Ketone Bodies, Potential theraputic uses [PDF]
Summary
Ketosis, meaning elevation of D-¯-hydroxybutyrate (R-3-
hydroxybutyrate) and acetoacetate, has been central to starving
man’s survival by providing nonglucose substrate to his
evolutionarily hypertrophied brain, sparing muscle from destruction
for glucose synthesis. Surprisingly, D-¯-hydroxybutyrate
(abbreviated “¯OHB”) may also provide a more efŽ cient source
of energy for brain per unit oxygen, supported by the same phenomenon
noted in the isolated working perfused rat heart and in
sperm. It has also been shown to decrease cell death in two human
neuronal cultures, one a model of Alzheimer’s and the other of
Parkinson’s disease. These observations raise the possibility that a
number of neurologic disorders, genetic and acquired, might bene
Ž t by ketosis. Other beneŽ cial effects from ¯OHB include an increased
energy of ATP hydrolysis (1G0 ) and its linked ionic gradients.
Thismay be signiŽ cant indrug-resistant epilepsy and in injury
and anoxic states. The ability of ¯OHB to oxidize co-enzyme Q and
reduce NADP+ may also be important in decreasing free radical
damage.
[...]
Fear of Ketosis
Physicians have long been taught to fear ketosis; the hallmark
of potentially fatal diabetic ketoacidosis
[...]
Ketosis is the Physiological Response to Fasting
in Homo sapiens
This fear of ketosis may be exaggerated. Mild ketosis can
have therapeutic potential in a variety of disparate disease states.
Blood ketone bodies reach 5–7 mM in fasting man (2) and are
essential to preserve muscle mass from conversion to glucose
for brain consumption. Episodic starvation was a normal state
during the evolution of the hunter-gatherer. Mild ketosis (2–
7 mM) remains today peculiar to man as a species (except in
some ruminants, particularly during exuberant lactation or during
twinning). Man is distinguished from other animals by his
large brain/body weight ratio and brain’s very high energy requirements.
At rest, 20% of oxygen consumption is needed to support the 1.5 kg of brain, which is2% of body weight. It can be
argued that since ketone bodies are the only available alternative
to glucose for brain’s energy, ketosis was a critical evolutionary
development to provision man’s hypertrophied brain while
sparing muscle mass (3). The survival beneŽ t is obvious; about
2 months for an average weight starving adult compared to a
calculated 2–3 weeks were ketone bodies not available.
Ketosis as Treatment for Epilepsy
The ability of brain to use ketone bodies, with one notable exception,
the treatment of epilepsy by prolonged fastings, has not
been utilized therapeutically.
[...]
(description of fasting and zero carb diets to stop seizures in epilepsy)
[...]
THE EFFECTS OF KETONE BODY METABOLISM
Improvement in Metabolic EfŽciency
In the 1940’s it was observed that ¯-hydroxybutyrat e and acetoacetate
were unique among the 16 carbohydrates, lipids, and
intermediary metabolites tested on sperm in their ability to decrease
oxygen consumption while increasing mobility (9, 10).
The reasons for this apparent increase in metabolic efŽ ciency
remained a mystery for 50 years. Recently, detailed studies by
Veech and colleagues of the metabolism of ketone bodies in the
working perfused rat heart showed that 5 mM ketone bodies
added to the glucose-containing perfusate resulted in a 25% increase
in hydraulic work with a signiŽ cant decrease in oxygen
consumption
[...]
It was thus apparent that the acute
metabolic effects of insulin in working heart could be mimicked
by ketone bodies. The implication was that ketosis, which
is the physiological response to insulin deprivation during starvation,
was equivalent in metabolic effects to the actions of insulin.
By providing an alternative substrate which is transported
into cells on the monocarboxylate carrier, ketones by-passed
the block in glucose transport caused by lack of insulin, even
stimulating glycogen synthesis (12). Ketones also by-passed the
blockade of pyruvate dehydrogenase induced by insulin deŽ -
ciency by providing an alternative source of mitochondrial acetyl
CoA.
[...]
Ketone bodies provide an alternative metabolic fuel which can act during
blockade of glycolysis, as occurs in diabetes or insulin resistance,
[...]
Owen et al. (3) found
ow and oxygen consumption to be 45 and 2.96 in 1-monthfasted
obese subjects, well below the normal levels reported for
adult humans of 57 and 3.6 by McHenry (15). These data suggest
a similar increase in metabolic efŽ ciency in human brain
using ketoacids as the principal source of energy in place of
glucose
[...]
KETOSIS FOR NEURODEGENERATIVE
AND OTHER DISEASES
Alzheimer’s Disease
Approximately one Ž fth of Alzheimer’s disease can be related
to 5 different genes, all of which lead in one way or another to
the accumulation of amyloid proteins. The remaining cases have
no apparent genetic cause for the increase in amyloid production.
The development of metabolic treatments, therefore, offers
novel alternatives to what appears to be a difŽ cult problem for
genetic manipulations. Several recently published articles give
a rationale for the use of mild ketosis as a treatment.
[...]
Parkinson's Disease
[...]
Although the mode of ketone body
action has not been thoroughly investigated, it would be reasonable
to suppose that they act by decreasing the source of
mitochondrial oxygen radical formation by oxidizing the coenzyme
Q couple while at the same time reducing the redox
potential of the NADP couple which, through glutathione, is the
Ž nal detoxiŽ cation step for H2O2. Trials of dopamine therapy in
combination with ketone bodies, might be expected to prolong
the useful therapeutic life of dopamine.
