 120 s)
RER was lower at 30% and
60% VT in the ketone group
compared with control group.
Total fat oxidation was greater

Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
in the ketone versus control.
Lower glycemia in the ketone
group immediately postexercise
and post-TT

Effects of Ketone Bodies on Endurance Exercise

affecting performance. Nevertheless, KD may be a support
in limiting weight gain in off-season, as often observed in
athletes involved in endurance events.
Ketogenic Salts and/or Esters
Taking into account the clinical studies and the empirical
experience of several athletes suggesting an ergogenic effect
of KD in endurance events requiring medium and higher
intensity, it appears that low muscular carbohydrate content
during heavy sustained exercise impairs physical perfor-
mance. Consequently, sport scientists proposed a mixed
solution that matches both the benefits of a high carbohy-
drate diet and of the presence of KB. This proposal requires
athletes to follow a high carbohydrate diet to guarantee
adequate muscular and hepatic glycogen content, and, at
the same time, to ingest a proper quantity of KS or KE be-
fore the efforts to ensure KB availability (Table) (56).
Ketone esters are compounds that are created through an
ester linkage between a ketone bodies and an alcohol,
consumption ranges from 16% to 18% with a net sparing
effect of glucose oxidation. Ingestion of KE 15 min before
the start of exercise and 45 min into the cycling trial sig-
nificantly lowered blood lactate by ~50% (~2Y3 mM) com-
pared with glucose or fat ingestion during 1 h of cycling
at 75% V̇O2max and suppressed the rise in plasma fatty free
acids and in glycemia. Theoretically, a lower lactate pro-
duction at given V̇O2 may translate to a lower metabolic
acidosis with potential ergogenic effects on high intensity
performance. It seems likely that lower lactate levels were
due to the suppression of glycolysis as indicated by skeletal
muscle biopsy which revealed a higher content of muscular
glycogen and a lower content of intramuscular tryacylglycerol
after 2 h of cycling at 70% of V̇O2max (58). These prom-
ising results were not replicated by Leckey et al. who
examined the effect of AcAc diester administration in a
setting resembling the racing conditions of elite cycling
and included top-level athletes. The athletes ate a high
carbohydrate meal pre-race supplemented with caffeine and
whereas KS comprise of the free acid form of -OHB buff-
ered with sodium, potassium, and/or calcium salts (26,57).
Indeed, ingestion of KS or KE represent a fast and effective
way to deliver nutritional ketosis for at least 2 h, with KE
better tolerated and more effective in elevating blood KB
levels compared with KS (56). Ingestion of large quantities
of KS is impractical due to resulting gastrointestinal dis-
tress, and potentially undesirable consequences of cation
overload or acidosis (15). To be effective, KS and/or KE
ingestion should not affect gastric emptying, carbohydrate
intake or cause gut distress (16). The rate of KB uptake and
oxidation by skeletal muscle during exercise at different
intensities and duration also should be considered to pro-
vide an adequate quantity of KB to exercising muscles
(15,58). Ketone ester consumption rather than KS at fasted
state with repetead administration may improve tolerabil-
diet cola prior to trial, and they followed a typical incre-
mental warm-up. Following on, the athletes performed an
all-out test mimicking the 2017 world championship 31-km
time trial course requiring maximum carbohydrate oxida-
tion rate and, consequently, placing great metabolic de-
mand on glycolysis. Ketone ester was administered È30 min
before and immediately before commencing the warm up,
and it was associated with a 2% reduction in overall per-
formance and with a 3.7% reduction in power output. From
a metabolic point of view, AcAc diester resulted in lower
lactate levels at the end of time trial (j4.5 mmolILj1;
j35%) and lower glycemia both after the ingestion of KS
and after the end of 31 km time trial compared with control
group. This evidence is consistent with the data of Cox et al.
and suggests that KS ingestion may decrease glucose con-
tribution to energy expenditure. An alternative reason
ity; moreover, ingestion of -OHB monoester rather AcAc
diester using flavored water may decrease gastrointestinal
symptoms (56,59).
