JOURNAL OF MEDICINAL FOOD

J Med Food 00 (0) 2013, 1–3

REVIEW ARTICLE
# Mary Ann Liebert, Inc., and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2012.2592

A Focused Review of the Role of Ketone Bodies in Health and Disease

Muhammad Akram
Department of Eastern Medicine and Surgery, Faculty of Medical and Health Sciences,
The University of Poonch, Rawalakot, Azad Jammu and Kashmir, Pakistan.

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ABSTRACT Ketone bodies are produced in the liver and are utilized in other tissues in the body as an energy source when

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hypoglycemia occurs in the body. There are three ketone bodies: acetoacetate, beta hydroxy butyrate, and acetone. Ketone
bodies are usually present in the blood, and their level increases during fasting and starvation. They are also found in the blood
of neonates and pregnant women. In diabetic ketoacidosis, high levels of ketone bodies are produced in response to low insulin

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levels and high levels of counter-regulatory hormones.

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KEY WORDS:  acetoacetate  acetone  beta hydroxy butyrate  diabetic ketoacidosis  ketone bodies  previous
research study

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INTRODUCTION concentrations less than 1 mg/dL in well-fed mammals, but
are produced excessively in conditions such as prolonged
K etogenesis occurs only in liver mitochondria and
only when the production of acetyl Coenzyme A from
fatty acids exceeds the capacity of the citric acid cycle to
starvation, diabetes mellitus, and other non-pathogenic
conditions such as a high-fat diet and severe exercise in the
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post-absorptive phase. When ketones are administered to

oxidize it. The excess acetyl Coenzyme A is then used to
patients intravenously as a sodium salt, they tend to produce
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produce ketones. Hydroxymethylglutaryl CoA (HMG CoA),

an alkalosis. Ketone bodies are acidic in nature, and, if levels
an intermediate in ketogenesis, is formed via mitochondrial
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of these ketone bodies are too high, the pH of the blood

HMG CoA synthase. HMG CoA is also formed in the cy-
drops, resulting in ketoacidosis. This usually occurs in un-
toplasm as a precursor of cholesterol biosynthesis. In keto-
controlled diabetes mellitus and also in alcoholics after
genesis, HMG CoA is cleaved by HMG CoA lyase to form
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binge drinking, subsequent to starvation, and as a result of

acetoacetate with acetyl Coenzyme A as the other product.
the alcohol-induced impairment of the liver’s ability to
b-Hydroxybutyrate, the primary ketone body in the blood, is
generate glucose by the process of gluconeogenesis.2
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formed from acetoacetate via b-hydroxybutyrate dehydro-

genase, which requires NADH as a coenzyme. Ketone
bodies are a soluble, easily transportable form of acetyl units
that can be oxidized to carbon dioxide and water to yield
energy.1 Ketone bodies include acetoacetate, beta hydroxy
butyrate, and acetone. Ketone bodies are an important source
of energy for peripheral tissues, because they are soluble in
aqueous solution and do not require to be carried by albumin
or lipoproteins. Ketone bodies are produced in the liver in
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Diabetic Ketoacidosis
Diabetic ketocidosis may be the presenting feature in a
patient not previously recognized as having diabetes.3 In a
patient with known diabetes, it may be precipitated by
omitting insulin doses, or by the insulin dose becoming in-
adequate because of an increase in hormones with opposing