Summary
Ketosis, meaning elevation of D-¯-hydroxybutyrate (R-3-
hydroxybutyrate) and acetoacetate, has been central to starving
man’s survival by providing nonglucose substrate to his
evolutionarily hypertrophied brain, sparing muscle from destruction
for glucose synthesis. Surprisingly, D-¯-hydroxybutyrate
(abbreviated “¯OHB”) may also provide a more efŽ cient source
of energy for brain per unit oxygen, supported by the same phenomenon
noted in the isolated working perfused rat heart and in
sperm. It has also been shown to decrease cell death in two human
neuronal cultures, one a model of Alzheimer’s and the other of
Parkinson’s disease. These observations raise the possibility that a
number of neurologic disorders, genetic and acquired, might bene
Ž t by ketosis. Other beneŽ cial effects from ¯OHB include an increased
energy of ATP hydrolysis (1G0 ) and its linked ionic gradients.
Thismay be signiŽ cant indrug-resistant epilepsy and in injury
and anoxic states. The ability of ¯OHB to oxidize co-enzyme Q and
reduce NADP+ may also be important in decreasing free radical
damage.
[...]
Fear of Ketosis
Physicians have long been taught to fear ketosis; the hallmark
of potentially fatal diabetic ketoacidosis
[...]
Ketosis is the Physiological Response to Fasting
in Homo sapiens
This fear of ketosis may be exaggerated. Mild ketosis can
have therapeutic potential in a variety of disparate disease states.
Blood ketone bodies reach 5–7 mM in fasting man (2) and are
essential to preserve muscle mass from conversion to glucose
for brain consumption. Episodic starvation was a normal state
during the evolution of the hunter-gatherer. Mild ketosis (2–
7 mM) remains today peculiar to man as a species (except in
some ruminants, particularly during exuberant lactation or during
twinning). Man is distinguished from other animals by his
large brain/body weight ratio and brain’s very high energy requirements.
At rest, 20% of oxygen consumption is needed to support the 1.5 kg of brain, which is2% of body weight. It can be
argued that since ketone bodies are the only available alternative
to glucose for brain’s energy, ketosis was a critical evolutionary
development to provision man’s hypertrophied brain while
sparing muscle mass (3). The survival beneŽ t is obvious; about
2 months for an average weight starving adult compared to a
calculated 2–3 weeks were ketone bodies not available.
Ketosis as Treatment for Epilepsy
The ability of brain to use ketone bodies, with one notable exception,
the treatment of epilepsy by prolonged fastings, has not
been utilized therapeutically.
[...]
(description of fasting and zero carb diets to stop seizures in epilepsy)
[...]
THE EFFECTS OF KETONE BODY METABOLISM
Improvement in Metabolic EfŽciency
In the 1940’s it was observed that ¯-hydroxybutyrat e and acetoacetate
were unique among the 16 carbohydrates, lipids, and
intermediary metabolites tested on sperm in their ability to decrease
oxygen consumption while increasing mobility (9, 10).
The reasons for this apparent increase in metabolic efŽ ciency
remained a mystery for 50 years. Recently, detailed studies by
Veech and colleagues of the metabolism of ketone bodies in the
working perfused rat heart showed that 5 mM ketone bodies
added to the glucose-containing perfusate resulted in a 25% increase
in hydraulic work with a signiŽ cant decrease in oxygen
consumption
[...]
It was thus apparent that the acute
metabolic effects of insulin in working heart could be mimicked
by ketone bodies. The implication was that ketosis, which
is the physiological response to insulin deprivation during starvation,
was equivalent in metabolic effects to the actions of insulin.
By providing an alternative substrate which is transported
into cells on the monocarboxylate carrier, ketones by-passed
the block in glucose transport caused by lack of insulin, even
stimulating glycogen synthesis (12). Ketones also by-passed the
blockade of pyruvate dehydrogenase induced by insulin deŽ -
ciency by providing an alternative source of mitochondrial acetyl
CoA.
[...]
Ketone bodies provide an alternative metabolic fuel which can act during
blockade of glycolysis, as occurs in diabetes or insulin resistance,
[...]
Owen et al. (3) found
ow and oxygen consumption to be 45 and 2.96 in 1-monthfasted
obese subjects, well below the normal levels reported for
adult humans of 57 and 3.6 by McHenry (15). These data suggest
a similar increase in metabolic efŽ ciency in human brain
using ketoacids as the principal source of energy in place of
glucose
[...]
KETOSIS FOR NEURODEGENERATIVE
AND OTHER DISEASES
Alzheimer’s Disease
Approximately one Ž fth of Alzheimer’s disease can be related
to 5 different genes, all of which lead in one way or another to
the accumulation of amyloid proteins. The remaining cases have
no apparent genetic cause for the increase in amyloid production.
The development of metabolic treatments, therefore, offers
novel alternatives to what appears to be a difŽ cult problem for
genetic manipulations. Several recently published articles give
a rationale for the use of mild ketosis as a treatment.
[...]
Parkinson's Disease
[...]
Although the mode of ketone body
action has not been thoroughly investigated, it would be reasonable
to suppose that they act by decreasing the source of
mitochondrial oxygen radical formation by oxidizing the coenzyme
Q couple while at the same time reducing the redox
potential of the NADP couple which, through glutathione, is the
Ž nal detoxiŽ cation step for H2O2. Trials of dopamine therapy in
combination with ketone bodies, might be expected to prolong
the useful therapeutic life of dopamine.
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