NUTRITION AND ERGOGENIC AIDS
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Nutritional Ketosis with Ketogenic Diets or
Exogenous Ketones: Features, Convergence,
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and Divergence
Angela M. Poff, PhD;1 Andrew P. Koutnik, PhD;1,2 and Brendan Egan, PhD2,3
Abstract
Athletes, clinicians, and practitioners are increasingly interested in the
proposed performance and therapeutic benefits of nutritional ketosis
(NK). NK is best operationally defined as a nutritionally induced metabolic
state resulting in blood β-hydroxybutyrate concentrations of ≥0.5 mM.
Most tissues readily metabolize ketone bodies (KBs), and KBs in turn regu-
late metabolism and signaling in both a systemic and tissue-specific
manner. During fasting, starvation, or ketogenic diets, endogenous synthe-
sis of KBs is amplified resulting in a state of NK. Orally administered exog-
enous ketone supplements rapidly elevate circulating KBs and produce a
similar, but far from identical, metabolic state. NK results in a number of
convergent features regardless of endogenous or exogenous induction;
however, important differences also are observed. The implications of NK
across health, disease, and performance is rapidly becoming more evident,
thus acknowledging the convergent and divergent features of NK is critical
for fully understanding the potential utility of this metabolic state.
Introduction
Athletes, clinicians, and practitioners often seek novel nutri-
tion strategies to optimize health and performance. Altering
substrate availability through dietary manipulation has been
the subject of increasing interest as a strategy to modulate
training adaptations, and competitive performance (1,2). Die-
tary supplements also demonstrate potential for augmenting
the adaptive response to exercise training (3), in addition to
their traditional role as ergogenic aids (4). A topic of intense
interest in sports medicine and beyond is the proposed perfor-
mance and therapeutic benefits of nutritional ketosis (NK)
(1,5–8). Because of the multifaceted effects of NK, its proposed
utility has led to an expansion of research into these effects in
1
Department of Molecular Pharmacology and Physiology, University of
South Florida, Tampa, FL; 2Florida Institute for Human & Machine Cognition,
Pensacola, FL; and 3School of Health & Human Performance, and National
Institute for Cellular Biotechnology, Dublin City University, Dublin, IRELAND.
Address for correspondence: Brendan Egan, PhD, Dublin City University
Dublin, Ireland; E-mail: brendan.egan@dcu.ie.
1537-890X/1907/251–259
Current Sports Medicine Reports
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athletic contexts, general health, and a di-
verse class of pathologies (8).
NK is best operationally defined as a
nutritionally induced metabolic state
resulting in blood b-hydroxybutyrate
(bHB) concentrations of 0.5 mM, re-
gardless of endogenous or exogenous
induction, or the systemic metabolic
or signaling effects elicited (1,9). bHB
along with acetoacetate (AcAc) and ace-
tone are collectively termed ketone bod-
ies (KBs). bHB is present in the body as
R-bHB and S-bHB enantiomers of bHB
(interchangeably termed D-bHB and L-
bHB, respectively), with the R-enantiomer
being the predominant circulating KB.
NK can be achieved “endogenously”
through dietary manipulation such as
prolonged fasting or ketogenic diets (KDs), or “exogenously”
with the oral administration of exogenous ketone supple-
ments (EKs) (10). In athletic contexts, recent reviews have
made the case for (1) and against (11) KDs for exercise perfor-
mance. For EKs, however, despite initial positive findings
(12), many studies since have failed to demonstrate benefits
to physical performance (13).
While both approaches produce NK and share some com-
mon metabolic features and consequences, there are several
divergent features of these approaches that should be recog-
nized (Table) and have important implications for perfor-
mance and therapeutics. Yet in our experience, it is
increasingly common for clinicians, practitioners, and the gen-
eral public to conflate these approaches. A recent review has
attempted to disentangle the approaches to NK in the context
of exercise metabolism (10), and the purpose of the present re-
view is to provide an overview of methods to produce NK, the
metabolic effects of KBs in key target organs, and features of
convergence and divergence between endogenous or exoge-
nous ketosis.
KB, Ketogenesis, and NK
Multiple physiological states increase the synthesis and cir-
culation of the KBs. When glucose availability is low, and
Current Sports Medicine Reports 251
 Table.
Features of convergence and divergence between NK achieved by KDs compared with EKs.
KDs
Total KB concentration ~0.5 to 5 mM (variable)
R-βHB/AcAc 2:1 to 4:1
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Time course of elevation in KB Days to weeks
concentrations
Adaptation period for metabolic Suggested to be months to years; termed
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effects “ketoadaptation”
Appetite Suppressed
Glucose availability Dietary intake of CHO <5% of EI
Circulating glucose concentrations lowered
Lipolysis Elevated
Elevated FFA conc.
Muscle protein synthesis Unknown
Fat utilization during exercise Markedly elevated
IMTG utilization elevated
CHO utilization during exercise Attenuated at high intensities
Blood lactate concentrations Unchanged or higher at same exercise intensity
compared to mixed/high CHO diet
EI, energy intake; IMTG, intramuscular triglyceride; KDE, R,S-BD AcAc ketone diester; KME, R-BD R-bHB ketone monoester.
insulin is suppressed, an elevation in fatty acid oxidation in he-
patic mitochondria results in an amplification of ketogenesis
(Fig. 1). During prolonged fasting, starvation, severe calorie
restriction, or consumption of a KD, the pancreas produces
less insulin and more glucagon, resulting in increased rates
of adipose tissue lipolysis and an elevation of circulating keto-
genic precursor metabolites, namely, long-chain fatty acids
(LCFAs).
The liver synthesizes the majority of KBs in the body, but
does not readily consume them, ensuring KBs can be utilized
by extrahepatic tissues (Fig. 1). Once in circulation, KBs are
rapidly taken up by the extrahepatic tissues, with the brain,
skeletal muscle, and heart, being avid users. Rates of ketone
utilization and synthesis are similar in normal weight adults
consuming a standard diet, keeping blood KB concentrations
typically 0.3 mM, even following an overnight fast (14).