The first evidence regarding the ergogenic effects of KE
supplement comes from data reported in a patent application
filed in April 2013 where the administration of a solution
containing 230 kcal of KB taken 60 min before exercise in a
fasted state improved 30-min rowing performance (averaging
1% and up to 2%) in 22 elite and subelite heavy and light-
weight male and female rowers. These improvements were
not considered significant but in professional sports races are
often won or lost with differences in performance less than
explaining both the lower glycemia and the reduction in
cycling performance may be represented by an impairment
in glycosis promoted by KS ingestion. Indeed, the alteration
of glycosis may decrease energy availability crucial in short-
term endurance performance (60). Nevertheless, all partic-
ipants reported gastrointestinal discomfort associated
with the intake of the KE and it can be suggested that
these side effects may play a role in explaining perfor-
mance impairments considering the different KE formula
used by Cox et al. which did not result in gut distress.
Finally, it should be considered that AcAc diester resulted
in serum AcAc concentration of 0.5 mmolILj1 and in serum
1% (16). Cox et al. confirmed an improvement of ~2% in the -OHB concentration 0.4 mmolILj1, much lower than plas-
distance covered in 30-min cycling time trial in the group ad- ma -OHB concentration of 2 to 4 mmolILj1 reported by
ministered with KE (573 mgIkgj1) + glucose (60% of total Cox et al. (59,61).
calories) compared with glucose alone. Indeed, the KE group Achieving an adequate ketonemia represents an essential
cycled on average 411 T 162 m further over the control group. requisite to evaluate ergogenic properties of KB; KE gen-
Ketone ester administration resulted in plasma -OHB erally provide a better gut absorption than KS, whose ad-
concentration of 2 to 2.5 mmolILj1. Nevertheless, this ministration may cause gut distress and a not sufficient
study also elucidated many effects of KE on human me- increase of ketonemia (15). Acute KS ingestion at both 60
tabolism during endurance exercise. First of all, circulating and 15 min before submaximal cycling exercise providing
-OHB levels decreased significantly when cycling inten- 0.38 gIkgj1 of -OHB (i.e., ~18.5 g -OHB) dissolved in
sity rose from 40% to 75% of V̇O2max indicating an in- 3.8 mLIkgj1 water for each bolus resulted in a significant
creasing -OHB oxidation rate, which increase from 0.35 increase in ketonemia (57). The graded cycling test
gIminj1 at 40% V̇O2max to 0.5 gIminj1 at 75% of V̇O2max. consisted of six stages of 8 min in duration. Ketonemia
The estimated amount of -OHB oxidation to total oxygen appears to also be affected by the intensity and the length of

www.acsm-csmr.org Current Sports Medicine Reports 449

Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
exercise; indeed, the highest plasma -OHB concentration
after KS ingestion was observed during the last stage of
exercise at 0.44 T 0.15 mmolILj1. Ketone salt administra-
tion brought about a significant decrease in glycemia
compared with the control group at all stages throughout
exercise (i.e., 30% V̇O2max, j0.19 T 0.36 mM, 40%
V̇O2max, j0.21 T 0.43 mM, 50% V̇O2max, j0.27 T 0.40
mM, 60% V̇O2max, j0.21 T 0.39 mM, 70% V̇O2max,
j0.17 T 0.54 mM, and 80% V̇O2max, j0.39 T 1.24 mM)
and an elevation in RER for intensity up to 60% V̇O2max,
being È0.03 higher in the KS group than control group.
The effects of KS on RER at higher intensity were negligible
and not significant, being È0.01 higher in the KS group
compared with control group (57). These outcomes suggest
the contribution of KB to energy expenditure during exer-
cise and KB sparing effect on glucose oxidation in well-
trained cyclists (57). Nevertheless, the majority of athletes
skeletal muscle Indeed, total glucose uptake was 1.26
in the control group and 1.66 gIkg j1 in KE group; si-
multaneously the increase in postexercise glycogen was
114 mmolIkg j1Imin j1 in the KE group compared with
70 mmolIkgj1Iminj1 in the control group These results seem
to be associated with an increased insulin release, with
insulin concentration twofold higher by the end of the
clamp in the ketone group compared with control group
(16 T 3 mUIILj1 for control glucose and 31 T 6 mUIILj1).
Nevertheless, this augmentation of insulin release in re-
sponse to KE administration requires the elevation of
blood glucose levels. Furthermore, an increase in insulin
level also may prevent muscular catabolism after exhaus-
tive exercise (16,63). Nevertheless, this effect on muscular
glycogen replenishment were not confirmed by Vandoorne
et al. In this study, ingestion of 1.5 gIkgj1 of KE supple-
ment and of a high dose mixture of carbohydrate and
(68%) reported gastrointestinal distress limiting, if con- protein raised plasma level of -OHB to ~ 5 mmolILj1 but
firmed, the potential effectiveness of KS ingestion (57). it did not affect glycogen resynthesis after exhaustive ex-
Similarly, the ingestion of KS containing 0.3 g -OHBIkg
30 minj1 before the start of the exercise significantly de-
creased glycemia immediately postexercise and posttime
trial (i.e., ~0.3Y0.7 mmolILj1 lower than the placebo con-
dition) and RER at 30% (i.e., ~0.85 in the placebo group vs
~0.83 in the ketone group) and 60% ventilatory threshold.
