Opinion

Disorders of the Nervous System

Glucose-Sparing Action of Ketones Boosts

Functions Exclusive to Glucose in the Brain
Yuri Zilberter,1,3 and Tanya Zilberter2

https://doi.org/10.1523/ENEURO.0303-20.2020
1
Institut de Neurosciences des Systèmes, Aix-Marseille Universite, Institut National de la Santé et de la Recherche
Médicale Unité Mixte de Recherche 1106, Marseille 13385, France, 2Infotonic Consultancy, Marseille 13009, France,
and 3Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290, Pushchino, Russia

Abstract
The ketogenic diet (KD) has been successfully used for a century for treating refractory epilepsy and is cur-
rently seen as one of the few viable approaches to the treatment of a plethora of metabolic and neurodegener-
ative diseases. Empirical evidence notwithstanding, there is still no universal understanding of KD mechanism
(s). An important fact is that the brain is capable of using ketone bodies for fuel. Another critical point is that
glucose’s functions span beyond its role as an energy substrate, and in most of these functions, glucose is ir-
replaceable. By acting as a supplementary fuel, ketone bodies may free up glucose for its other crucial and
exclusive function. We propose that this glucose-sparing effect of ketone bodies may underlie the effective-
ness of KD in epilepsy and major neurodegenerative diseases, which are all characterized by brain glucose
hypometabolism.
Key words: aerobic glycolysis; antioxidant system; glucose metabolism; glycogen; ketogenic diet; ketosis

Significance Statement
The ketogenic diet (KD) was created in the 1920s as a therapy for refractory epilepsy. Since then, evidence
accumulated showing its potential for other major neurodegenerative disorders. The exact mechanism of
KD’s protective activity still remains unknown, nonetheless. In the brain, ketone bodies can be used for cel-
lular energy, at least partially substituting glucose as brain fuel. However, glucose has essential functions
beyond those of just energy supply that cannot be provided by alternative substrates. We propose that the
glucose-sparing effect of ketone bodies may underlie the effectiveness of KD in epilepsy and other major
neurodegenerative diseases which are all characterized by brain glucose hypometabolism.

Introduction quantitative criteria (Zilberter and Zilberter, 2018) intro-

There is no universally accepted definition of ketogenic duced almost a century ago (Wilder and Winter, 1922)
diets (KDs). Moreover, there is a tendency to relax previous that were based on macronutrient composition. Perhaps
the most practical notion of whether a diet can be consid-
Received July 8, 2020; accepted August 27, 2020; First published November ered to be ketogenic is made by Seyfried (2012): it is “as
9, 2020. long as the individual has reduced blood glucose and is
The authors declare no competing financial interests.
producing ketones.” Although protein is included in the
Acknowledgements: This study was supported by the RSF Grant 20-65-
46035 to Y.Z. ketogenic ratio equation (Shaffer, 1921), glucose, ketone
Correspondence should be addressed to Yuri Zilberter at yuri.zilberter@ bodies, and their interplay determine the dominating met-
univ-amu.fr. abolic mode: whether the predominant energy supply is
https://doi.org/10.1523/ENEURO.0303-20.2020 glucose or ketone bodies (Westman et al., 2003). The cur-
Copyright © 2020 Zilberter and Zilberter
rent data allow us to conclude that the functional interac-
This is an open-access article distributed under the terms of the Creative
Commons Attribution 4.0 International license, which permits unrestricted use,
tion between glucose and ketone bodies is not a binary
distribution and reproduction in any medium provided that the original work is winner-take-all process. Here, we attempt to describe
properly attributed. more intricate relationships between them.