response to elevated acetyl Coenzyme A levels and are used action, due to intercurrent infection, trauma, or unusual
in extrahepatic tissues (including brain) proportionately to physical or psychological stress.4 The clinical features are
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their concentration in blood and are not used by the liver as a
fuel source, as the liver lacks thiophorase. Ketone bodies are
utilized under normal circumstances by cardiac muscle and
renal cortex, in preference to glucose. They are present in
Manuscript received 31 October 2012. Revision accepted 15 July 2013.
Address correspondence to: Muhammad Akram, BEMS, Mphil, PhD, Department of
Eastern Medicine and Surgery, Faculty of Medical and Health Sciences, The University
of Poonch, Rawalakot, 05824, Azad Jammu and Kashmir, Pakistan, E-mail:
makram_0451@yahoo; makram_0451@hotmail.com
dehydration, ketosis, and hyperventilation. The degree of
hyperglycemia does not correlate with the severity of the
metabolic disturbance in diabetic ketoacidosis (DKA), and
in some patients, it may not be very high (e.g., in children,
pregnant women, malnourished or alcoholic patients). Ke-
toacidosis is due to insulin deficiency, accompanied by
raised plasma concentrations of the counter-regulatory
hormones (adrenaline, cortisol, growth hormone, and glu-
cagon) The changes in these circulating hormones result in
hyperglycemia and in mobilization of free fatty acids from
adipose tissue, and, subsequently, increased ketone body

