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Measuring Ketone Bodies for the Monitoring of Pathologic and Therapeutic Ketosis


Abstract and Figures

Background The ketone bodies β‐hydroxybutyrate and acetone are generated as a by‐product of the fat metabolism process. In healthy individuals, ketone body levels are ∼0.1 mM for blood β‐hydroxybutyrate (BOHB) and ∼1 ppm for breath acetone (BrAce). These levels can increase dramatically as a consequence of a disease process or when used therapeutically for disease treatment. For example, increased ketone body concentration during weight loss is an indication of elevated fat metabolism. Ketone body measurement is relatively inexpensive and can provide metabolic insights to help guide disease management and optimize weight loss. Methods This review of the literature provides metabolic mechanisms and typical concentration ranges of ketone bodies, which can give new insights for these conditions and rationale for measuring ketone bodies. Results Diseases such as heart failure and ketoacidosis can affect caloric intake and macronutrient management which can elevate BOHB 30‐fold and BrAce 1,000‐fold. Other diseases associated with obesity such as brain dysfunction, cancer, and diabetes may cause dysfunction because of an inability to use glucose, an excessive reliance on glucose, or poor insulin signaling. Elevating ketone body concentrations (e.g., nutritional ketosis) may improve these conditions by forcing utilization of ketone bodies, in place of glucose, for fuel. During weight loss, monitoring ketone body concentration can demonstrate program compliance and can be used to optimize the weight loss plan. Conclusions The role of ketone bodies in states of pathologic and therapeutic ketosis indicates that accurate measurement and monitoring of BOHB or BrAce will likely improve disease management. Bariatric surgery is examined as a case study for monitoring both types of ketosis. This article is protected by copyright. All rights reserved.
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Received: 12 February 2021
Revised: 29 March 2021
Accepted: 11 April 2021
DOI: 10.1002/osp4.516
Measuring ketone bodies for the monitoring of pathologic
and therapeutic ketosis
Joseph C. Anderson
|Samer G. Mattar
|Frank L. Greenway
|Richard J. Lindquist
Department of Bioengineering, University of
Washington, Seattle, Washington, USA
Department of Surgery, Baylor College of
Medicine, Houston, Texas, USA
Pennington Biomedical Research Center,
Baton Rouge, Louisiana, USA
Department of Family Medicine, Swedish
Medical Center, Seattle, Washington, USA
Joseph C. Anderson, Department of
Bioengineering, University of Washington,
Box 355061, Seattle, WA 981955061, USA.
Funding information
Medamonitor Corp, Seattle, WA; National
Institute of General Medical Sciences, Grant/
Award Number: 1 U54 GM104940
Background: The ketone bodies β‐hydroxybutyrate (BOHB) and acetone are
generated as a byproduct of the fat metabolism process. In healthy individuals,
ketone body levels are 0.1 mM for BOHB and 1 part per million for breath
acetone (BrAce). These levels can increase dramatically as a consequence of a
disease process or when used therapeutically for disease treatment. For example,
increased ketone body concentration during weight loss is an indication of elevated
fat metabolism. Ketone body measurement is relatively inexpensive and can provide
metabolic insights to help guide disease management and optimize weight loss.
Methods: This review of the literature provides metabolic mechanisms and typical
concentration ranges of ketone bodies, which can give new insights into these
conditions and rationale for measuring ketone bodies.
Results: Diseases such as heart failure and ketoacidosis can affect caloric intake and
macronutrient management, which can elevate BOHB 30fold and BrAce 1000fold.
Other diseases associated with obesity, such as brain dysfunction, cancer, and
diabetes, may cause dysfunction because of an inability to use glucose, excessive
reliance on glucose, or poor insulin signaling. Elevating ketone body concentrations
(e.g., nutritional ketosis) may improve these conditions by forcing utilization of
ketone bodies, in place of glucose, for fuel. During weight loss, monitoring ketone
body concentration can demonstrate program compliance and can be used to
optimize the weightloss plan.
Conclusions: The role of ketone bodies in states of pathologic and therapeutic
ketosis indicates that accurate measurement and monitoring of BOHB or BrAce will
likely improve disease management. Bariatric surgery is examined as a case study
for monitoring both types of ketosis.
β‐hydroxybutyrate, acetone, bariatric surgery, metabolism
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.
Obes Sci Pract. 2021;7:646656.
The recent popularity of the ketogenic diet (KD) has kindled a
renewed interest in the creation and metabolism of ketone bodies
and the state of ketosis. This diet, characterized by highfat and very
lowcarbohydrate (<50 g/day) intake, appears to result in improve-
ments in weight management, metabolic syndrome, and cognition.
Implicitly, the diet mandates a marked reduction in carbohydrate
intake, which results in the generation and utilization of ketone
bodies, instead of carbohydrates, to fuel the brain and other neuro-
logic tissues. Many authorities assumed that ketone bodies, in states
of carbohydrate restriction, are the primary drivers for the perceived
benefits of the KD. Because of this success, an explosion in research
has taken place to identify additional interventions that may increase
ketosis (e.g., intermittent fasting and exogenous supplementation)
and to better understand the effects of ketosis in health and dis-
Ketosis is defined as the elevated concentration of ketone bodies
in the blood. Ketone bodies are comprised of three chemicals: ace-
toacetate, β‐hydroxybutyrate (BOHB), and acetone. Acetoacetate is
created in the liver from free fatty acids (FFAs) when glucose avail-
ability is limited. Acetoacetate can be enzymatically interconverted
into BOHB.
Additionally, acetoacetate can be decarboxylated,
spontaneously or by catalytic action, into acetone (Figure 1).
tone body concentrations increase with corresponding increases in
fat metabolism.
Recent studies have also demonstrated a number of nondiet
related disease conditions that can cause elevated ketosis.
These diseases cause hyperketonemia for a variety of reasons,
including poor insulin signaling in diabetes, impaired fatty acid
metabolism in heart failure (HF), and slow ketone body elimination as
a result of genetic disorders. It is logical, therefore, that monitoring
ketosis levels may provide a complete picture of the behavior and
severity of the underlying disease. Additionally, periodic ketosis
monitoring may help in the management and treatment of the
Some diseases appear to respond favorably to an increase in
ketosis. It has been demonstrated that once ketones reach “thera-
peutic” levels, they help attenuate disease severity or result in dis-
ease regression.
Examples include neurologic diseases where the
ketone bodies provide fuel to metabolically compromised brain re-
gions and treatment of type 2 diabetes to improve diabetic sequelae
and reduce medications. Thus, monitoring ketosis levels can help
maintain therapeutic concentrations of ketone bodies to optimize
disease treatment.
Additionally, weight loss creates an elevation in fat metabolism
that is reflected in elevated ketone body concentrations.
Elevated fat metabolism is correlated with increased ketone body
Thus, medical weight loss and weight loss prior to
bariatric surgery may be optimized and compliance assessed by
monitoring ketone bodies as surrogate markers of subjectspecific fat
Measurement of ketone bodies is becoming more common
because of an increase in the number of relatively inexpensive con-
sumer devices. These chemical sensors typically measure acetoace-
tate in urine, BOHB in blood, or acetone in breath (BrAce). While
urine samples are common, urine acetoacetate is not typically
assessed using a quantitative method causing significant measure-
ment uncertainty.