Ketone salt administration alters substrate oxidation low-
ering total carbohydrates oxidation and augmenting total
fat oxidation rates with a net glucose-sparing effect; how-
ever, KS administration impaired cycling time trial perfor-
mance resulting in a significant decrease of power output
by ~7%. Time to complete time trial was ~8% longer in KS
than the control group (711 T 137 s vs 665 T 120 s; P = 0.03).
ercise. Subjects were asked to warm up by unilateral cy-
cling with the right leg on a cycle ergometer. The subjects
then started an intermittent exercise protocol aimed to
deplete muscle glycogen in the right leg by unilateral knee-
extensions (70-Y130- knee-angle) at a rate of 0.5 Hz.
Subjects first performed an exercise bout, during which
they produced a mean power output as high as possible for
5 min. Thereafter, they did 9 series of 30 knee-extensions at
30% of 1RM, followed by 5 series of 6 contractions at 70%
of 1RM. The contraction series was interspersed by 30-s
passive rest intervals (64). Notwithstanding, KE administra-
tion markedly augmented mTORC1 signaling increasing
phosphorylation of p-S6K1and 4E-BP1. This observation
It should be considered that racemic mixture of -OHB suggests that KE may improve anabolic response to exercise
resulted in lower concentrations of blood -OHB (~1Y1.2 increasing protein synthesis in C2C12 myotubes, being
mmolILj1) than KE supplements (~3 mmolILj1) (60). In a mTORC1 a master regulator of protein synthesis in human
study led by Rodger et al. administration of a supplement skeletal muscle (64).
containing 11.7 g of -OHB salt diluted with 100 mL of KE supplementation also seems to be able to suppress
sugar-free lemonade increased average blood -OHB con-
centrations from 0.20 mmolILj1 to 0.63 mmolILj1 far below
the levels required for therapeutic ketosis (Q2 mmolILj1). The
supplement was ingested 20 min before the trial and at the
halfway point (45 min) during the 90-min submaximal cy-
cling trial. Subjects were asked to cycle for 90 min at 80% of
their second ventilatory threshold, prior to a 4-min maximal
cycling test, separated by 2 min passive rest. It is likely that
low ketonemia may explain the absence of significant change
between placebo and treated group, apart from a not signif-
icant increase in RER (0.87 T 0.05 vs 0.85 T 0.03) during
submaximal exercise and a significant increase in mean RER
during the maximal test (1.01 T 0.07 vs 0.96 T 0.05) in the
treated group compared with the control group. Also, a sig-
nificant increase in power output was not observed in treated
group (364 T58 Wvs 355 T46 W) (62).
Finally, it has been observed that ingestion of KE beverage
containing 0.573 mLIkgj1 of the KE (R)-3-hydroxybutyl (R)-
3-hydroxybutyrate in well-trained athletes after exhaustive
exercise consisting in cycling at intermittent intensity for
2-minintervals, alternating 90% peak power efforts with
50% peak power recovery, is able to increase muscle gly-
cogen content by 50% and glucose uptake by 32% during
hyperglycemic clamp enhancing glycogen synthesis in
450 Volume 17 & Number 12 & December 2018
Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
appetite decreasing ghrelin and representing a potential
support for athletes willing to lose weight in those sports
where weight plays a pivotal role (65).
Conclusions
It can be concluded that long-term KD may be favorable
for endurance athletes, during the preparatory season, when
a high volume and low to moderate intensity of training
loads are performed during training. Indeed, KD may pro-
vide a high amount of calories avoiding the ingestion of a
great quantity of carbohydrates which are able to cause
gastrointestinal distress and hyperinsulinemia with delete-
rious effects on fat oxidation. The KD is able to maximize
the increase of FatMax during exercise and the reduction of
body mass and fat content promoted by high volume
training. Furthermore, keeping in mind that KD represents
a fat-rich diet, a well-formulated KD may provide a high
amount of marine omega-3 coming from fatty fish (i.e.,
mackarel, salmon, tuna). Omega-3 fatty acids may decrease
inflammation, insulin resistance, and postexercise muscle
damage, and they also may increase the anabolic response
to training stimuli and FatMax (36,53). The increased reli-
ance on fat oxidation promoted by KD seems to increase
mitochondrial function, augmenting the adaptive response
Effects of Ketone Bodies on Endurance Exercise
Figure: Possible aims of further research on ketone metabolism in endurance performance.