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2 AKRAM
production in the liver.5 The major metabolic abnormalities
result from hyperglycemia or ketoacidosis or both.6 Hy-
perglycemia causes extracellular hyperosmolarity, which, in
turn, leads to intracellular dehydration as well as to an os-
motic diuresis. The osmotic pressure diuresis causes loss of
water, sodium, potassium, calcium, and other inorganic
constituents, and leads to a fall in circulating blood volume.
Ketone bodies stimulate the chemoreceptor trigger zone, so
vomiting may exacerbate all these effects. The increased
production of ketone bodies causes a metabolic acidosis
with associated hyperkalaemia. Lactic acidosis and pre-
renal uaemia may also be present. DKA is a state of absolute
or relative insulin deficiency that is aggravated by ensuing
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hyperglycemia, dehydration, and acidosis-producing de-
rangements in intermediary metabolism.7 The most com-
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mon causes are underlying infection, disruption of insulin
treatment, and new onset of diabetes. DKA is typically
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characterized by hyperglycemia over 300 mg/dL, low bi-
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carbonate level (< 15 mEq/L), and acidosis (pH < 7.30) with
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ketonemia and ketonuria. While definitions vary, moderate
DKA can be categorized by pH < 7.2 and serum bicarbon-
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ate < 10 mEq/L; whereas severe DKA has pH < 7.1 and
bicarbonate < 5 mEq/L. Mental status changes can be seen
with mild-to-moderate DKA with more severe deterioration
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in mental status typical with moderate-to-severe diabetic
ketoacidosis. The hallmark of potentially fatal DKA is
when severe insulin deficiency causes free fatty acids to pour
out of adipose tissue and undergo conversion in the liver to
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the ketone bodies, D-hydroxybutyrate (R-3-hydroxybutyrate)
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and acetoacetate. In this condition, ketone bodies can reach
25 mM in blood, causing blood bicarbonate to fall to near
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zero, resulting in severe acidosis. This and the accompa-
nying hypovolemia due to urinary loss of water from the
hyperglycemia and glycosuria, combined with loss of so-
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dium and potassium from the ketonuria, result in death if
untreated.8
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RESEARCH STUDIES
Genetic obesity affects neural ketone body utilization
in the rat brain
It has been shown that ketone bodies are utilized for the
synthesis of lipidic substances, and these are responsible for
causing metabolic disorders in the nervous system.9
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Lipogenesis and streptozocin-induced diabetes
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A study in streptozocin-induced diabetic rats concluded
that in streptozocin-induced diabetes, ketosis can not stim-
ulate hepatic lipogenesis via cytosolic activation of acet-
oacetate.10
Ketone bodies are beneficial in patients
with Alzheimer’s disease
It has been observed that in patients with Alzheimer’s
disease (AD), there is a region-specific decline in brain
glucose metabolism.11 The preferred energy source of the
brain is glucose, and it mainly depends on glucose as an
energy substrate. Therefore, impairment of glucose metab-
olism can have profound effects on brain function. This
impairment of glucose metabolism in patients with AD has
recently attracted attention as a possible target for inter-
vention in the disease process. One promising approach is to
supplement the normal glucose supply of the brain with ke-
tone bodies, which include acetoacetate, b-hydroxybutyrate,
and acetone. Ketone bodies are usually produced from fat
stores when glucose supplies are limited, such as during
starvation and fasting.12 Ketone bodies have been induced
both by direct infusion and by the administration of high-fat,
low-carbohydrate, low-protein, ketogenic diets. Both ap-
proaches have demonstrated efficacy in animal models of
neurodegenerative disorders and in human clinical trials,
including AD trials. Much of the benefit of ketone bodies
can be attributed to their ability to increase mitochondrial
efficiency and supplement the brain’s normal reliance on
glucose. Research into the therapeutic potential of Ketone
bodies and ketosis represents a promising new area of Al-
zeimer’s disease research.13
Role of ketone bodies in epilepsy
Seizures that are resistant to standard treatments remain a
major clinical problem. Such types of patients who are re-
sistant to standard medications are advised to consume high-
fat, low-carbohydrate ketogenic diets that produce ketone
bodies such as acetoacetate, beta hydroxybutyrate, and
acetone. The exact mechanisms of the diet are unknown,
but ketone bodies are considered as contributing to anti-
convulsant antiepileptic effects. Ketone bodies may be
useful in the treatment of epilepsy.14
Neuroprotective and disease-modifying effects
of the ketogenic diet
The ketogenic diet is prescribed for patients with epi-
lepsy. There is evidence that the ketogenic diet is effective
in neurodegenerative disorders such as Parkinson disease
and AD. Furthermore, it may be useful in traumatic brain
injury and stroke. Neuroprotective effects of ketone bodies
are evident from various studies carried out in animal
models and isolated cells. Ketone bodies confer neuropro-
tection against diverse types of cellular injury. Ketone
bodies have demonstrated neuroprotective effects, but the
mechanism is not defined. It has been suggested that neu-
roprotection may be due to energy reserves which resist
metabolic changes in the brain.15