Currently, blood BOHB is the gold standard
for assessing ketosis. However, the measurement of BrAce is
becoming more widely accepted as a reliable indicator, particularly at
low ketone body levels where BrAce has greater sensitivity to change
than blood BOHB.
Ketone body concentrations for two reference
states are as follows (Table 1): (1) healthy individuals on a balanced
macronutrient diet typically have ketone body concentrations of
BOHB 0.1 mM or BrAce 1 part per million (ppm); and (2) subjects
in nutritional ketosis (i.e., ketoadaptation) have ketone body con-
centrations of at least BOHB =0.5 mM
or BrAce 9 ppm.
The concentrations of ketone bodies observed for a range of
diseases haven't been summarized. This review describes diseases
that cause ketosis (ketogenic diseases), their underlying ketogenic
mechanisms, and the ranges of ketosis (as defined by blood BOHB
and BrAce concentrations) that are associated with the disease. For
diseases that can be treated with an elevation in ketosis (therapeutic
ketosis), the underlying mechanism of therapeutic ketosis and the
thresholds of ketone body concentrations associated with a thera-
peutic benefit are detailed. Measurement of ketone body concen-
trations is needed to demonstrate the achievement of a therapeutic
ketone body level. Additionally, ketone body elevation during weight
loss and how it can be used to optimize fat loss are reviewed. Finally,
a case study on bariatric surgery provides a vignette for how moni-
toring ketone bodies can be used for disease and therapeutic benefit.
Heart failure
In health, fatty acids provide 50%–70% of the heart's energy.
In HF,
myocardial fatty acid metabolism is impaired which may be due to a
downregulation of myocardial proteins used to metabolize fatty
acids. However, lipolysis and FFAs are elevated in HF because of
increases in stress hormones (e.g., cortisol), cytokines, malnutrition,
FIGURE 1 Acetoacetate, formed primarily from β‐oxidation of
fatty acids, can be reduced to β‐hydroxybutyrate (BOHB) or
decarboxylated to acetone. Betahydroxybutyrate dehydrogenase
(BDH) interconverts acetoacetate and BOHB depending on
intercellular conditions (e.g., NADH). Acetone is produced via
spontaneous or catalytic decarboxylation of acetoacetate. NADH,
nicotinamide adenine dinucleotide
or cardiac cachexia.
Unable to metabolize FFA, the failing
heart shifts to other fuels including ketone bodies which are elevated
in HF.
Greater concentrations of ketone bodies are observed
because (1) the abundance of serum FFA causes a rise in liver
ketogenesis, the source of ketone bodies; and (2) skeletal muscles
have lower consumption of BOHB.
BOHB can be rapidly utilized
by the metabolically compromised myocardium because the enzymes
required for ketone body metabolism are more abundant in HF.
In scientific studies, subjects with HF have 2–20fold greater
levels of the ketone body acetone in breath (BrAce, Table 1) as
compared to healthy controls (BrAce 1 ppm) or to cardiac patients
without HF.
Increases (decreases) in BrAce correspond to
increased (decreased) HF severity.
Thus, monitoring BrAC may
provide a marker of HF deterioration or improvement.
In healthy individuals, insulin in the blood interacts with the cell
membrane to facilitate the uptake of blood glucose by the cell.
Additionally, the interaction of insulin with adipose tissue suppresses
lipolysis. In individuals with diabetes, cells are unable to receive the
insulin signal because either insulin is not present (type 1 diabetes) or
the cell is insensitive to insulin and doesn't respond to its presence
(type 2 diabetes). Thus, glucose is not taken up by the cell, and the
concentration of glucose in the blood rises. Without the insulin signal,
lipolysis is no longer inhibited, plasma FFA rises, and hepatic ketone
body production increases.
In lieu of glucose as a primary fuel
source, cells can use fatty acids and ketone bodies to meet their
energy requirements. Without the insulin signal to reduce blood
sugar and suppress fat breakdown, glucose (hyperglycemia), ketone
bodies (hyperketonemia), and hydrogen ions (acidosis) can increase
dramatically in the blood and, without intervention, lead to diabetic
ketoacidosis (DKA).
Because ketone bodies are a precursor and marker of DKA,
measurement of ketone bodies can help identify the development,
assess the severity, and assist in monitoring the resolution of DKA.
As ketoacidosis develops, BOHB and BrAce increase from healthy
levels (BOHB 0.1 mM or BrAce 1 ppm) to those associated with
the onset of ketoacidosis (BOHB >3 mM or BrAce >75 ppm) (Ta-
ble 1). Because of the large concentration range between healthy
ketone body levels and ketoacidosis, ketone body monitoring can
provide a critical tool to alert providers and patients that a healthy
ketosis state is developing into ketoacidosis, allowing expedient
treatment before it reaches a critical level.
When DKA is present,
measurement of BOHB and BrAce may help to assess the severity of
ketoacidosis. BOHB (3–20 mM) and BrAce (75–1250 ppm) range
considerably in people with DKA, and the magnitude of these ketone
bodies may be associated with increased severity of DKA.
the intervention, scientific studies have demonstrated that ketone
body measurement can improve the course of DKA resolution.
Four diabetes associations recommend ketone body monitoring,
TABLE 1Ketone body (BOHB in mM or BrAce in ppm) concentration ranges observed in health, for disease states and for therapeutic
benefit (minimum concentration thresholds)
Ketosis Condition
Range or threshold
ReferencesBOHB (mM) BrAce (ppm)
Health Balanced macronutrient diet 0.1 1
Nutritional ketosis 0.5 9
Disease Heart failure >0.2 2–20
Ketoacidosis >3.0 >75
Genetic disorders See text
Therapy Brain function: Alzheimer’s 0.5 9
a 29,30
Brain function: Parkinson’s 1.0
Brain function: Dementia 0.5 9
a 32
Brain function: Migraine 4.0 See text
Cancer 0.5 9
a 33,34
Type 2 diabetes 0.5 9
a 35,36
Epilepsy 4.0
Weight loss 2
Bariatric surgery Ketoacidosis >3.0 >75 See text and references above
Weight loss 2
Abbreviations: BOHB, β‐hydroxybutyrate; BrAce, breath acetone.
Nutritional ketosis. BrAce 9 ppm when BOHB =0.5 mM.
typically BOHB, during DKA resolution.
During DKA, the concen-
tration of BOHB is much greater than acetoacetate.
As DKA is
treated, BOHB decreases by conversion to acetoacetate, which
causes an elevation of acetoacetate. Because DKA is not resolved
until both BOHB and acetoacetate concentrations return to baseline,
monitoring BrAce, a product of acetoacetate decarboxylation, at 30
min intervals, can demonstrate the full resolution of DKA.
Additionally, monitoring ketone bodies during resolution should
reduce the duration and cost of medical treatment.
Prevention of DKA may be the best use of ketone body mea-
surement. DKA requires immediate medical attention (e.g., emer-
gency room visit), with an average cost for hospitalization of $26,566
in 2014.
To reduce DKA events and hospitalization, scientific
studies recommend selfmonitoring of ketone bodies in patients with
type 1 diabetes, insulindependent type 2 diabetes, sustained blood
glucose concentration >300 mg/dl, acute illness, or stress.