Within a few days of fasting or consumption of a KD, KB con-
centrations rise by approximately 10-fold due to increased ke-
togenesis, and can then serve as an alternative fuel source to
glucose for most of the body (15).
Although NK is operationally defined as blood bHB con-
centration of 0.5 mM (1), there is no obvious metabolic
“switch” that occurs at this threshold. Rather it is indicative
of a state in which KBs serve as a prominent metabolite,
and important substrate to overall energy supply on a
whole-body level (1,14,16). For example, infusion of R-bHB
in healthy young men to a concentration of just ~0.2mM to
0.5 mM results in reduction in estimates of hepatic glucose
output and adipose tissue lipolysis, and an increase in cerebral
R-bHB uptake (17). The magnitude of elevation of R-bHB in
response to ketogenic stimuli varies depending on factors, in-
cluding age, sex, height, body mass and composition, aerobic
fitness and physical activity level, caloric intake, and even
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EKs
Ketone salts and KDE: ~0.3 to 1.0 mM
KME: ~3.0 to 6.0 mM
3:1 to 6:1
Minutes to hours
Unknown
Suppressed
Performance: coingested with CHO (~1
g·min−1 CHO)
Health: acutely lower fasting glucose and
attenuate postprandial glycemia
Attenuated
Acute lowering of FFA conc.
Increased
Measurement confounded
IMTG utilization elevated
Attenuated at high intensities
Attenuated rise during exercise
individual metabolic and genetic variability (1,5,7,18). In
pathological conditions most typically associated with insuffi-
cient insulin, KBs can accumulate to produce a state of
ketoacidosis wherein R-bHB is often 10 mM and blood
pH declines and produces a life-threatening metabolic state
known as diabetic ketoacidosis (18). In contrast, the normal
physiological range of NK is commonly observed to be 0.5
to ~5 mM R-bHB (1,5,7).
Ketogenic Diets
NK has long been used to manage disease, regardless of the
terminology used to describe it. Texts from antiquity reference
anticonvulsant effects of fasting, and throughout the 19th and
20th centuries, ketogenic-type diets were described to benefit
patients with metabolic disorders, such as diabetes mellitus.
The “Classical Ketogenic Diet” developed at the Mayo Clinic
in 1921 was restricted in protein (1 g·kg−1 body weight) and
carbohydrate (CHO) (10 g to 15 g·d−1), with the remainder
of calories from fat. The efficacy of this diet in epilepsy was es-
tablished, and around the same time, KDs were being used to
prolong the lives of type 1 diabetes mellitus patients. How-
ever, with the advent of antiepileptic drugs (AEDs) and the
Nobel Prize-winning discovery of insulin, the classical KD de-
clined in its therapeutic use despite its demonstrated efficacy.
Interest in KDs resurged in the 1990s as it became apparent
that the KD was a useful tool for treating patients that failed to
respond to AEDs (7), and evidence was accumulating that
KDs may be efficacious for a host of metabolic disorders
(19). Intrigued by the emerging and multifaceted mechanisms
of therapeutic ketosis, other fields have expanded research ef-
forts into NK. Encouraging data spurred public interest, espe-
cially in relation to widely applicable topics like weight loss
and exercise performance, leading to mainstream popularity.
Ketogenic Diets versus Exogenous Ketones
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Figure 1: Pathways of ketogenesis in liver and ketolysis in extrahepatic tissues, and methods to produce NK. Ketogenesis primarily occurs in
the hepatocyte mitochondria wherein two acetyl-CoA, the primary metabolite generated during beta-oxidation of fatty acids, combine in a reaction
catalyzed by ACAT to form AcAc-CoA. AcAc-CoA reacts with another acetyl-CoA to produce HMGCoA via catalysis by HMGCS. HMGCoA is then
cleaved by HMGCL to produce AcAc and acetyl-CoA. AcAc can be reduced by to produce R-βHB or can undergo spontaneous decarboxylation to
produce acetone. Ketogenesis also occurs in small quantities in cells such as astrocytes, intestinal stem cells, and cardiomyocytes. NK can be
achieved by dietary means incorporating CHO restriction, for example, fasting and KDs, or by exogenous ketone supplements that either directly
increase blood R-βHB concentrations (e.g., ketone salts), or comprise ketogenic precursors (MCFAs, BD), or a combination of a KB and a ketogenic
precursor in the form of a ketone ester. During ketolysis in extrahepatic tissues, R-βHB is reoxidized to AcAc, before covalent activation of AcAc by
CoA is catalyzed by OXCTresulting in generation of AcAc-CoA. Two molecules of Ac-CoA are liberated by thiolytic cleavage of AcAc-CoA by ACAT,
after which Ac-CoA is incorporated into the TCA cycle. However, distinct from ketolysis, R-βHB also can act as signaling molecule through
interaction with cell surface receptors and regulators of gene expression (see Fig. 2). ACAT, thiolase; ADH, alcohol dehydrogenase; BDH,
3-hydroxybutyrate dehydrogenase; HMGCoA, 3-hydroxy-3-methylglutaryl-CoA; HMGCS, 3-OH-3-methylglutaryl-CoA synthase; HMGCL
HMGCoA lyases; OXCT, succinyl-CoA:3-oxoacid CoA transferase.

In the most general sense, a KD can be defined as any diet
that amplifies ketogenesis, not just the strict therapeutic KDs
used in early medical literature. There are now a number of
defined alternative KDs including the medium chain triglycer-
ide (MCT) KD, the Modified Atkins Diet, and the Low Glyce-
mic Index Treatment Diet. Each dietary approach induces a
state of NK, but are formulated with more liberal allowances
of protein and CHO to improve palatability and compliance
(20). Regardless of the specific alterations involved, it is now
clear that KDs now expand far beyond the original strict 4:1
ratio of fat-to-protein and CHO and can be customized to
meet individual preferences and tolerability without necessar-
ily sacrificing benefits. Indeed, several studies suggest that
these alternative KDs can elicit similar seizure control with im-
proved compliance and palatability (20).