November/December 2020, 7(6) ENEURO.0303-20.2020 1–7

 Opinion 2 of 7

Glycolytic ATP Production has not been studied yet. However, unlike glucose, ke-
In the case of acute energy demand such as during in- tones cannot be involved in aerobic glycolysis, and thus
tense network activity, the brain is able to intensify glyco- they contribute to ATP production via oxidative phospho-
lytic ATP production for rapid supply. Aerobic glycolysis rylation only (Cunnane et al., 2020).
(when glucose is partially converted to lactate in the pres-
ence of oxygen, producing two ATP molecules) is dispro- The Cytoplasmic Antioxidant System
portionate to the oxygen consumption of glucose utilization Reactive oxygen species (ROS) in brain cells originate
when the oxygen delivery is adequate (Dienel and Cruz, from multiple sources and most of them are generated as
2016). In the resting brain, glycolysis and oxidative phos- byproducts of metabolic reactions. Intracellular ROS come
phorylation rates appear well-matched, indicating nearly mainly from NADPH oxidase (NOX), xanthine oxidase, nitric
complete oxidation of glucose. However, in the activated oxide synthase, and mitochondria. NOX is the only enzyme
brain at physiological conditions, e.g., during sensory stimu- with the primary function of generating ROS (Bedard and
lation and mental testing, aerobic glycolysis has been ob- Krause, 2007; Koju et al., 2019) that are mostly used for the
served in various brain regions (Dienel and Cruz, 2016; “host defense” (e.g., microbial killing) in organisms. NOX
Dienel, 2019a). The cellular contribution to aerobic glycolysis enzymes are predominantly expressed in the cellular plas-
is yet unclear and is a matter of debate (Dienel and Cruz, ma membrane (Ma et al., 2017). The enzyme consists of a
2016; Barros et al., 2020). As lactate (in addition to pyruvate) membrane-bound catalytic core and several cytosolic reg-
is the end-product of the glycolytic pathway during aerobic ulatory subunits (Bedard and Krause, 2007). There are
glycolysis, it can either be cleared out from the brain or par- seven known isoforms of NOX with NOX1, NOX2, and
tially consumed as supplementary fuel for neurons (Pellerin NOX4 expressed in multiple brain regions including the
and Magistretti, 2012; Dienel and Cruz, 2016). Indeed, aero- cerebral cortex, hippocampus, cerebellum, hypothalamus,
bic glycolysis as an ATP production mechanism, while low- midbrain, and/or striatum (Hou et al., 2020). These NOX
capacity, is rapid, ensuring fast ATP resupply in neurons variants are the most prominent isoforms detected in a va-
where the dynamic demand for energy is highest (Yellen, riety of brain cell types (Cahill-Smith and Li, 2014; Rastogi
2018). The notion of fast ATP synthesis (aerobic glycolysis) et al., 2016; Hou et al., 2020), with NOX2 the dominant
is supported by an immediate rise in extracellular lactate form expressed by microglia, neurons, and astrocytes.
and reduction in glucose levels during brief visual stimula- Activation of NOX results in an increase of extracellular
tion coincident with spiking activity (Li and Freeman, 2015). H2O2 levels followed by H2O2 entry into the cells via aqua-
Neurons are rich in mitochondria, a major source of porins (Bienert and Chaumont, 2014). Under “resting con-
ATP (Hall et al., 2012). However, for some of the neuronal ditions” in the brain, NOX is normally dormant and