Patients have indicated that measurements of elevated BOHB were
useful in determining subsequent insulin dose and food intake.
During sick days, particularly those involving nausea, vomiting, or
infections, scientific studies recommend monitoring BOHB
throughout the day, specifically for young children because of the
frequency of illness in this population.
Studies indicate that chil-
dren and adults who measure BOHB during “sick days” can prevent
the onset of DKA, reduce the time to DKA resolution, reduce mon-
etary costs, and decrease the rate of hospitalizations.
Euglycemic ketoacidosis
In addition to ketoacidosis associated with poorly controlled dia-
betes, ketoacidosis can occur in patients with diabetes who control
their blood sugar with a sodium–glucose cotransporter2 (SGLT2)
inhibitor. The SGLT2 inhibitor eliminates excess blood glucose
through excretion by the kidneys and may lead to ketoacidosis, in a
subset of individuals with diabetes, even though blood glucose is well
controlled (i.e., euglycemic ketoacidosis).
This condition appears to be driven by low insulin levels in in-
dividuals with impaired insulin secretion, poor fluid intake, low car-
bohydrate intake, and/or fasting.
Because the SGLT2 inhibitor
maintains blood glucose within a “healthy range”, blood glucose
monitoring will not alert individuals or clinicians to the developing
ketoacidosis. Thus, measurement of ketone bodies is important for
these subjects, perhaps even more so on sick days. The monitoring
guidelines outlined for ketoacidosis (above) could be applied. The
large concentration differential between healthy ketone body levels
and ketoacidosis can be exploited to monitor elevations in ketosis.
Significant elevations can be addressed before a crisis develops.
Interestingly, pregnant women with diabetes (<3% of all diabetic
gestations) can have euglycemic ketoacidosis which may progress
more rapidly as compared to nonpregnancy states.
Thus, ketone
body measurement may identify the early stages of hyperketonemia
before it escalates to DKA.
Genetic disorders
Genetic disorders can elevate ketosis through the overproduction
of ketone bodies or impairment of ketone body utilization. Hepatic
ketone body production elevates when low blood glucose causes a
reduction in insulin and an increase in circulating fatty acids.
Normal glucose levels, maintained via glycogen metabolism
or gluconeogenesis, are dependent on key enzymes such
as glycogen synthase, glycogen phosphorylase kinase, fructose
1,6diphosphatase, or glucose6phosphatase. Genetic disorders
can prevent the expression of these enzymes, which would cause
fasting hypoglycemia and accelerated ketogenesis leading to
A lack of peripheral tissue utilization will cause ketone body
elevation. The pathway for ketolysis is controlled by two enzymes
(Figure 2): succinylCoA:3oxoacidCoA transferase (SCOT) and
acetylCoA acetyltransferase1 (ACAT1), which early literature iden-
tified as 2methylacetoacetylCoA thiolase (MAT). A lack of these
enzymes causes hyperketonemia and ketoacidosis, particularly in a
fasting state.
Monitoring ketonemia via BOHB or BrAce measurement can
provide a quantitative check on dietary compliance, particularly on
sick days, and a method to minimize the conversion of hyper-
ketonemia to ketoacidosis. Ketone body thresholds have not been
described but would likely be similar to those for ketoacidosis
(BOHB >3 mM or BrAce >75 ppm—see Section 2.2).
FIGURE 2 Pathway for utilization of ketone bodies (ketolysis) where deficiencies in SCOT or ACAT1 cause significant ketonemia (adapted
from Aubert et al.
). β‐oxidation is output from β‐oxidation of fatty acids. ACAT1, acetylCoA acetyltransferase1; BDH, β‐hydroxybutyrate
dehydrogenase; MCT, monocarboxylate transporter; SCOT, succinylCoA:3oxoacidCoA transferase
In addition to weight loss, multiple obesityassociated diseases
respond favorably to elevated ketosis. These diseases appear to have
impaired glucose metabolism (e.g., brain dysfunction) or an inability
to manage elevated insulin and glucose (e.g., cancer, diabetes).
Elevated BOHB may provide relief by replacing glucose as a primary
source of energy and removing oxidant species.
For these
obesityassociated diseases, carbohydrate restriction may be the
optimal modality for elevating ketone bodies while decreasing insulin
and blood glucose concentration. Therapeutic BOHB concentrations
are primarily disease dependent and modulated by a multitude of
factors including age, gender, weight, diet, and disease severity. Thus,
sequential ketone body measurements over time can demonstrate
that the threshold for therapeutic ketosis has been achieved and
Brain function
In health, glucose fuels the brain. During starvation, glucose is scarce
and FFAs are abundant. Because the brain cannot use fat for fuel, the
body converts fat into ketone bodies to fuel the brain.
studies have demonstrated that elevated ketone bodies (via KD,
supplementation with medium chain triglyceride, fasting, etc.) can
improve brain function in subjects with Alzheimer's, dementia, and
Parkinson's disease.
It appears that these diseases are characterized by the
inability of specific brain regions to use glucose for fuel, which
causes regional dysfunction in the brain. When available, ketone
bodies can fuel diseased brain regions resulting in improvement of
neurologic function. At BOHB concentrations >4 mM, ketone
bodies are estimated to supply more than 50% of the brain's en-
ergy requirement.
Many factors drive Alzheimer's disease including insulin resistance,
genetic defects, and a regional reduction in glucose metabolism
which is correlated to decrements in cognitive scores.
Elevation in
BOHB to 0.5 mM (BrAce 9 ppm) via consumption of ketogenic
foods appears to improve cognitive function.
improvement in cognitive function is associated with increased
BOHB concentrations.
The benefits of elevated ketone bodies on mitochondrial activity
have been proposed for Parkinson's disease. While similar to the
mechanisms for other brain maladies, it is hypothesized that
BOHB increases energy production because BOHB may bypass a
defect in complex I of the electron transport chain.
In one
study, subjects with Parkinson's on a 4week KD showed
improvement on the Unified Parkinson's Disease Rating Scale. A
pilot study showed some symptom resolution when BOHB =1.0
While additional studies are needed, it is expected that
BOHB must range between 2 and 7 mM to provide a therapeutic
Older subjects with mild cognitive impairment may experience
improved verbal memory performance using a very low carbohydrate
diet (<35 g/day on average). Improved memory performance corre-
lated with increases in ketone levels and reductions in insulin
Healthy geriatric individuals will also likely benefit from the
best improvement found in subjects with strong dietary compli-
Based on the dietary criteria, subjects with cognitive
impairment may need BOHB concentrations >0.5 mM (BrAce 9
ppm) to achieve a benefit.
Migraine can be characterized as a neurologic inflammation and a
reduction in brain metabolism.
To prevent or protect against
migraines, elevated ketone bodies may reduce neuroinflammation,
inhibit oxidative stress, and modulate mitochondrial function.
Ketotherapeutic benefits for migraines have been known for
almost 100 years.
In recent studies, consumption of a very low
carbohydrate (<30 g/day) and lowcalorie KD was associated with
significant reductions in the number of migraine attacks per
month (76% drop) and the number of days with headaches (82%
One subject had complete remission of migraine
Relief was observed within a few days of diet
Because the diets used are similar to those used for
epilepsy therapy, a BOHB greater than 4 mM may be required
(Table 1).