Exogenous Ketone Supplements and Ketogenic
Precursors
Hopes of extending NK to a wider range of applications,
and recognition of the pleiotropic effects of KBs, has led to
the development of ingestible EKs (7,10). Until their develop-
ment, the only reliable means of elevating circulating KBs out-
side of a research setting was through dietary restrictions that
can present limitations regarding feasibility and practicality.
EKs were developed to elicit a dose-dependent elevation of
R-bHB and/or AcAc regardless of dietary macronutrient in-
take. EKs allow for rapid and controlled induction of ketosis
and may offer an alternative tool to induce NK in individuals
unable, uninterested, or unwilling to consume a KD.
Moreover, some benefits of NK can be attributed to mech-
anisms induced by the KBs themselves, rather than the other
metabolic features of KDs. Thus, EKs could mimic beneficial
effects of NK for specific applications, ranging from health op-
timization, to cognitive and physical performance, to medical
therapeutics. Furthermore, there may be situations wherein
KDs are contraindicated, with EKs providing the only feasible
tool to induce NK (7,21).
A large number of natural and synthetic EKs are being de-
veloped and tested (22,23). The various formulations have
distinct properties in terms of degree and duration of ketosis

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 induced, and even in regard to metabolic and signaling effects
(22). Therefore, research is needed and underway to elucidate
the utility and application of individual EKs, and many are be-
ing evaluated for safety and efficacy for performance enhance-
ment (10), as well as therapeutic potential (8).
Ketone salts
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The most direct method of exogenously inducing NK
would be to administer isolated KBs. However, R-bHB and
AcAc in their free acid form can be unstable, expensive, and
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ineffective at producing sustained ketosis. Thus, the ketone
acids can be buffered with sodium or other electrolytes to en-
hance efficacy and prevent overload of any single mineral. Bal-
anced mineral formulations of ketone salts may even be useful
in attenuating symptoms of mineral depletion that occur early
in keto-adaptation, but at large doses, excessive mineral in-
take could lead to gastric hyperosmolarity or other adverse ef-
fects, such as inappropriate sodium load. Ketone salts have
been the subject of several investigations for ergogenic poten-
tial in a variety of exercise challenges, but to date, none have
produced performance benefits (13).
Medium chain triglycerides
MCTs contain fatty acids 6 to 12 carbons in length
(medium-chain fatty acids [MCFAs]). Compared with LCFAs
being absorbed via the lymphatic system, MCFAs can be ab-
sorbed via hepatic portal circulation and enter the hepatic mi-
tochondria without requiring carnitine transport, where they
are rapidly metabolized to acetyl CoA, and subsequently, to
KBs. Therefore, MCTs are considered ketogenic fats as they
result in ketogenesis without requiring dietary CHO restric-
tion. A known side effect of high MCT consumption is gastro-
intestinal discomfort, which can be mitigated by a slow,
progressive introduction over a 1- to 2-wk period (24).
Combination ketone salts and medium chain triglycerides
One promising combination of EKs is that of ketone salts
and MCTs, which have been administered most typically in
1:1 or 1:2 ratios. Animal research suggests that this method re-
sults in a more sustained induction of NK because KBs are de-
livered directly in the form of ketone salts, while ketogenesis is
stimulated by MCTs (22). This approach allows for lower
dosing of individual components, with lesser potential for side
effects from high intake of individual EKs or minerals. This
formulation is available in popular commercialized products
but has not been extensively evaluated in human trials.
1,3-Butanediol
1,3-butanediol (BD) is a Food and Drug Administration
(FDA)-approved organic diol used as a food flavoring solvent
and has been considered as a potential synthetic food for
long-duration space missions (25). BD is metabolized by the
liver to produce bHB, and in rodents, R,S-BD was demon-
strated to produce a dose-dependent elevation of KBs in a ra-
tio of 6:1 of R-bHB to AcAc (26). Extensive toxicology studies
in a variety of preclinical models show that BD is safe and tol-
erable (27). BD is an EK itself and also is used as a backbone in
the synthesis of some ketone esters. Like ketone salts, investi-
gations, to date, of the ergogenic potential of R-BD in trained
male athletes demonstrate a lack of benefit in endurance exer-
cise settings (13).
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Ketone esters
Several existing synthetic ketone esters (KEs) potently in-
duce a dose-dependent elevation in blood KB concentration.
KEs are held together by ester bonds that are cleaved by gas-
tric esterases to liberate KBs in their free acid form from a
backbone molecule. The choice of backbone molecule can
vary, but often is a ketogenic precursor molecule, such as
R-BD or R,S-BD. KEs are currently the most potent EKs
available in terms of reliably producing NK, a promising fea-
ture but one that also requires a thorough investigation of
their long-term safety. Encouragingly, some of the most
well-characterized KEs have received Generally Recognized
as Safe (GRAS) status by the FDA, such as the R,S-BD AcAc dies-
ter and R-BD R-bHB monoester, and the latter appears safe and
well tolerated at known doses in healthy adults, whether acutely
(12,23,28,29) or daily when consumed for up to 28 d (30).
bHB enantiomers
Currently, most commercially available ingestible EKs,
with the exception of the R-BD R-bHB monoester and some
specific ketone salt products, are a racemic mixture of R-bHB
and S-bHB enantiomers of bHB. This is largely because the syn-
thesis of racemic mixtures is more affordable than the pure en-
antiomers. R-bHB is considered the endogenous metabolite
and an efficient fuel for ATP production. S-bHB is biologically
present in small quantities, but does not contribute significantly
to energy production and after ingestion of racemic EKs S-bHB
remains elevated in circulation longer than R-bHB (23). De-
spite divergent metabolic roles, R-bHB and S-bHB have been
shown to share similar molecular interactions and intracellular
signal transduction cascades (31), but the specific effects of the
two enantiomers remain a hotly debated topic.