functions, aerobic glycolysis may be the preferential therefore its contribution to the total cellular ROS produc-
method of fuel generation, for instance, for fast axonal tion under resting or physiological conditions is not clear
vesicle transport (Zala et al., 2013). Although synaptic (Brown and Borutaite, 2012). In pathology, when NOX is
transmission is a very energy-demanding process, many activated by specific stimulation (Rastogi et al., 2016), its
presynaptic nerve terminals lack mitochondria (Devine cytosolic subunits translocate to the membrane and asso-
and Kittler, 2018; Tourigny et al., 2019), although mito- ciate to the functioning complex. Under these conditions,
chondria can migrate to and/or ATP can diffuse into the mitochondria and NOX are the major ROS producers
presynaptic boutons during enhanced synaptic activity (Tarafdar and Pula, 2018; Barua et al., 2019). However, be-
(Chamberlain and Sheng, 2019; Rossi and Pekkurnaz, fore its diffusion to the cytoplasm, the internal consumption
2019). Recent studies indicate that presynaptic transmis- of H2O2 in mitochondria is much higher than originally an-
sion is dependent on activity-induced glycolysis (Ashrafi ticipated (Munro and Pamenter, 2019) and during oxidative
and Ryan, 2017), while presynapses can use ATP pro- stress, mitochondria may be victims rather than producers
duced by both glycolysis and oxidative phosphorylation of oxidative damage (Gandhi and Abramov, 2012). Indeed,
to sustain neurotransmission (Ashrafi and Ryan, 2017; in AD models, the effects of mitochondrial ROS were found
Chamberlain and Sheng, 2019; Rossi and Pekkurnaz, to be much smaller compared with those of NOX-pro-
2019). Moreover, dendritic spines that receive most exci- duced ROS (Angelova and Abramov, 2018).
tatory synaptic inputs have been shown to contain no mi- In the cytoplasm, an efficient anti-oxidative system
tochondria (Kasthuri et al., 2015), despite being sites of based largely on the glycolysis-associated pentose-phos-
intense energy utilization. Although some ATP might dif- phate pathway strictly regulates ROS levels to avoid any
fuse to spine heads from nearby dendritic mitochondria, it oxidative injury (Bolaños and Almeida, 2010; Franco et al.,
is conceivable that spines are reliant on glycolysis instead 2019; Cherkas et al., 2020). Thus, brain cells use glucose
(Kasthuri et al., 2015). Glycolytic ATP alone, with its limited as an energy provider as well as the substrate for cyto-
production capacity, is unlikely to be sufficient to power plasmic ROS detoxification mechanisms. The combina-
ion pumping required for the maintenance of ion gradient tion of ROS overproduction with inadequate antioxidant
and membrane potential (Hall et al., 2012), but it may defenses (such as when glucose utilization is inhibited) re-
nevertheless play an important role in fast refueling. For in- sults in oxidative stress and consequent damages, e.g.,
stance, the preferential role of glycolytic energy supply was neural cell death and neurodegeneration (Avery, 2011;
demonstrated for Na/K-ATPase in fast-twitch skeletal mus- Tarafdar and Pula, 2018).
cle (Okamoto et al., 2001) and cardiac Purkinje cells An extreme example of the importance of glucose-
(Glitsch and Tappe, 1993). Aerobic glycolysis during KD based antioxidant defense for cellular function was