Some subjects with epilepsy have intractable seizures, which are
unresponsive to antiepileptic drugs.
The frequency of these sei-
zures can, in many cases, be reduced with a KD. In children,
approximately 50% of subjects experienced an improvement in
seizure frequency when adhering to this diet for a few months.
children adhering to the diet for 1 year, almost 50% of subjects re-
ported a nearly complete (90%) reduction in seizures; similar out-
comes persisted for years after study termination.
Adults with
epilepsy also experienced a reduction in seizure frequency when
placed on KDs. It is clear that elevations in ketone bodies correspond
to successful ketogenic therapy.
Scientific studies have shown a
relationship between elevated BOHB and improved seizure control
in children.
Ketone body measurement can demonstrate dietary compliance
required for therapeutic benefit.
The therapeutic benefit ap-
pears to be around 4 mM for BOHB
(Table 1). When adverse
effects of the diet occur (e.g., constipation, bloating, or irregular
menstrual cycles), ketone body measurement can provide positive
reinforcement, provide information to optimize dietary composition,
and hasten return to therapeutic ketosis after a “cheat” day.
Rapid and uncontrolled cell growth in cancer is fueled by glucose, an
observation named the Warberg effect.
Thus, restricting circulating
glucose (e.g., by consumption of a very lowcarbohydrate and highfat
diet) should cause tumor cells to starve and die.
In healthy cells,
energy is produced via aerobic respiration of glucose, fats, or ketone
bodies which requires healthy mitochondria, an intact tricarboxylic
acid cycle, and a functional electron transport chain. In cancer cells,
compromised aerobic respiration forces cancer cells to rely solely on
anaerobic glycolysis and aerobic fermentation of glucose for en-
High corresponding insulin levels signal the expression of
glucose transporters (e.g., GLUT3) and glycolytic enzymes.
Carbohydrate restriction will slow cancer growth in three ways.
Without fuel, these cells starve and become more susceptible to
A decrease in circulating insulin inhibits the
signal to upregulate the glucose transporters (e.g., GLUT3) and
glycolytic enzymes required for metabolism. Increased BOHB re-
duces oxidative stress and inflammation, induces apoptosis, and is
associated with regression of cancer growth.
healthy cells thrive via aerobic metabolization of fats and ketone
The few studies using ketotherapy have shown potential benefits
(e.g., tumor stability or regression) to the brain (i.e., glioblastoma),
breast, lung, and colon cancer.
This regimen likely requires
carbohydrate restriction combined with one or more of the following:
highfat consumption, caloric restriction, fasting, or exogenous ke-
tone supplementation. Measurement of ketosis in cancer patients
may help monitor compliance, facilitate dietary modifications, and
achieve therapeutic levels of ketone bodies. The minimum threshold
for therapeutic benefit appears to be 0.5 mM (BrAce 9 ppm) and
likely depends on the cancer type.
Type 2 diabetes
One hallmark of diabetes is elevated blood glucose. In people with
type 2 diabetes, tissues are insensitive to insulin, resulting in the rise
of blood glucose due to increased liver production and a lack of up-
take. To achieve normal levels of blood glucose, clinical investigators
have proposed “prescribing” a KD to restrict dietary carbohydrates
to <50 g/day.
After adaption to KD, subjects, on average,
experience an improvement in diabetic sequelae and medications,
including weight reduction, reduced exogenous insulin, improved
insulin sensitivity, and reduced HbA1c.
To achieve these results, clinical studies have measured BOHB
levels to verify carbohydrate restriction, to guide the reduction of
diabetes medication, and to adjust dietary therapy.
strive to maintain a state of nutritional ketosis, defined as BOHB
0.5 mM.
As an alternative to BOHB, a BrAce 9 ppm, which
corresponded to BOHB 0.5 mM for 95% of measurements, could
be used to demonstrate nutritional ketosis.
Daily ketone body
measurements demonstrate dietary and lifestyle compliance and may
provide a rationale for weaning patients from diabetic medica-
As lifestyle and dietary factors change with time, ketone
body measurements will reflect changes in carbohydrate restriction
and, thus, can be used to help compensate for these changes.
Weight loss
During calorie restriction, energy needs are met by mobilizing fat
from adipose cells. A portion of the circulating fatty acids is con-
verted into ketone bodies within the liver. The amount of ketone
bodies produced is proportional to the rate of fatty acid metabolism
within the liver. For subjects on a calorierestricted diet, the BrAce
concentration has been shown to be proportional to the rate of fat
While BrAce is 1 ppm for a typical subject, individuals who
lost onehalf pound of fat mass per week on a calorierestricted diet
had BrAce =2 ppm. Further elevations in BrAce correlated linearly
with increases in fat mass loss.
As a result of the relationship between BrAce and fat mass loss,
frequent monitoring of BrAce can be used as a tool by individuals and
clinicians to optimize fat loss. During calorie restriction, BrAce 2
ppm indicates an elevated state of fat metabolism and predicts fat
loss if these levels can be maintained. Frequent monitoring provides
individuals with immediate feedback to understand how their well-
ness choices (e.g., diet, exercise, sleep, stress, etc.) affect their state of
fat metabolism. Using this feedback, individuals can adjust their
choices, daily if needed, to optimize and maintain fat loss and in-
crease compliance (unpublished observations). Coaches and clinicians
can utilize longitudinal BrAce measurements to understand individual
fat metabolism, to customize the program for each individual, and to
counsel patients on how to overcome weightloss obstacles. Addi-
tionally, BrAce can be used in weightloss strategies when preparing
for bariatric surgery (discussed below).
One case for measuring BrAce could be tailoring the macronu-
trient composition to optimize weight loss. In general, customization
is difficult because the optimal macronutrient composition for weight
loss is not clear. Scientific debates between proponents of a high
carbohydrate diet
and supporters of a low carbohydrate diet
have not provided resolution. Optimal diet composition is likely
subject dependent. A recent study
suggests a high carbohydrate
diet (60% carbohydrate, 20% fat, and 20% protein) is preferred for
women with obesity who were insulin sensitive (fasting insulin <10
µU/ml) while a lower carbohydrate diet (40% carbohydrate, 40% fat
and 20% protein) is preferred for women with obesity who were
insulin resistant. For all subjects, the preferred macronutrient
composition gave a twofold increase in body weight loss as
compared to the alternative. These findings would indicate that the
ability (inability) to efficiently metabolize carbohydrates, as predicted
by insulin sensitivity (resistance), may predict the best macronutrient
composition for weight loss.
As weight is lost, the body becomes more insulin sensitive. Thus,
at some point during weight loss, the best diet may change from a low
to a high carbohydrate diet. This change could be monitored with
measurements of fasting insulin. However, the cost and invasive
nature make this measurement impractical. A different inflection
point occurs for others during the first 6 months of dieting. Often
when people reach a plateau in their weight loss, they give up dieting
and regain the weight.