Metabolic Effects of KBs on Target Organs
AcAc and R-bHB are pleiotropic signaling molecules and
influence a diverse range of physiological processes (Fig. 2)
(9). As such, KBs elicit multiorgan effects that can be similar
or differ widely depending on the tissue of interest. Here we
will briefly consider effects of KBs on brain, skeletal muscle,
and adipose tissue.
Brain
In the adult brain, glucose is typically the predominant and
preferred fuel source, but as long as half a century ago, KBs
were demonstrated to replace glucose as the predominant fuel
during starvation (i.e., low glucose availability), supplying up
to two thirds of the brain's energy requirements under such
conditions (32). More recently, experimental elevation of R-
bHB (infusion) or KBs (MCT ingestion) increases KB uptake
and utilized by the brain in proportion to the circulating con-
centration (14,17). In turn, elevated uptake and utilization of
KBs elicits a reduction in brain glucose utilization (14). KBs
are, therefore, an alternative and prominent substrate in the
brain when circulating concentrations are elevated to the level
of NK. These developments have ignited interest in NK as a
unique strategy to provide additional substrate during times of
limited glucose availability or impaired brain bioenergetics, such
as those that are featured in conditions as varied as epilepsy,
Alzheimer's disease, and traumatic brain injury (TBI) (33,34).
Interestingly, NK enhances, or attenuates the decline in,
cognition in a variety of preclinical and human settings, ranging
Ketogenic Diets versus Exogenous Ketones
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Figure 2: Effects of ketone bodies on various tissues and organs. Ketone bodies βHB, AcAc, and/or acetone have been described to facilitate
multiple systemic and/or tissue specific effects which extend beyond extra-hepatic energetic needs. These pluripotent effects include direct or in-
direct epigenetic regulation, reduced oxidative stress via antioxidant production, increased and/or neutral anabolic hormone secretion, increased
skeletal muscle anabolic and regenerative signaling, decreased skeletal muscle catabolic signaling, altered tissue lipid metabolism and energetic
efficiency, reduced methylglyoxal, multi-metabolite and systemic metabolic regulation, altered hunger hormones, altered intestinal stem cell fate,
function, and regeneration, increased cardiac tissue hydraulic efficiency, neuroprotective mechanisms, and reduced cellular inflammatory signal-
ing. Readers interested in further details on the effects described are directed to several other excellent reviews (5–7,9,35–38). COX-2, cycloox-
ygenase-2; ERK, extracellular signal-regulated kinases; FOXO3a, Forkhead Box O3a; GABA, glutamate and gamma-aminobutyric acid; GPR, G-
protein-coupled receptor; HCAR2, hydroxycarboxylic acid receptor 2; HDAC, histone deacetylase; IGF-1, insulin-like growth factor-1; MEK,
mitogen-activated protein kinase/extracellular signal-regulated kinases; MnSOD, magnesium-dependent superoxide dismutase; mTORC, mecha-
nistic target of rapamycin; NLRP3, nucleotide-binding protein, leucine-rich-containing family, pyrin domain-containing-3.

from young to old, and including athletic settings, neurological
disorders, and psychiatric disorders (34). Of particular interest
to the sports medicine community is the potential of NK to
mitigate adverse sequelae following traumatic brain injury
(TBI). Preclinical studies of moderate and severe TBI via
blunt force trauma strongly support a therapeutic role, show-
ing reduced tissue death and cerebral edema, and improved
cognition (33). Clinical studies have established safety of
the KD in human TBI patients with diverse injury type with
nonspecified origin (33). However, due to the diverse nature
of TBI across athletic contexts and nascent interest in NK for
TBI, larger studies across multiple settings are needed to eval-
uate the efficacy of NK in sport-related TBI.
Skeletal muscle
AcAc and R-bHB exert metabolic actions, particularly in
relation to substrate utilization and anticatabolic processes,
in many organs (16) (Fig. 2). In skeletal muscle, for instance,
KB infusion results in inhibition of glycolysis and stimulation
of protein synthesis in skeletal muscle (39,40) and attenuation
of muscle protein breakdown (41). In vitro studies demonstrate
attenuation of pathways of muscle atrophy with KB treatment
of skeletal muscle (42), and an increased mitochondrial func-
tion and reduction of selected ceramide species (43). In rodent
skeletal muscle, bHB impairs insulin-stimulated glucose up-
take, but this effect is produced by R-, but not S-bHB, and oc-
curs in oxidative, but not glycolytic, skeletal muscle (44). Thus,
a better understanding the effects of these bHB enantiomers on
skeletal muscle metabolism will be important given the afore-
mentioned prevalence of racemic EKs. During exercise, ele-
vated demands for ATP resynthesis in skeletal muscle are the
primary driver of increases in rates of whole body substrate uti-
lization (45). Ketosis achieved by ingestion of R-BD R-bHB
monoester prior to exercise may attenuate CHO utilization,
and increase reliance on intramuscular lipids during exercise
(12), likely via the inhibition of adipose tissue lipolysis and con-
sequent reduction in circulating free fatty acids (FFAs).
Adipose tissue
KBs also are known to directly and rapidly modulate lipid
metabolism. R-bHB binds HCAR2/GPR109a and results in
the inhibition of lipolysis by attenuating NF-kB activity in

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 adipose tissue (46). To this end, EK administration, whether
as ingestion of R-BD R-bHB monoester or infusion of R-b
HB or R,S-bHB, reduces FFA and glycerol concentrations, with
or without changes in insulin concentration (12,17,23,29,47), a
phenomenon that appears to be dose-dependent (21). Con-
versely, AcAc binds GPR43 to upregulate lipolysis via increas-
ing lipoprotein lipase activity in adipose tissue (48). These
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mechanisms and direct effects of KBs demonstrate differential
regulation of adipose tissue lipolysis that may be dependent
on factors such as the duration of fasting and KDs, or the type
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of EK administered. For example, prolonged fasting and KDs
upregulate lipolysis and FFA mobilization in contrast to admin-
istration of EKs that primarily raise R-bHB concentrations
given that R-bHB inhibits lipolysis via HCAR2/GPR109a
(46) and acutely lowers circulating FFAs both at rest and during
exercise (12). However, chronic administration of EKs that re-
sult in significant elevations in AcAc concentrations have re-
sulted in adipose tissue atrophy that is not wholly explained
by reduced calorie intake (49), suggesting that much remains
to be learned on regulation of adipose tissue lipolysis during
NK induced by different means.