to oxidative stress generated in oxidative processes during
mitochondrial energy production (31). However, KD seems
not be able to sustain moderate-high exercise activity lim-
iting exercise performance because of the low intake of
carbohydrates in KD does not guarantee an adequate con-
tent of muscle and hepatic glycogen stores and reduces the
capacity to use carbohydrate resulting from inhibition of
pyruvate dehydrogenase (PDH) (66). Reduced glycolytic flux
sustained by decrease of PDH activity may impair perfor-
mance during high intensity efforts that rely heavily on energy
coming from glycolytic pathways (28). Otherwise, elevated
ketone concentrations may suppress glycolysis without
causing any impairment in glycolytic flux but simply because
ketones metabolism may hold hierarchical preference over
carbohydrate metabolism. A decreased reliance on glycolysis
may lower lactate production and attenuate accumulation of
hydrogen ion and other metabolic by-products partly re-
sponsible to fatigue during high intensity efforts; moreover, a
reduction of glycolytic metabolism may contribute to spare
muscle glycogen stores (28,58).
The potential ergogenic effects of exogenous intake of KE
or KS may be related both to the suggested higher efficiency
of KB in relatively short endurance activities where glyco-
gen stores are not supposed to be depleted and to KB met-
abolic role as alternative fuel source in whose events where
glycogen stores are likely to become depleted for a glucose-
sparing effect. Theoretically, KB also should be able to
support higher metabolic intensity compared with fat con-
sidering the higher RER. Ketone esters or KS also could be
administered to increase postexercise muscle glycogen syn-
thesis when co-ingested with carbohydrate after exhaustive
exercise to enhance the recovery process (Fig.). Finally,
suppression of appetite after KE ingestion may be helpful to
decrease body fat (Fig.). However, it seems likely that a
necessary prerequisite of any potential ergogenic effect of
KB is reaching blood ketone concentrations 92 mmolILj1,
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Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
and it also should be taken into consideration the meta-
bolic differences and distinct pharmacokinetics properties
between the ketone molecules delivered by exogenous KS
and KE and this can impact their effects on exercise per-
formance (56,59). It is likely that optimal window of
ketonemia ranges from 1 to 3 mmolILj1 for a proposed
performance benefit (61). Indeed, KS administration gen-
erally failed to achieve ketonemia 92 mmolILj1 and this
evidence may explain the lack of ergogenic effects. There-
fore, it is necessary to evaluate carefully ketonemia when
evaluating ergogenic properties of KB (Fig.). It is crucial to
elucidate if KB capacity of sparing carbohydrate reserves is
due to a reduction of glycolytic capacity via inhibition of
PDH and phosphofructokinase-1 (PFK-1) by increases in
NADH:NAD+, acetyl-CoA:CoA ratio or citrate (13). In
this case carbohydrate utilization would be impaired by
KB, limiting exercise performance at higher intensity in
those physiological conditions that rely almost solely on
anaerobic glycolysis or high glycolytic flux for ATP pro-
duction (Fig.). Similarly, the suggested inhibition of lipol-
ysis promoted by KB via inhibition of the nicotinic acid
receptor (PUMA-G) should be carefully evaluated as it may
impair endurance performance, as fatty acids are the pre-
ferred fuel source at low-moderate intensity (26). Other
studies are warranted to elucidate the effects of KB on
substrate selection which represents the basic tenet to ex-
plain the interaction between KB and the human endurance
performance (Fig.). So far, only the effects of acute inges-
tion of KE or KS have been investigated; it remains to be
determined if chronic administration of KE or KS may
cause different effects on human metabolism and perfor-
mance. It can be hypothesized an adaptive metabolic process
to KE or KS administration that may enhance responsiveness
to KS or KE ingestion (Fig.). Finally, it should be noted that
top-level athletes may respond differently to KS and/or KS
ingestion compared with sedentary subjects considering the
Current Sports Medicine Reports 451
impact of genetics and of training on energy substrate me-
tabolism and therefore further research is required to define
these differences.
The authors declare no conflict of interest and do not
have any financial disclosures.
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