Measuring BrAce over days and weeks can give feedback on
metabolic changes within the patient. A reduction in BrAce from
above 2 ppm to near 1 ppm indicates a loss of fat oxidation and, when
combined with a weightloss plateau, may suggest the need for a
dietary change. One cause of this plateau could be the increase in
insulin sensitivity which can be quantified via measurement of fasting
insulin. If insulin sensitivity has improved, an increase in the carbo-
hydrate content could restart weight loss. Thus, regular monitoring of
BrAce during a weightloss program could potentially enable
personalization of dietary carbohydrates and optimize weight loss
over the weightloss journey.
Bariatric surgery
Bariatric surgery serves as a case study for monitoring ketone bodies
for both pathologic (i.e., ketoacidosis) and therapeutic (i.e., weight
loss) ketosis. Over the past halfcentury, bariatric surgery has
emerged as a valid and effective treatment for significant weight loss
and improvement, if not resolution, of associated comorbidities,
including diabetes, hypertension, and sleep apnea.
Most of these
operations, typically indicated for patients with a BMI >35, result in
the correction of the metabolic dysfunction at the center of the
metabolic syndrome and morbid obesity. The dramatic reduction in
hunger and the normalization of disturbed metabolic processes result
in significant weight loss that is derived from a reduction in both fat
and fatfree mass.
Prior to bariatric surgery, weight loss can reduce surgical com-
plications, surgery time, and length of hospital stay.
Very low
calorie diets (VLCD) are commonly used prior to bariatric surgery
as a means to both reduce initial weight and to reduce liver fat
Although VLCDs vary somewhat in calorie and nutrient
composition (typically <800 calories/day), they are as a group
effective in weight loss and metabolic improvement
while typically
maintaining fatfree mass.
VLCD with carbohydrate levels of
<50 g/day result in nutritional ketosis. To demonstrate compliance
with the dietary plan and optimize weight loss, BrAce can be moni-
tored. In fact, measurement of BrAce has been shown to correlate
with weight loss and adherence to the prescribed VLCD
After bariatric surgery, patients are monitored by a multidisci-
plinary team of physicians, nurses, and dietitians, whose main
objective is to ensure that patients maintain optimal benefits with
minimal harm, including that weight loss be predominantly from fat
mass components, and the sparing of fatfree mass. While many
patients do achieve these healthy weightloss objectives, there is a
minority who, for a variety of reasons, may be unable to adhere to
nutritional recommendations and suffer the consequences of poor
oral intake if not rescued in a timely manner. It is imperative,
therefore, that patients at risk should have their fluid status, elec-
trolyte levels, acid–base balance, and nutritional parameters closely
monitored. Comprehensive monitoring may benefit from quantita-
tive measurement of ketone bodies (e.g., BrAce), which could be
used to enhance postbariatric diabetes management and distin-
guish between types and degrees of ketoacidosis such as SGLT2
associated euglycemic ketoacidosis and postsurgery starvation
Starvation ketoacidosis can result secondary to poor oral intake
following bariatric surgery.
Poor oral intake rapidly depletes
hepatic and muscular glycogen stores. Aggravating this situation is
the vomiting and dehydration that are occasionally present and
stimulate the sympathetic system resulting in released cortisol,
adrenaline, glucagon, and growth hormone, which in turn suppress
insulin secretion. The cumulative effects of these changes are
lipolysis and FFA production from adipose tissue and hepatic ke-
tone formation, the basis for starvation ketoacidosis.
all patients who present with severe acid–base imbalance should
undergo ketone body measurement since their elevation is a key
determinant that ketoacidosis is the underlying mechanism for
metabolic acidosis.
In clinical settings, it is important to differentiate starvation
ketoacidosis from DKA, since the treatment for each condition can
have a critical impact on the outcome of these emergency conditions.
DKA is a potentially lethal condition that is more common in patients
with type 1 diabetes who exhibit poor compliance or inadequate
insulin replacement therapy. It is usually associated with hypergly-
cemia and dehydration, and is typically managed with dedicated
protocols that call for aggressive rehydration and insulin adminis-
tration in an attempt to correct the acid–base imbalance. It is
important to distinguish diabetic from starvation ketoacidosis since
glucose administration can be a lifesaving measure in the latter
situation. Although DKA after bariatric surgery is an uncommon
event, it has been documented in patients with type 1 diabetes who
have undergone gastric bypass.
Anesthesia and surgical stress,
abrupt discontinuation of insulin or inadequate treatment in the
perioperative period, postoperative infection, prolonged poor oral
intake, and severe dehydration can be the precipitating causes for
postoperative DKA.
The measurement of ketone body concentration (BOHB or acetone)
can provide valuable information. Diseases such as congestive heart
failure, ketoacidosis, and genetic disorders create an elevated
ketosis which, in many cases, correlates to disease severity. Because
the magnitude of the increased ketosis is typically related to dis-
ease severity, early detection can aid in modifying behaviors before
disease symptoms clinically manifest. The intentional induction of
elevated BOHB concentrations can be used to treat obesity and
obesityassociated diseases such as brain disorders and type 2
diabetes. Elevated BOHB levels provide a benefit through modifi-
cation of mitochondrial energy production and through reduction of
insulin and blood glucose when achieved via glucose restriction.
Measurement of ketosis is critical to verify that a therapeutic level
of ketosis has been achieved and maintained. Frequent measure-
ment of ketosis can allow users to adjust and personalize their diet
and behaviors to maintain therapeutic levels of ketosis. A case
study of bariatric surgery demonstrates that monitoring ketone
bodies before and after surgery may optimize surgical outcomes
and reduce complications.
To date, monitoring ketone concentrations has been shown to
address three conditions: ketoacidosis (prevention, acidosis severity,
and resolution monitoring), improvement of type 2 diabetes (achieve
nutritional ketosis and dietary adherence), and epilepsy (optimize
seizure control). These methods of ketone monitoring can be used as
starting points for the other conditions reviewed. Additional studies
are needed to demonstrate the value of ketone body monitoring for
the other diseases that generate elevated ketosis. For therapeutic
ketosis, ketone monitoring is necessary, at a minimum, to demon-
strate a therapeutic dose has been achieved. Additional research is
needed to better quantify the therapeutic dose as a function of
subjectspecific factors, which include disease severity, de-
mographics, and genetics.
All authors were involved in literature search, writing the manuscript
and final approval of the submitted and published versions.
This work was supported, in part, by Medamonitor Corp, Seattle,
WA and by the National Institute of General Medical Sciences Grant
1 U54 GM104940 which funds the Louisiana Clinical and Trans-
lational Science Center. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the
National Institutes of Health.
Joseph C. Anderson consults for and holds stock in Medamonitor.
Samer G. Mattar has no conflicts to report. Frank L. Greenway re-
ports serving on science advisory boards for JC USA, Regeneron
Pharmaceuticals, and Pfizer; consulting for Jazz Pharmaceuticals,
Basic Research, Dr. Reddy's Laboratories, General Nutrition Corpo-
ration, Melior Discovery Inc., Novmeta Pharma, Novo Nordisk; grants
from Melior Discoveries, Novmeta Pharma; and stock/stock options
from Ketogenic Health Systems, Inc., Plensat Inc., UR Labs. Richard J.
Lindquist consults for Medamonitor.
Joseph C. Anderson
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How to cite this article: Anderson JC, Mattar SG, Greenway
FL, Lindquist RJ. Measuring ketone bodies for the monitoring
of pathologic and therapeutic ketosis. Obes Sci Pract.