Points of Convergence and Divergence in NK: Comparing
and Contrasting NK Induced by Endogenous versus
Exogenous Means
These divergent effects of KDs and EKs on adipose tissue li-
polysis illustrate an important and often neglected aspect of
NK—recognition of overlapping and unique features of en-
dogenous versus exogenous induction of NK. In fact, there
are many known points of convergence and divergence be-
tween the two approaches (Table), with many questions re-
maining about metabolic and molecular regulation under each.
Dietary requirements, safety, and compliance
Inherent to traditional KDs is the restriction of CHO intake
with secondary considerations for protein quantity as both
stimulate insulin secretion. However, EKs require no direct di-
etary CHO restriction. While data suggest that KDs and EKs
can both be safe and tolerable in healthy individuals, only
KDs have undergone extensive evaluation in pathological
contexts. KDs have similar compliance issues as other dietary
strategies (50), while compliance in short-term daily supple-
mentation studies using EKs is reportedly high (30).
Circulating KB concentrations and bHB/AcAc ratio
KDs generally elevate circulating R-bHB to a range of ~0.5
mM to 3.0 mM at a ratio of approximately 4:1 R-bHB/AcAc
(18). Typically, ketone salts, MCTs, and R-BD elevate R-bHB
by approximately 0.3 mM to 1.0 mM above resting values (13),
with their impact on circulating R-bHB being limited primar-
ily by factors including the gastric tolerance of the dose pro-
vided of the different molecules, the capacity for hepatic
conversion of BD to bHB, and proportions of the R- and S-en-
antiomers in racemic formulations. The elevation in circulat-
ing KBs and the respective contributions of AcAc and R-b
HB after ingestion of KEs depends on the composition of the
specific KE ingested. For example, the R-BD R-bHB monoes-
ter produces little change in AcAc concentrations but eleva-
tions of R-bHB in the range of ~3 mM to 6 mM at tolerable
doses (23), and concentrations during exercise in the ~1.5 mM
to 3 mM range (13). These lower concentrations likely
256 Volume 19  Number 7  July 2020
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reflect KBs being oxidized during exercise (12). Conversely,
the R,S-BD AcAc diester elevates both R-bHB and AcAc in a
dose-dependent manner in animal models (22), but little hu-
man data are available on this agent to date.
Onset, timing, and adaptation
KDs require a number of days before the amplification of
rates of ketogenesis produces sustained NK, whereas ingestion
of EKs elevate KB concentrations within minutes to hours.
With prolonged adherence to KDs, the phenomenon termed
“keto-adaptation” is proposed to occur after weeks to
months. Although objective markers of keto-adaptation re-
main to be defined, the process refers to the symphony of
physiologic and metabolic changes that accompany a shift
from glucose-based to fat-based metabolism and requires var-
iable amounts of time depending on the metabolic conse-
quence of interest (1,10). Whether there are temporal
adaptive responses to the metabolism of EKs with repeated
consumption remains to be explored.
Direct effects of KBs
Importantly, features related to direct effects of KB metabo-
lism and signaling properties tend to be a point of convergence
between KD- and EK-induced NK. The superior metabolic ef-
ficiency of KBs has been known for decades, with studies
showing that R-bHB and AcAc can uniquely increase work
and ATP production while decreasing oxygen consumption
(51) because of molecular changes resulting in an increase in
the energy of ATP hydrolysis (52). Thus, KBs are often consid-
ered a more efficient fuel for ATP production compared with
glucose and fatty acids. Once in circulation, KBs elicit a host
of direct signaling effects that are not dependent on their me-
tabolism and therefore likely to occur regardless of the method
of NK induction, but in turn may be dependent on the circu-
lating concentration achieved. This includes the ability to reg-
ulate intracellular metabolism by binding and activating
HCAR2 receptor signaling, the ability to regulate epigenetic
and redox function by acting as histone deacetylase inhibitors,
and the ability to regulate cellular regeneration in response to
insult (9).
Regulation of appetite
KDs produce subjective reports of reduced appetite and the
desire to eat even in calorie deficit, and these effects have been
attributed to the state of NK (53). Similarly, acute NK pro-
duced by the ingestion of the R-BD R-bHB monoester reduced
subjective ratings of appetite and the desire to eat measured by
visual analog scales, which coincided with the suppression of
the appetite hormone ghrelin (28). While the exact mecha-
nisms linking elevated KBs with the regulation of appetite hor-
mones are not clear and likely involves multiple organ systems
(54), this is an example of a physiological effect that appears
common to KDs and EKs (15).
Glucoregulatory aspects
An effect on circulating glucose concentrations is a promi-
nent feature of NK induced by both KDs and EKs, but the
method of induction of NK results in divergent regulation of
these effects. For example, as KDs require dietary CHO restric-
tion, lower glucose concentrations, and an absence of postpran-
dial glycemia are a consistent feature of their application (19).
Ketogenic Diets versus Exogenous Ketones
 Conversely, several reports have demonstrated that EKs can
acutely regulate glycemia by either lowering fasting glucose
concentrations (12,17,28,47), and/or by attenuation the post-
prandial rise in glucose after a CHO-containing bolus (29).
These effects occur with or without alterations in circulating in-
sulin (12,28,47), and are most likely via attenuated hepatic glu-
cose output, rather than an increase in skeletal muscle glucose
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uptake (21,29,55).