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 Opinion 3 of 7

reported by us when glucose in artificial CSF (ACSF) was 75% of the entire glucose consumption in the cortex
exchanged for pyruvate in hippocampal slices (Malkov et (Schousboe et al., 2013; Hertz and Rothman, 2016).
al., 2014, 2019). The substitution resulted in oxidative Glucose metabolism is required for the synthesis of gluta-
stress leading to massive network depolarization (analo- mate from glutamine in glutamatergic neurons (Bak et al.,
gous to spreading depression; Pietrobon and Moskowitz, 2006; Lund et al., 2009; Chowdhury et al., 2014; Hertz
2014) together with a “metabolic collapse.” Importantly, and Rothman, 2016), but in GABAergic neurons, b -hy-
we obtained similar results replacing glucose with other droxybutyrate is capable of replacing glucose for GABA
mitochondrial fuels such as lactate or b -hydroxybutyrate production (Hertz and Rothman, 2016).
(unpublished), indicating again the unique importance of
glucose. Glucose Utilization in the Brain during
KD improves antioxidant defense by stimulating the en- Ketosis
dogenous antioxidant system. Mild oxidative stress follow- The KD is an efficient clinical treatment used for over a
ing KD onset drives nuclear translocation of transcription century to decrease brain hyperexcitability and seizures
factor Nrf2, leading to increased synthesis of glutathione via a yet unclear mechanism. Carbohydrate limitation in
which is one of the major components of the antioxidant KD led to a popular notion that glycolysis inhibition may
defense (Pinto et al., 2018; Camberos-Luna and Massieu, partially reproduce the effects of KD. However, this hy-
2020). pothesis ignores the important fact that glycolysis inhibi-
tion a priori results in energy deprivation; meanwhile, no
Glycogen Production in Astrocytes energy deficiency occurs under KD [in rats on KD, the
The major energy reserve in the brain is glycogen, a brain ATP level was found either unchanged (Al-Mudallal
macromolecular storage form of glucose (Dienel, 2019b). et al., 1996; Bough et al., 2006) or increased (DeVivo et
Found mostly in astrocytes (Dienel and Carlson, 2019; al., 1978; Nakazawa et al., 1983)]. However, do ketones
neurons can store less significant amounts; Saez et al., inhibit glycolysis [as, for instance, does 2-deoxy-D-glu-
2014), glycogen is a dynamic participant in brain activity cose (Pajak et al., 2019) or iodoacetate (Schmidt and
and is regulated by neurotransmitters. Dysregulation of Dringen, 2009)] or do they just compete with glucose as
glycogen turnover may cause severe consequences, e.g., mitochondrial fuel? The NMR study of Valente-Silva et al.
Lafora disease with progressive neurodegeneration and (2015) is often cited as evidence of glycolysis inhibition.
epilepsy leading to death in early adulthood (Duran et al., There are a number of important flaws in this study, how-
2019). During intense brain activity, glycogen converted ever: (1) the 400-mm-thick brain slices were superfused
to lactate and released from astrocytes can be used by with oxygenated ACSF at 3 ml/min rate that results in an-
neurons as mitochondrial fuel. Meanwhile, rapid glyco- oxic conditions within the tissue (Ivanov and Zilberter,
genolytic generation of ATP may be important for astro- 2011), making oxidative phosphorylation impossible; and
cytic energy demands (Dienel and Rothman, 2019), and (2) the authors used 4-AP to induce network activity, while
thus glycogenolysis, by reducing the astrocytic require- epileptiform activity induced by 4-AP was itself shown to
ment for blood-borne glucose, can spare an equivalent be a strong inhibitor of glycolysis (Malkov et al., 2018). To
amount of glucose for neuronal utilization (Dienel, 2019a; the best of our knowledge, there are no other reports on
DiNuzzo et al., 2019). The estimated glucose equivalent of ketones’ direct inhibitory action on glycolysis.
glycogen concentration in astrocytes is up to 40–100 mM. There have been many attempts to estimate brain glu-
Considering the high rate of glycogenolysis, the amount cose utilization under KD, with variable results. In awake
of glucose that can be released via glycogen breakdown animals, glucose utilization either increased (Yudkoff et
is very significant (Dienel, 2019a; DiNuzzo et al., 2019). al., 2005), did not change (Al-Mudallal et al., 1995) or de-
Unfortunately, glycogen levels in the human brain during creased (Melø et al., 2006), while brain glucose levels ei-
KD have yet to be investigated. In rats, one study reported ther increased (Melø et al., 2006), did not change (DeVivo
increased inbound glucose (reflecting glycogen content; et al., 1978; Yudkoff et al., 2005) or decreased (Samala et
DeVivo et al., 1978) under KD, while no change in glyco- al., 2011). Utilization of the fluorodeoxyglucose (18F)-posi-
gen content was found in another study (Al-Mudallal et tron emission tomography (FDG-PET) technique in ani-
al., 1995) or glycogen was decreased (Bough et al., 2006). mals requires anesthesia that introduces a brain state
Carbohydrate intake does not affect brain glycogen con- quite different from an awake one. Nevertheless, under
tent, while in both muscle and liver it does significantly anesthesia, glucose utilization either increased (Pifferi et
correlate with glycogen levels (Soya et al., 2018). al., 2011; Roy et al., 2012), remained unchanged (Yudkoff
et al., 2005), or decreased (LaManna et al., 2009; Zhang
Production of Major Neurotransmitters et al., 2013). The variability of the results may be ex-
Glucose fuels de novo synthesis of major neurotrans- plained by the presence of confounding factors such as,
mitters. Precursors for glutamate or GABA are synthe- e.g., the use of anesthesia, significant age difference and
sized by astrocytes and then transferred to neurons in the the relatively high interindividual variation in plasma ke-
glutamine–glutamate/GABA cycle (Dienel, 2019a). The tones during KD (Pifferi et al., 2011; Roy et al., 2012).
transmitters released during synaptic activity are trans- Interestingly, in healthy young/middle age humans, cer-
ported back to astrocytes, where a fraction (;25%) is de- ebral glucose utilization evaluated by arteriovenous differ-
graded with the remainder released and reused by the ence was decreased under acute hyperketonemia (a
neurons. The process is very intense, consuming up to blood infusion of b -hydroxybutyrate; Hasselbalch et al.,