2021;7(5):646656. doi:10.1002/osp4.516
... For exposure, we categorized KBs into two groups, e.g., high vs normal levels, based on the assumption that KBs could have a therapeutic benefit when the concentrations reach a certain level [24]. Due to the unknown cutoff, we varied the thresholds across the KB range. ...
... In clinical trials, either ketogenic diet or various types of KB supplement intakes were used to investigate the therapeutic effect on neurodegenerative diseases [24,37]. The suggested therapeutic levels of KB for Alzheimer's and epilepsy were 0.5 mmol/L and 2 mmol/L, respectively [24]; however, no investigation was shown for an early stage of cognitive decline. ...
... In clinical trials, either ketogenic diet or various types of KB supplement intakes were used to investigate the therapeutic effect on neurodegenerative diseases [24,37]. The suggested therapeutic levels of KB for Alzheimer's and epilepsy were 0.5 mmol/L and 2 mmol/L, respectively [24]; however, no investigation was shown for an early stage of cognitive decline. In our study, by varying KB cutoffs, we observed that BOHBUT was associated with the general cognitive performance score, when its concentration reached 0.32 mmol/L. ...
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Background Ketone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function. Methods In observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer’s disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer’s Project (N = 54,162), respectively. Both strong (P < 5 × 10⁻⁸) and suggestive (P < 1 × 10⁻⁵) sets of instrumental variables for BOHBUT were applied. Finally, we performed cis-MR on OXCT1, a well-known gene for KB catabolism. Results BOHBUT was positively associated with general cognitive function (β = 0.26, P = 9.74 × 10⁻³). In MR analyses, we observed a protective effect of BOHBUT on cognitive performance (inverse variance weighted: βIVW = 7.89 × 10⁻², PIVW = 1.03 × 10⁻²; weighted median: βW-Median = 8.65 × 10⁻², PW-Median = 9.60 × 10⁻³) and a protective effect on AD (βIVW = − 0.31, odds ratio: OR = 0.74, PIVW = 3.06 × 10⁻²). Cis-MR showed little evidence of therapeutic modulation of OXCT1 on cognitive impairment. Conclusions Triangulation of evidence suggests that BOHBUT has a beneficial effect on cognitive performance. Our findings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive impairment and reducing the risk of AD.
... Magnesium and calcium are all important electrolytes and micronutrients that are excreted through urine, and abnormal levels of these substances can indicate deficiencies or imbalances in the body that lead to health problems such as muscle weakness and osteoporosis (Schiefermeier-Mach et al. 2020;Fiorentini et al. 2021). Ketone is a byproduct of fat metabolism and its presence in urine can indicate conditions such as diabetes and certain types of cancer (Anderson et al. 2021). pH is a measure of the acidity of urine and can thus indicate the presence of certain medical conditions such as urinary tract infections (UTIs) and kidney stones (Wagner and Mohebbi 2010). ...
Point-of-care diagnostics (POC), including urine test strips, offer several advantages over traditional laboratory-based urine analysis. POC allows us to regulate our nutritional needs. Urine analysis is a common diagnostic and well-being monitoring tool used to evaluate the overall health of an individual. It involves the examination of a sample of urine to detect and measure various substances and markers found in urine, such as proteins, glucose, leukocytes, ketones, and bilirubin, among others. Urine test strips, also known as dipstick tests, are a quick and convenient method of urine analysis that can be performed in conjunction with smartphone and AI-based analyses. These tests use a small strip of paper with chemically-treated reagents that change color when they react with specific substances found in urine. Dietary intake can have a significant impact on the composition of urine, as certain nutrients and compounds are metabolized and excreted through the kidneys. Understanding the effects of dietary intake on urine biomarkers can provide valuable insight into the overall health and nutritional status of individuals. This review explores existing literature to highlight the intersection between strip-based urine analysis, smartphone-based analysis, gold standards, and recent developments in urine analysis.
... The degree of ketosis as per blood concentration was measured as an exploratory outcome rather than a feasibility endpoint due to the limited literature of ketosis in Parkinson's of varying study diet composition and infrequent data capture in the prior studies. However, the convention of nutritional ketosis as de ned by blood concentration > 0.5 mM [29] was used as a con rmatory marker. Additionally, we tested the hypothesis that acute ketosis would improve mobility on the Timed Up & Go (TUG) test to a clinically meaningful extent on day 7 of diet intervention. ...
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BACKGROUND A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson’s disease (PD). OBJECTIVE Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson’s Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 – Sept 13, 2022.
... On the other hand, ketone levels represent an objective biomarker for determining KD adherence. The KD stimulates the synthesis of ketone bodies in the liver as an energy source, resulting in elevated levels of circulating ketones in the blood and urine [45]. Using ketone levels as a means of assessing adherence is advantageous by overcoming errors and recall bias of subjective measures [43]. ...
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Background/Objectives Despite the evidence supporting the efficacy of the ketogenic diet (KD) on weight and type 2 diabetes (T2D) management, adherence to the KD is challenging. Additionally, no studies have reported changes in PA among individuals with overweight/obesity and T2D who have followed KD. We mapped out the methods used to assess adherence to the KD and level of physical activity (PA) in lifestyle interventions for weight and T2D management in individuals with overweight/obesity and T2D and compared levels of KD adherence and PA in these interventions. Methods Articles published between January 2005 and March 2022 were searched in MEDLINE, CINAHL, and Scopus. Studies that included KD in lifestyle interventions for adults with T2D and overweight/obesity and measured ketone levels were included. Results The eleven included studies comprised eight randomized controlled trials. They mainly used self-reported measures to evaluate adherence to the KD and level of PA. We found studies reported higher carbohydrate intake and lower fat intake than the KD regimen. Great inconsistencies were found among studies on the measurement and reporting of ketone and PA levels. Conclusion Our results demonstrated the need to develop intervention strategies to improve adherence to the KD, as well as the necessity of developing standardized diet and PA assessment tools to establish a stronger evidence base for including KD in lifestyle interventions for weight and T2D management among adults with overweight/obesity and T2D.
... Wang et al. [34] showed that Rhodiola reduced plasma concentrations of non-esterified fatty acids following exogenous glucose stimulation, but that it has minimal effects on sucroseand olive-oil-induced acute hyperglycemia in animals. This result is consistent with our metabolomic profiling results that Rhodiola drinking significantly affects fat catabolism, which may lead to increased ketone bodies in the urine [35]. ...
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Background: SHR-5 has been used as an “adaptogen” for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action. Methods: UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.25 and 6.25 mg/mL SHR-5 in drinking water for 6 months. The survival of the mice, obstructive uropathy, tumor burden and morphology, and proliferation were evaluated by pathological, molecular, metabolic, and statistical analyses. Results: Approximately 95% or more of the male UPII-mutant Ha-ras mice that drank SHR-5 daily survived over 6 months of age, while only 33.3% of those mice that drank normal water survived over 6 months of age (p < 0.0001); SHR-5 drinking exposure also reduced tumor-bearing bladder weight and urinary tract obstruction and inhibited mTOR signaling in neoplastic tissues. Global metabolic analysis revealed that SHR-5 resulted in increased phenolic metabolites and decreased CoA, a critical metabolic cofactor for lipid metabolism. Conclusions: Our findings highlight the potential of SHR-5 as an anti-aging agent for bladder cancer prevention through reshaping tumor metabolism via the inhibition of the mTOR signaling. Global metabolomics profiling provides a unique and efficient tool for studying the mechanisms of complex herb extracts’ action.