Anabolic and anticatabolic effects
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 04/12/2024
KDs are reported to impact the adaptive response to exer-
cise training measured by change in lean body mass (56), but
currently, the understanding of this relationship is conflicting
and confounded by the methods of assessment of lean body
mass, relative protein consumption, anabolic hormone levels,
and caloric intake (56). There also has been a suggestion that a
KD may elicit an anticatabolic effect as evidenced by increas-
ing circulating leucine and decreased circulating alanine con-
centrations (57). Similarly, anabolic and anticatabolic effects
of infused EKs have been demonstrated in humans (40,41),
in addition to anticatabolic effects of EKs in rodent models
of atrophy-based pathologies (21).
Exogenous versus Endogenous NK: Lessons from Applied
Contexts
Considering the above examples of convergence and diver-
gence between KDs and EKs when inducing NK, it appears er-
roneous to assume that the respective methods will elicit
identical effects or can be applied interchangeably in all con-
texts. Illustrative examples of this include applications in anti-
seizure and exercise performance contexts.
For example, in epilepsy, significant questions remain sur-
rounding the mechanisms by which KDs exert antiseizure
and neuroprotective effects (16), and debates on the therapeu-
tic potential of EKs continue. The clinical data do not yet
strongly support the notion that KBs elicit anticonvulsant ef-
fects independent of their role as a metabolic substrate as most
human studies have failed to demonstrate a correlation be-
tween blood KB concentrations and seizure control (7). De-
spite this, all three KBs and various EK formulations elicit
antiseizure effects in cell culture or animals (7). However, it
also is clear that the individual KBs elicit unique effects as
AcAc and acetone possess more potent anticonvulsant proper-
ties than R-bHB (7), highlighting an important need for EKs
that can intentionally elevate specific KBs, rather than simply
relying on the physiological equilibrium produced by KDs.
This relationship between endogenous and exogenous
sources of KBs and their respective actions is further muddled
by the experimental methodologies that are employed to un-
derstand NK. Much of what is speculated about the molecular
mechanisms that underlie the pleiotropic effects of KDs (i.e.,
chronic effects) is extrapolated from studies that administer
EKs or KBs directly (i.e., acute effects) in an attempt to isolate
effects of these molecules. However, the central theme of this
review (Table), and others (10), is to highlight that the effects
of KDs and EKs are not synonymous and should not be con-
flated. Similarly, caution should be applied when mechanisms
of effects of NK are extrapolated primarily from reductionist
experiments performed in vitro with KBs exogenously applied
to cells or tissues, in the absence of the sequalae produced by
longer-term adherence to a KD. Moreover, recent studies have
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Copyright © 2020 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
described EK-supplemented diets (54,58), that is, diets pro-
ducing sustained NK in the absence of effects produced by
CHO restriction of traditional KD approaches. Overall, these
experimental approaches provide valuable insight into effects
of NK per se, but conversely make teasing apart the effects of
NK induced by endogenous versus exogenous means even
more difficult, and further supports defining NK by R-bHB
concentration, with the secondary consideration being the
method of induction.
In exercise contexts, there is considerable debate about the
merits of KDs for athletic performance (1,2), and the perfor-
mance benefits of acute ingestion of EKs are equivocal (13).
However, it is clear that NK alters the metabolic response to
exercise at the level of substrate utilization, and in terms of
contribution from circulating or intramuscular substrates
(12,59–61). Common to KDs and EKs would be a reduction
in CHO utilization during exercise, but this occurs under very
different metabolic states. For example, low CHO availability
is a de facto feature of KDs (2,60), whereas to date, most stud-
ies of EKs have been performed with EKs coingested with high
rates of CHO supply (~1 g·min−1) (12,13). As described
above, EKs have antilipolytic effects, which results in lower
circulating FFAs concentrations and may augment the reliance
on intramuscular triglycerides during exercise (12). Con-
versely, circulating FFAs and glycerol are elevated during ex-
ercise after a KD, and whole-body fat oxidation rates
increase two-fold to three-fold over mixed/high CHO diets
(1,60). These shifts in patterns of substrate utilization under-
score the distinct metabolic states during exercise and have im-
portant implications for performance (10). Specifically,
current speculation is that KDs may be beneficial for long du-
ration (12 h), low-intensity ultraendurance-type event,
where fats, being the primary source of ATP provision, can
match lower rates of ATP demand, whereas the combination
of NK and high CHO intake may confer performance benefits
in endurance events of moderate intensity and durations of
8 h (62). Several years of research will be required to explore
these contentions, but the salient point is that despite the com-
mon feature of inducing NK, KDs and EK are distinct meta-
bolic states and should not be conflated as analogous fueling
approaches for athletes.
Conclusions
Interest into the performance and therapeutic applications
of NK has rapidly expanded. Regardless if induced by endog-
enous or exogenous means, NK can be defined as a metabolic
state wherein R-bHB concentrations are elevated 0.5 mM,
eliciting widespread physiological changes at both a systemic
and cellular level. These effects can overlap or differ and can
be universal or tissue-specific. Because NK is a potential candi-
date for performance-enhancing and therapeutic benefits, it
will be critical to understand these points of convergence
and divergence to fully evaluate its utility for sports perfor-
mance and medicine in the future.
The authors thank Dr. Mark Evans for his constructive
comments on the manuscript.
This submission was not supported by any specific grant
from funding agencies in the public, commercial, or not-for-
profit sectors.
Current Sports Medicine Reports 257
 AMP is a scientific advisor to Pruvit Ventures, LLC, and is
an inventor on the following patent: Dominic P. D’Agostino;
Angela M. Poff; Patrick Arnold; “Targeting Cancer with Met-
abolic Therapy and Hyperbaric Oxygen” (Patent Number:
9801903). AMP is an owner of Poff Medical Consulting and
Communications, LLC and Metabolic Health Initiative, LLC.
AMP and APK are inventors on pending patents “Composi-
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tions and Methods for Weight Loss Maintenance.” APK is an
inventor on pending patent “Prevention of Muscle Wasting
with Ketone Supplementation.” At the time of this publica-
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 04/12/2024
tion, pending patents were still under review. Should patents
become accepted, AMP and APK will receive a share under
the patent terms prescribed by the University of South
Florida. BE declares no conflicts of interest and does not
have any financial disclosures.