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 Opinion 4 of 7

Figure 1. Roles of glucose and ketone bodies in brain cells: parallel, converging, and exclusive. Red: ketone bodies’ pathway to mi-
tochondria. Blue: glucose pathway to mitochondria. Purple: the point of convergence. Green: exclusive roles of glucose.

1996) or following 3 d of fasting (Hasselbalch et al., 1994). 2016a; Croteau et al., 2018b), it is logical to conclude that in
Recent studies using the FDG-PET technique confirmed a normal brain, where glucose can fully cover energy needs,
these results reporting decreased brain glucose utilization in the addition of ketones as mitochondrial fuel competitors re-
healthy humans under KD (Courchesne-Loyer et al., 2017) duces the need for a part of glucose function and the total
or acute hyperketonemia (Svart et al., 2018). Importantly glucose utilization goes down. In pathology, when glucose
and however, similar recordings during ketogenic interven- utilization is impaired leading to energy deficiency, ketone
tion in humans suffering mild cognitive impairment (Fortier bodies compensate at least partially this energy gap, leaving
et al., 2019) or mild-moderate Alzheimer’s disease (AD; more glucose available for its other vital functions such as
Croteau et al., 2018b) revealed no change in brain glucose mentioned above.
utilization, while brain ketone metabolism was found to be In fact, the glucose-sparing effect may be dominant in
normal (Castellano et al., 2015; Croteau et al., 2018a). ketone’s beneficial therapeutic function ensemble. Clinical
Notably, glucose hypometabolism is a hallmark of AD effects of KD are mostly known regarding epilepsy as
pathogenesis (Caminiti et al., 2018; Gordon et al., 2018; childhood epilepsy has been successfully treated with KD
Butterfield and Halliwell, 2019). Indeed, disrupted glucose since the 1920s (Wilder, 1921). Recently, however, the KD
metabolism associated with oxidative stress is the common began to be used in preclinical studies of other disorders,
feature of major neurodegenerative diseases (Zilberter and including neurodegenerative, psychiatric, and brain injury
Zilberter, 2017; Cunnane et al., 2020; Tang, 2020) and epi- (McDonald and Cervenka, 2018; Camberos-Luna and
lepsy (Pearson-Smith and Patel, 2017; Zilberter and Massieu, 2020; Kraeuter et al., 2020), demonstrating prom-
Zilberter, 2017; Patel, 2018). For instance, AD pathology oc- ising efficiency that has also been confirmed in clinical tri-
curs well before (up to two decades prior) the onset of clini- als in mild cognitive impairment, AD, and Parkinson’s
cal symptoms (Caminiti et al., 2018; Gordon et al., 2018; disease patients (for review, see Cunnane et al., 2020).
Butterfield and Halliwell, 2019) with dysfunctional glucose Meanwhile, it has been noted that the efficacy of KD in an
metabolism as one earliest manifestation. In human epi- array of disorders with distinct pathophysiologies may indi-
lepsy, clinical tests using FDG-PET imaging have estab- cate shared underlying pathologic mechanisms (Kraeuter
lished that decreased brain glucose utilization during et al., 2020). In the case of major neurodegenerative dis-
quiescent (interictal) periods is a widely recognized bio- eases, one such mechanism is glucose hypometabolism
marker of epileptogenesis (Sarikaya, 2015; Lotan et al., (Zilberter and Zilberter, 2017; Cunnane et al., 2020; Tang,
2020). Since glucose utilization underlies vital brain func- 2020). Definitely, impaired glucose metabolism may lead to
tions such as energy supply and antioxidant defense (see energy deficiency that ketones can partially compensate
above), it is not surprising that disturbances in glucose me- by boosting mitochondrial oxidation. Here, it is interesting
tabolism can lead to a chain of harmful consequences, and to note that in the case of early AD stages, neither cerebral
thus likely represent a major underlying cause of disease ini- oxygen consumption (Hoyer et al., 1988; Hoyer, 1992) nor
tiation and progression (Pearson-Smith and Patel, 2017; mitochondrial ability for ketone utilization changed
Zilberter and Zilberter, 2017; Butterfield and Halliwell, 2019). (Castellano et al., 2015; Croteau et al., 2018a), suggesting
Therefore, as also suggested previously (Cunnane et al., normal mitochondrial functioning (Cunnane et al., 2016b,