... The free fatty acids obtained from adipocytes are released into the bloodstream and enter liver cells, where they undergo β-oxidation to form ketone bodies or are esterified to phospholipids and triacylglycerol 45 . For this reason, high levels of ketone bodies are observed during weight loss due to low-energy diets or in various acute or chronic health conditions and are an indication of elevated fat metabolism 46 . In addition to nutrients, hormonal events affect ketogenesis: glucagon and catecholamines promote the process, and insulin inhibits it 47 . ...
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Metabolomics has proven to be an important omics approach to understand the molecular pathways underlying the tumour phenotype and to identify new clinically useful markers. The literature on cancer has illustrated the potential of this approach as a diagnostic and prognostic tool. The present study aimed to analyse the plasma metabolic profile of patients with oral squamous cell carcinoma (OSCC) and controls and to compare patients with metastatic and primary tumours at different stages and subsites using nuclear magnetic resonance and mass spectrometry. To our knowledge, this is the only report that compared patients at different stages and subsites and replicates collected in diverse institutions at different times using these methodologies. Our results showed a plasma metabolic OSCC profile suggestive of abnormal ketogenesis, lipogenesis and energy metabolism, which is already present in early phases but is more evident in advanced stages of the disease. Reduced levels of several metabolites were also associated with an unfavorable prognosis. The observed metabolomic alterations may contribute to inflammation, immune response inhibition and tumour growth, and may be explained by four nonexclusive views—differential synthesis, uptake, release, and degradation of metabolites. The interpretation that assimilates these views is the cross talk between neoplastic and normal cells in the tumour microenvironment or in more distant anatomical sites, connected by biofluids, signalling molecules and vesicles. Additional population samples to evaluate the details of these molecular processes may lead to the discovery of new biomarkers and novel strategies for OSCC prevention and treatment.
... Importantly, ketoacidosis is also accompanied by acidosis (i.e., pH < 7.35), and a raised anion gap (23). Thus, the range for therapeutic ketosis may extend as high as 5 mM in the absence of clinically significant anion gap or pH abnormalities, particularly in neurological treatments (24). ...
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In recent times, advances in the field of metabolomics have shed greater light on the role of metabolic disturbances in neuropsychiatric conditions. The following review explores the role of ketone bodies and ketosis in both the diagnosis and treatment of three major psychiatric disorders: major depressive disorder, anxiety disorders, and schizophrenia. Distinction is made between the potential therapeutic effects of the ketogenic diet and exogenous ketone preparations, as exogenous ketones in particular offer a standardized, reproducible manner for inducing ketosis. Compelling associations between symptoms of mental distress and dysregulation in central nervous system ketone metabolism have been demonstrated in preclinical studies with putative neuroprotective effects of ketone bodies being elucidated, including effects on inflammasomes and the promotion of neurogenesis in the central nervous system. Despite emerging pre-clinical data, clinical research on ketone body effectiveness as a treatment option for psychiatric disorders remains lacking. This gap in understanding warrants further investigating, especially considering that safe and acceptable ways of inducing ketosis are readily available.
The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.
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Preclinical data provide evidence for synergism between ketogenic diets (KDs) and other oncological therapies. The aim of this systematic review was to summarize data from clinical studies that have tested KDs along with other treatments used within medical oncology. The PubMed database was searched using the key words "ketogenic" AND ("cancer" OR "glioblastoma"). A secondary search was conducted by screening the reference lists of relevant articles on this topic. Relevant studies for this review were defined as studies in which KDs were used complementary to surgery, radio-, chemo-, or targeted therapy and at least one of the following four outcomes were reported: (i) Overall survival (OS); (ii) progression-free survival (PFS); (iii) local control rate; (iv) body composition changes. Twelve papers reporting on 13 clinical studies were identified. Nine studies were prospective and six had a control group, but only two were randomized. KD prescription varied widely between studies and was described only rudimentarily in most papers. Adverse events attributed to the diet were rare and only minor (grade 1–2) except for one possibly diet-related grade 4 event. Studies reporting body composition changes found beneficial effects of KDs in both overweight and frail patient populations. Beneficial effects of KDs on OS and/or PFS were found in four studies including one randomized controlled trial. Studies in high-grade glioma patients were not sufficiently powered to prove efficacy. Evidence for beneficial effects of KDs during cancer therapy is accumulating, but more high-quality studies are needed to assess the overall strength of evidence.
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Objectives: The loss of fat-free mass (FFM) that occurs during weight loss secondary to low-calorie diet can lead to numerous and deleterious consequences. We performed a review to evaluate the state of the art on metabolic and nutritional correlates of loss of fat free mass during low calorie diet and treatment for maintaining fat free mass. Methods: This review included 44 eligible studies. There are various diet strategies to maintain FFM during a low-calorie diet, including adoption of a very low carbohydrate ketogenic diet (VLCKD) and taking an adequate amount of specific nutrients (vitamin D, leucine, whey protein). Results: Regarding the numerous and various low-calorie diet proposals for achieving weight loss, the comparison of VLCKD with prudent low-calorie diet found that FFM was practically unaffected by VLCKD. There are numerous possible mechanisms for this, involving insulin and the insulin-like growth factor-1-growth hormone axis, which acts by stimulating protein synthesis. Conclusions: Considering protein and amino acids intake, an adequate daily intake of leucine (4 g/d) and whey protein (20 g/d) is recommended. Regarding vitamin D, if the blood vitamin D has low values (<30 ng/mL), it is mandatory that adequate supplementation is provided, specifically calcifediol, because in the obese patient this form is recommended to avoid seizure in the adipose tissue; 3 to 4 drops/d or 20 to 30 drops/wk of calcifediol are generally adequate to restore normal 25(OH)D plasma levels in obese patients.
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: The preservation of muscle mass and muscle function after weight loss therapy is currently a considerable challenge in the fight against obesity. Muscle mass secretes proteins called myokines that have relevant functions in the regulation of metabolism and health. This study was aimed to evaluate whether a very low-calorie ketogenic (VLCK) diet may modulate myokine levels, in addition to changes in body composition, compared to a standard, balanced low-calorie (LC) diet or bariatric surgery in patients with obesity. Body composition, ketosis, insulin sensitivity and myokines were evaluated in 79 patients with overweight/obesity after a therapy to lose weight with a VLCK diet, a LC diet or bariatric surgery. The follow-up was 6 months. The weight loss therapies induced changes in myokine levels in association with changes in body composition and biochemical parameters. The effects on circulating myokine levels compared to those at baseline were stronger after the VLCK diet than LC diet or bariatric surgery. Differences reached statistical significance for IL-8, MMP2 and irisin. In conclusion, nutritional interventions or bariatric surgery to lose weight induces changes in circulating myokine levels, being this effect potentially most notable after following a VLCK diet.