References
1. Volek JS, Noakes T, Phinney SD. Rethinking fat as a fuel for endurance exercise.
Eur. J. Sport Sci. 2015; 15:13–20.
2. Burke LM, Hawley JA. Swifter, higher, stronger: what's on the menu? Science.
2018; 362:781–7.
3. Rothschild JA, Bishop DJ. Effects of dietary supplements on adaptations to en-
durance training. Sports Med. 2020; 50:25–53.
4. Close GL, Hamilton DL, Philp A, et al. New strategies in sport nutrition to in-
crease exercise performance. Free Radic. Biol. Med. 2016; 98:144–58.
5. Evans M, Cogan KE, Egan B. Metabolism of ketone bodies during exercise and
training: physiological basis for exogenous supplementation. J. Physiol. 2017;
595:2857–71.
6. Koutnik AP, D'Agostino DP, Egan B. Anticatabolic effects of ketone bodies in
skeletal muscle. Trends Endocrinol. Metab. 2019; 30:227–9.
7. Poff AM, Rho JM, D'Agostino DP. Ketone administration for seizure disorders:
history and rationale for ketone esters and metabolic alternatives. Front.
Neurosci. 2019; 13:1041.
8. Masino SA. Ketogenic Diet and Metabolic Therapies: Expanded Roles in Health
and Disease. Oxford University Press; 2016, p 424.
9. Newman JC, Verdin E. Beta-hydroxybutyrate: a signaling metabolite. Annu.
Rev. Nutr. 2017; 37:51–76.
10. Shaw DM, Merien F, Braakhuis A, et al. Exogenous ketone supplementation
and keto-adaptation for endurance performance: disentangling the effects of
two distinct metabolic states. Sports Med. 2020; 50:641–56.
11. Burke LM. Re-examining high-fat diets for sports performance: did we call the
‘nail in the coffin’ too soon? Sports Med. 2015; 45(Suppl. 1):S33–49.
12. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and
thereby endurance performance in athletes. Cell Metab. 2016; 24:256–68.
13. Valenzuela PL, Morales JS, Castillo-Garcia A, Lucia A. Acute ketone supple-
mentation and exercise performance: a systematic review and meta-analysis of
randomized controlled trials. Int. J. Sports Physiol. Perform. 2020; 1–11.
14. Balasse EO, Fery F. Ketone body production and disposal: effects of fasting, di-
abetes, and exercise. Diabetes Metab. Rev. 1989; 5:247–70.
15. Cahill GF Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 2006; 26:1–22.
16. Robinson AM, Williamson DH. Physiological roles of ketone bodies as sub-
strates and signals in mammalian tissues. Physiol. Rev. 1980; 60:143–87.
17. Mikkelsen KH, Seifert T, Secher NH, et al. Systemic, cerebral and skeletal muscle
ketone body and energy metabolism during acute hyper-D-b-hydroxybutyratemia
in post-absorptive healthy males. J. Clin. Endocrinol. Metab. 2015; 100:636–43.
18. Laffel L. Ketone bodies: a review of physiology, pathophysiology and applica-
tion of monitoring to diabetes. Diabetes Metab. Res. Rev. 1999; 15:412–26.
19. Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the
therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur. J. Clin. Nutr.
2013; 67:789–96.
20. Kossoff E, Turner Z, Doerrer S, Cervenka M, Henry B. The Ketogenic and Mod-
ified Atkins Diets. Treatments for Epilepsy and Other Disorders. Springer Pub-
lishing Company. 2016, p 384.
21. Koutnik AP, Poff AM, Ward NP, et al. Ketone bodies attenuate wasting in
models of atrophy. J. Cachexia. Sarcopenia Muscle. 2020.
22. Kesl SL, Poff AM, Ward NP, et al. Effects of exogenous ketone supplementation
on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley
rats. Nutr. Metab. (Lond). 2016; 13:9.
258 Volume 19  Number 7  July 2020
Copyright © 2020 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
23. Stubbs BJ, Cox PJ, Evans RD, et al. On the metabolism of exogenous ketones in
humans. Front. Physiol. 2017; 8:848.
24. Thorburn MS, Vistisen B, Thorp RM, et al. Attenuated gastric distress but no
benefit to performance with adaptation to octanoate-rich esterified oils in
well-trained male cyclists. J. Appl. Physiol. (1985). 2006; 101:1733–43.
25. Dymsza HA. Nutritional application and implication of 1,3-butanediol. Fed.
Proc. 1975; 34:2167–70.
26. D'Agostino D, Pilla R, Held H, et al. Therapeutic ketosis with ketone ester delays
central nervous system oxygen toxicity seizures in rats. Am. J. Physiol. Regul.
Integr. Comp. Physiol. 2013; 304:R829–36.
27. Scala RA, Paynter OE. Chronic oral toxicity of 1, 3-butanediol. Toxicol. Appl.
Pharmacol. 1967; 10:160–4.
28. Stubbs BJ, Cox PJ, Evans RD, et al. A ketone ester drink lowers human ghrelin
and appetite. Obesity. 2018; 26:269–73.
29. Myette-Cote E, Neudorf H, Rafiei H, et al. Prior ingestion of exogenous ketone
monoester attenuates the glycaemic response to an oral glucose tolerance test in
healthy young individuals. J. Physiol. 2018; 596:1385–95.
30. Soto-Mota A, Vansant H, Evans RD, Clarke K. Safety and tolerability of
sustained exogenous ketosis using ketone monoester drinks for 28 days in
healthy adults. Regul. Toxicol. Pharmacol. 2019; 109:104506.
31. Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite
beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory
disease. Nat. Med. 2015; 21:263–9.
32. Owen OE, Morgan AP, Kemp HG, et al. Brain metabolism during fasting. J.
Clin. Invest. 1967; 46:1589–95.
33. McDougall A, Bayley M, Munce SE. The ketogenic diet as a treatment for trau-
matic brain injury: a scoping review. Brain Inj. 2018; 32:416–22.
34. Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse
neurological disorders. Front. Pharmacol. 2012; 3:59.
35. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can ketones help res-
cue brain fuel supply in later life? Implications for cognitive health during aging
and the treatment of Alzheimer's disease. Front. Mol. Neurosci. 2016; 9:53.
36. Deemer SE, Plaisance EP, Martins C. Impact of ketosis on appetite regulation-a
review. Nutr. Res. 2020; 77:1–11.
37. Rogawski MA, Loscher W, Rho JM. Mechanisms of action of antiseizure drugs
and the ketogenic diet. Cold Spring Harb. Perspect. Med. 2016; 6:a022780.
38. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel me-
tabolism, signaling, and therapeutics. Cell Metab. 2017; 25:262–84.
39. Maizels EZ, Ruderman NB, Goodman MN, Lau D. Effect of acetoacetate on
glucose metabolism in the soleus and extensor digitorum longus muscles of the
rat. Biochem. J. 1977; 162:557–68.
40. Nair KS, Welle SL, Halliday D, Campbell RG. Effect of beta-hydroxybutyrate
on whole-body leucine kinetics and fractional mixed skeletal muscle protein syn-
thesis in humans. J. Clin. Invest. 1988; 82:198–205.
41. Thomsen HH, Rittig N, Johannsen M, et al. Effects of 3-hydroxybutyrate and
free fatty acids on muscle protein kinetics and signaling during LPS-induced in-
flammation in humans: anticatabolic impact of ketone bodies. Am. J. Clin. Nutr.
2018; 108:857–67.
42. Zou X, Meng J, Li L, et al. Acetoacetate accelerates muscle regeneration and
ameliorates muscular dystrophy in mice. J. Biol. Chem. 2016; 291:2181–95.
43. Parker BA, Walton CM, Carr ST, et al. beta-Hydroxybutyrate elicits favorable
mitochondrial changes in skeletal muscle. Int. J. Mol. Sci. 2018; 19:2247.
44. Yamada T, Zhang SJ, Westerblad H, Katz A. {beta}-Hydroxybutyrate inhibits
insulin-mediated glucose transport in mouse oxidative muscle. Am. J. Physiol.
Endocrinol. Metab. 2010; 299:E364–73.
45. Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal
muscle adaptation. Cell Metab. 2013; 17:162–84.
46. Taggart AK, Kero J, Gan X, et al. (D)-beta-Hydroxybutyrate inhibits adipocyte
lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 2005; 280:
26649–52.
47. Binkiewicz A, Sadeghi-Najad A, Hochman H, et al. An effect of ketones on the
concentrations of glucose and of free fatty acids in man independent of the re-
lease of insulin. J. Pediatr. 1974; 84:226–31.
48. Miyamoto J, Ohue-Kitano R, Mukouyama H, et al. Ketone body receptor
GPR43 regulates lipid metabolism under ketogenic conditions. Proc. Natl. Acad.
Sci. U. S. A. 2019; 116:23813–21.
49. Davis RAH, Deemer SE, Bergeron JM, et al. Dietary R, S-1,3-butanediol
diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat
diet. FASEB J. 2019; 33:2409–21.
50. Dansinger ML, Gleason JA, Griffith JL, et al. Comparison of the Atkins, Ornish,
Weight Watchers, and Zone diets for weight loss and heart disease risk reduc-
tion: a randomized trial. JAMA. 2005; 293:43–53.
Ketogenic Diets versus Exogenous Ketones
 51. Kashiwaya Y, Sato K, Tsuchiya N, et al. Control of glucose utilization in work-
ing perfused rat heart. J. Biol. Chem. 1994; 269:25502–14.
52. Cahill GF Jr., Veech RL. Ketoacids? Good medicine? Trans. Am. Clin. Climatol.
Assoc. 2003; 114:149–61; discussion 62-3.
53. Gibson AA, Seimon RV, Lee CM, et al. Do ketogenic diets really suppress appe-
tite? A systematic review and meta-analysis. Obes. Rev. 2015; 16:64–76.
54. Deemer SE, Davis RAH, Gower BA, et al. Concentration-dependent effects of a
dietary ketone ester on components of energy balance in mice. Front. Nutr.
Downloaded from http://journals.lww.com/acsm-csmr by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCyw
2019; 6:56.
55. Lauritsen KM, Sondergaard E, Luong TV, et al. Acute hyperketonemia does not
affect glucose or palmitate uptake in abdominal organs or skeletal muscle. J.
Clin. Endocrinol. Metab. 2020; 105:dgaa122.
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 04/12/2024
56. Kang J, Ratamess NA, Faigenbaum AD, Bush JA. Ergogenic properties of keto-
genic diets in normal-weight individuals: a systematic review. J. Am. Coll. Nutr.
2020; 1–11.
www.acsm-csmr.org
Copyright © 2020 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
57. Phinney SD, Bistrian BR, Wolfe RR, Blackburn GL. The human metabolic re-
sponse to chronic ketosis without caloric restriction: physical and biochemical
adaptation. Metabolism. 1983; 32:757–68.
58. Poff AM, Ari C, Arnold P, et al. Ketone supplementation decreases tumor cell
viability and prolongs survival of mice with metastatic cancer. Int. J. Cancer.
2014; 135:1711–20.
59. Volek JS, Freidenreich DJ, Saenz C, et al. Metabolic characteristics of
keto-adapted ultra-endurance runners. Metabolism. 2016; 65:100–10.
60. Burke LM, Ross ML, Garvican-Lewis LA, et al. Low carbohydrate, high fat diet
impairs exercise economy and negates the performance benefit from intensified
training in elite race walkers. J. Physiol. 2017; 595:2785–807.
61. Leckey JJ, Ross ML, Qoud M, et al. Ketone diester ingestion impairs time-trial
performance in professional cyclists. Front. Physiol. 2017; 8:806.
62. Maunder E, Kilding AE, Plews DJ. Substrate metabolism during ironman triath-
lon: different horses on the same courses. Sports Med. 2018; 48:2219–26.
Current Sports Medicine Reports 259