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 Opinion 5 of 7

2020), despite pronounced glucose hypometabolism. Bedard K, Krause KH (2007) The NOX family of ROS-generating
Indeed, we demonstrated recently in hippocampal slices NADPH oxidases: physiology and pathophysiology. Physiol Rev
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Mitochondrial biogenesis in the anticonvulsant mechanism of the
available for other vital functions (Fig. 1) that may be espe-
ketogenic diet. Ann Neurol 60:223–235.
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tential importance of the glucose-sparing effect of ketones are the main source of reactive oxygen species in mammalian
has been noted previously in reports considering neurode- cells. Mitochondrion 12:1–4.
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Conclusions Cahill-Smith S, Li JM (2014) Oxidative stress, redox signalling and
Glucose does not share some of its functions in the endothelial dysfunction in ageing-related neurodegenerative dis-
brain with other metabolic substrates, which makes it an eases: a role of NADPH oxidase 2. Br J Clin Pharmacol 78:441–
453.
exclusive neurometabolite. The frequent claim that ke-
Camberos-Luna L, Massieu L (2020) Therapeutic strategies for keto-
tones directly inhibit the process of glycolysis is not sup- sis induction and their potential efficacy for the treatment of acute
ported by experimental evidence and seems theoretically brain injury and neurodegenerative diseases. Neurochem Int
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ber of cellular functions that lead to unpredictable varia- Caminiti SP, Ballarini T, Sala A, Cerami C, Presotto L, Santangelo R,
tions of network excitability, and in the long-run has been Fallanca F, Vanoli EG, Gianolli L, Iannaccone S, Magnani G, Perani
shown to result in epileptogenesis (Samokhina et al., D, Parnetti L, Eusebi P, Frisoni G, Nobili F, Picco A, Scarpini E,
BIOMARKAPD Project (2018) FDG-PET and CSF biomarker accu-
2017, 2020). In pathology, ketones are capable of partially racy in prediction of conversion to different dementias in a large
taking over the glucose’s energy fuel role in mitochondria multicentre MCI cohort. Neuroimage Clin 18:167–177.
and presumably spare glucose for its other exclusive Castellano CA, Nugent S, Paquet N, Tremblay S, Bocti C, Lacombe
functions. Here, we summarized the evidence and offer a G, Imbeault H, Turcotte E, Fulop T, Cunnane SC (2015) Lower
non-antagonistic view of the ketone bodies-glucose inter- brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoace-
play during metabolic shifting. The glucose-sparing effect tate metabolism in mild Alzheimer’s disease dementia. J
Alzheimers Dis 43:1343–1353.
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