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BACKGROUND Metabolic syndrome (MetS) is highly correlated with obesity and cardiovascular risk, but the importance of dietary carbohydrate independent of weight loss in MetS treatment remains controversial. Here, we test the theory that dietary carbohydrate intolerance (i.e., the inability to process carbohydrate in a healthy manner) rather than obesity per se is a fundamental feature of MetS.METHODS Individuals who were obese with a diagnosis of MetS were fed three 4-week weight-maintenance diets that were low, moderate, and high in carbohydrate. Protein was constant and fat was exchanged isocalorically for carbohydrate across all diets.RESULTSDespite maintaining body mass, low-carbohydrate (LC) intake enhanced fat oxidation and was more effective in reversing MetS, especially high triglycerides, low HDL-C, and the small LDL subclass phenotype. Carbohydrate restriction also improved abnormal fatty acid composition, an emerging MetS feature. Despite containing 2.5 times more saturated fat than the high-carbohydrate diet, an LC diet decreased plasma total saturated fat and palmitoleate and increased arachidonate.CONCLUSION Consistent with the perspective that MetS is a pathologic state that manifests as dietary carbohydrate intolerance, these results show that compared with eucaloric high-carbohydrate intake, LC/high-fat diets benefit MetS independent of whole-body or fat mass.TRIAL Identifier: NCT02918422.FUNDINGDairy Management Inc. and the Dutch Dairy Association.
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Ketone bodies are a promising area of neuroprotection research that may be ideally suited to the injured newborn. During normal development, the human infant is in significant ketosis for at least the first week of life. Ketone uptake and metabolism is upregulated in the both the fetus and neonate, with ketone bodies providing at least 10% of cerebral metabolic energy requirements, as well as being the preferred precursors for the synthesis of fatty acids and cholesterol. At the same time, ketone bodies have been shown to have multiple neuroprotective effects, including being anticonvulsant, decreasing oxidative stress and inflammation, and epigenetically upregulating the production of neurotrophic factors. While ketogenic diets and exogenous ketosis are largely being investigated in the setting of adult brain injury, the adaptation of the neonate to ketosis suggests that developmental brain injury may be the area most suited to the use of ketones for neuroprotection. Here, we describe the mechanisms by which ketone bodies exert their neuroprotective effects, and how these may translate to benefits within each of the phases of neonatal asphyxial brain injury.
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OBJECTIVE To analyze the changes in the body composition of morbidly obese patients induced by a very low-calorie diet. METHODS We evaluated 120 patients selected from a university hospital. Body composition was assessed before and after the diet provided during hospitalization, and changes in weight, body mass index, and neck, waist and hip circumferences were analyzed. Bioimpedance was used to obtain body fat and fat-free mass values. The data were categorized by gender, age, body mass index and diabetes diagnosis. RESULTS The patients consumed the diet for 8 days. They presented a 5% weight loss (without significant difference among groups), which represented an 85% reduction in body fat. All changes in body circumference were statistically significant. There was greater weight loss and a greater reduction of body fat in men, but the elderly showed a significantly higher percentage of weight loss and greater reductions in body fat and fat-free mass. Greater reductions in body fat and fat-free mass were also observed in superobese patients. The changes in the diabetic participants did not differ significantly from those of the non-diabetic participants. CONCLUSIONS The use of a VLCD before bariatric surgery led to a loss of weight at the expense of body fat over a short period, with no significant differences in the alteration of body composition according to gender, age, body mass index and diabetes status.
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It has been established that there is a correlation between Alzheimer’s disease and apolipoprotein E, specifically the ApoE4 genetic variant. However, the correlation between Apoe4, insulin resistance and metabolic syndrome (MetS) pathologies still remains elusive. As apolipoprotein E has many important physiological functions, individuals with the ApoE4 allele variant, also known as the Alzheimer’s disease gene, are primarily at a greater risk for physiological consequences, specifically cognitive impairment (Chan et al., 2016). In this case study, a 71-year old female, heterozygous for ApoE4 with a family history of Alzheimer’s Disease (AD) and the dual diagnosis of mild AD/metabolic syndrome (MetS) was placed on a 10-week nutrition protocol purposed at raising plasma ketones through carbohydrate restricted, high fat ketogenic diet (KD), time-restricted eating and physical/cognitive exercise. Primary biomarkers for MetS were measured pre/mid-/post intervention. The MoCA (Montreal Cognitive Assessment) was administered pre/post intervention by a licensed clinical therapist. The results were statistically significant. The HOMA-IR decreased by 75% from 13.9 to 3.48. Triglycerides decreased by 50% from 170 to 85. VLDL dropped by 50% from 34 to 17, and HgA1c decreased from 5.7% to 4.9%. The baseline MoCA score was 21/30; post treatment score was 28/30. The significant results in both MetS biomarkers and the MoCA score suggest that a ketogenic diet may serve to rescue cognition in patients with mild AD. The results of this case study are particularly compelling for ApoE4 positive (ApoE4+) subjects as ketogenic protocols extend hope and promise for AD prevention.
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Ketogenic diet (KD; high fat, low carb) is a standard treatment for obesity, neurological diseases (e.g., refractory epilepsy) and a promising method for athletes to improve their endurance performance. Therein, the level of ketosis must be regulated tightly to ensure an effective therapy. Here, we introduce a compact and inexpensive breath sensor to monitor ketosis online and non-invasively. The sensor consists of Si-doped WO3 nanoparticles that detect breath acetone selectively with non-linear response characteristics in the relevant range of 1 to 66 ppm, as identified by mass spectrometry. When tested on eleven subjects (five women and six men) undergoing a 36-h KD based on the Johns Hopkins protocol, this sensor clearly recognizes the onset and progression of ketosis. This is in good agreement to capillary blood β-hydroxybutyrate (BOHB) measurements. Despite similar dieting conditions, strong inter-subject differences in ketosis dynamics were observed and correctly identified by the sensor. These even included breath acetone patterns that could be linked to low tolerance to that diet. As a result, this portable breath sensor represents an easily applicable and reliable technology to monitor KD, possibly during medical treatment of epilepsy and weight loss.
Ketone bodies are produced by the liver and used peripherally as an energy source when glucose is not readily available. The two main ketone bodies are acetoacetate (AcAc) and 3-β-hydroxybutyrate (3HB), while acetone is the third, and least abundant, ketone body. Ketones are always present in the blood and their levels increase during fasting and prolonged exercise. They are also found in the blood of neonates and pregnant women. Diabetes is the most common pathological cause of elevated blood ketones. In diabetic ketoacidosis (DKA), high levels of ketones are produced in response to low insulin levels and high levels of counterregulatory hormones. In acute DKA, the ketone body ratio (3HB:AcAc) rises from normal (1:1) to as high as 10:1. In response to insulin therapy, 3HB levels commonly decrease long before AcAc levels. The frequently employed nitroprusside test only detects AcAc in blood and urine. This test is inconvenient, does not assess the best indicator of ketone body levels (3HB), provides only a semiquantitative assessment of ketone levels and is associated with false-positive results. Recently, inexpensive quantitative tests of 3HB levels have become available for use with small blood samples (5–25 µl). These tests offer new options for monitoring and treating diabetes and other states characterized by the abnormal metabolism of ketone bodies. Copyright © 1999 John Wiley & Sons, Ltd.