DISCUSSION
One possible fate for the fatty acids released as a result of
triacylglycerol breakdown is conversion to ketone bodies.16
Ketone bodies, unlike fatty acids, cross the blood-brain
barrier. Ketone bodies, unlike glucose, can be synthesized
from acetyl-Coenzyme A. Ketone bodies can, therefore,
provide energy to the brain when glucose availability is
limited.17 Ketone bodies are synthesized from acetyl-
 KETONE BODIES AND THEIR MANIFESTATIONS
Coenzyme A in liver mitochondria by a short pathway be-
ginning with thiolase. One control for the production of
ketone bodies is feed-back regulation of high levels of
acetyl-Coenzyme A favoring the thiolase condensation re-
action that forms acetoacetyl-Coenzyme A, rather than the
thiolase cleavage reaction which produces additional acetyl-
Coenzyme A. Ketone bodies are converted back to acetyl-
Coenzyme A using ketoacyl-Coenzyme A transferase. Liver
mitochondria lack this enzyme; starvation causes the brain
and some other tissues to increase the synthesis of ketoacyl-
Coenzyme A transferase, and, therefore, to increase their
ability to use these compounds for energy.
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Regulation of ketone bodies
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Ketone bodies accumulate in the plasma in conditions of
fasting and uncontrolled diabetes. The initiating event is a
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change in the molar ratio of glucagon: insulin. Insulin de-
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ficiency triggers the lipolytic process in adipose tissue with
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the result that free fatty acids pass into the plasma for uptake
by the liver and other tissues. Glucagon appears to be the
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primary hormone involved in the induction of fatty acid
oxidation and ketogenesis in the liver. It acts by acutely
lowering hepatic malonyl-CoA concentrations as a conse-
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quence of inhibitory effects exerted in the glycolytic path-
way and on acetyl-Coenzyme A carboxylase. The fall in
malonyl-CoA concentration activates carnitine acyl-
transferase I, which facilitates the transport of long-chain
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fatty acids through the inner mitochondrial membrane to the
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enzymes of fatty acid oxidation and ketogenesis. The latter
are high-capacity systems assuring that fatty acids entering
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the mitochondria are rapidly oxidized to ketone bodies.
Thus, the rate-controlling step for ketogenesis is carnitine
acyltransferase I. Administration of food after a fast, or of
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insulin to the diabetic subject, reduces plasma-free fatty acid
concentrations, increases the liver concentration of malonyl-
CoA, inhibits carnitine acyltransferase I, and reverses the
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ketogenic process.18
AUTHOR DISCLOSURE STATEMENT
No competing financial interests exist.
REFERENCES
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1. Veech RL: Insulin, ketone bodies, and mitochondrial energy
transduction. FASEB J 1995;9:651–658.
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2. Wu GY, Gunasekara A, Brunengraber H, Marliss EB: Effects of
extracellular pH, CO2, and HCO3- on ketogenesis in perfused rat
liver. Am J Physiol 1991;261:221–226.
3. Newton CA, Raskin P: Diabetic ketoacidosis in type 1 and type 2
diabetes mellitus: clinical and biochemical differences. Arch
Intern Med 2004;164:1925–1931.
4. Wilson V: Diagnosis and treatment of diabetic ketoacidosis.
Emerg Nurse 2012;20:14–18.
5. DiMarco JP, Hoppel C: Hepatic mitochondrial function in ke-
togenic states. Diabetes, starvation, and after growth hormone
administration. J Clin Invest 1975;55:1237–1244.
6. Rewers A, Klingensmith G, Davis C, Petitti DB, Pihoker C,
Rodriguez B, Schwartz ID, Imperatore G, Williams D, Dolan
LM, Dabelea D: Presence of diabetic ketoacidosis at diagnosis of
diabetes mellitus in youth: the Search for Diabetes in Youth
Study. Pediatrics 2008;121:1258–1266.
7. Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda
GK, Chance B, Clarke K, Veech RL: Insulin, ketone bodies, and
mitochondrial energy transduction. FASEB J 1995;9:651–658.
8. Ming V, Bishop G, Maria B: Diabetic ketoacidosis in Type 2
diabetics: a novel presentation of pancreatic adenocarcinoma.
J Gen Intern Med 2010;25:369–373.
9. Ryota N: Genetic obesity affects neural ketone body utilization in
the rat brain. Obesity 2009;17:611–615.
10. Freed LE, Endemann G, Tomera JF, Gavino VC, Brunengraber
H: Lipogenesis from ketone bodies in perfused livers from
streptozocin-induced diabetic rats. J Diabetes 1988;37:50–55.
11. Handerson ST: Ketone bodies as a therapeutic for Alzheimer’s
disease. Neurotherapeutics 2008;5:470–480.
12. Daniel W, Foster A: Studies in the ketosis of fasting. J Clin
Invest 1967;46:1283–1296.
13. Samuel T, Janet L, Linda J, Fiona G, Julie J, Lauren C: Study of
the ketogenic agent AC-1202 in mild to moderate Alzheimer’s
disease: a randomized, double-blind, placebo-controlled, multi-
center trial. Nutr Metab 2009;6:1743–1747.
14. Mcnally MA, Hartman AL: Ketone bodies in epilepsy. J Neu-
rochem 2012;121:28–35.
15. Maciej G, Michael A, Adam L, Hartmana B: Neuroprotective
and disease-modifying effects of the ketogenic diet. Behav
Pharmacol 2006;17:431–439.
16. Yeh YY, Klein LB, Zee P: Long and medium chain triglycerides
increase plasma concentrations of ketone bodies in suckling rats.
Lipids 1978;13:566–571.
17. Macallum AB: The significance of ketogenesis. Can Med Assoc J
1930;22:3–11.
18. McGarry J, Wright PH, Foster DW: Hormonal control of keto-
genesis. Rapid activation of hepatic ketogenic capacity in fed rats by
anti-insulin serum and glucagon. J Clin Invest 1975;55:1202–1209.