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Effect of a Sodium and Calcium DL- β -Hydroxybutyrate Salt in Healthy Adults



Background Ketone body therapy and supplementation are of high interest for several medical and nutritional fields. The intake of ketone bodies is often discussed in relation to rare metabolic diseases, such as multiple acyl-CoA dehydrogenase deficiency (MADD), that have no alternatives for treatment. Case reports showed positive results of therapy using ketone bodies. The number of ketone body salts offered on the wellness market is increasing steadily. More information on the kinetics of intake, safety, and tolerance of these products is needed. Methods In a one-dose kinetic study, six healthy subjects received an intervention (0.5 g/kg bw) using a commercially available ketone body supplement. The supplement contained a mixture of sodium and calcium D-/L-β-hydroxybutyrate (βHB) as well as food additives. The blood samples drawn in the study were tested for concentrations of D-βHB, glucose, and electrolytes, and blood gas analyses were done. Data on sensory evaluation and observed side effects of the supplement were collected. The product also went through chemical food analysis. Results The supplement led to a significant increase of D-βHB concentration in blood 2.5 and 3 h after oral intake (p=0.033; p=0.043). The first significant effect was measured after 2 h with a mean value of 0.598 ± 0.300 mmol/L at the peak, which was recorded at 2.5 h. Changes in serum electrolytes and BGA were largely unremarkable. Taking the supplement was not without side effects. One subject dropped out due to gastrointestinal symptoms and two others reported similar but milder problems. Conclusions Intake of a combination of calcium and sodium D-/L-βHB salt shows a slow resorption with a moderate increase of D-βHB in serum levels. An influence of βHB salts on acid-base balance could not be excluded by this one-dose study. Excessive regular consumption without medical observation is not free of adverse effects. The tested product can therefore not be recommended unconditionally.
Research Article
Effect of a Sodium and Calcium DL-β-Hydroxybutyrate Salt in
Healthy Adults
Tobias Fischer ,
Ulrike Och,
Ira Klawon,
Tim Och,
Marianne Gr¨
Manfred Fobker,
Ursula Bordewick-Dell,
and Thorsten Marquardt
Department of Food, Nutrition, and Facilities, FH M¨
unster-University of Applied Sciences Muenster, Corrensstraße 25,
48149 Muenster, Germany
Department of Pediatrics, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany
Center of Laboratory Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany
Correspondence should be addressed to Tobias Fischer;
Received 8 December 2017; Revised 1 February 2018; Accepted 12 February 2018; Published 12 April 2018
Academic Editor: Jos´
ıa Huerta
Copyright ©2018 Tobias Fischer et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. Ketone body therapy and supplementation are of high interest for several medical and nutritional fields. e intake of
ketone bodies is often discussed in relation to rare metabolic diseases, such as multiple acyl-CoA dehydrogenase deficiency
(MADD), that have no alternatives for treatment. Case reports showed positive results of therapy using ketone bodies. e
number of ketone body salts offered on the wellness market is increasing steadily. More information on the kinetics of intake,
safety, and tolerance of these products is needed. Methods. In a one-dose kinetic study, six healthy subjects received an in-
tervention (0.5 g/kg bw) using a commercially available ketone body supplement. e supplement contained a mixture of sodium
and calcium D-/L-β-hydroxybutyrate (βHB) as well as food additives. e blood samples drawn in the study were tested for
concentrations of D-βHB, glucose, and electrolytes, and blood gas analyses were done. Data on sensory evaluation and observed
side effects of the supplement were collected. e product also went through chemical food analysis. Results. e supplement led to
a significant increase of D-βHB concentration in blood 2.5 and 3 h after oral intake (p0.033;p0.043). e first significant
effect was measured after 2 h with a mean value of 0.598 ±0.300 mmol/L at the peak, which was recorded at 2.5h. Changes in
serum electrolytes and BGA were largely unremarkable. Taking the supplement was not without side effects. One subject dropped
out due to gastrointestinal symptoms and two others reported similar but milder problems. Conclusions. Intake of a combination
of calcium and sodium D-/L-βHB salt shows a slow resorption with a moderate increase of D-βHB in serum levels. An influence of
βHB salts on acid-base balance could not be excluded by this one-dose study. Excessive regular consumption without medical
observation is not free of adverse effects. e tested product can therefore not be recommended unconditionally.
1. Introduction
Interest in the importance of ketone bodies has risen in the
recent past. Ketone bodies are an alternative fuel produced
in the liver, in a process referred to as ketogenesis, in the
event of reduced availability of glucose [1]. Insulin inhibits
ketogenesis as opposed to glucagon and epinephrine, which
both stimulate this process [2–4]. e base material is acetyl-
CoA which is derived from the β-oxidation of fatty acids.
e basis of all three “ketone” bodies is acetoacetate. Ace-
toacetate can then either be reduced to beta-hydroxybutyrate
(βHB), or acetone is generated by spontaneous de-
carboxylation of acetoacetate. Only acetoacetate and βHB
are relevant for energy expenditure [5, 6]. e maximum
amount of daily ketone body production in adults is 150 g [7].
Normal postprandial βHB serum levels are less than
0.1 mmol/L [8]. ey increase to approximately 0.1-
0.2 mmol/L after fasting overnight in healthy subjects [9]. e
term ketosis describes an increased concentration of ketone
bodies in blood. In clinical application, ketosis is often defined
as a concentration of ketone bodies in the range of 2
7 mmol/L and 35 mmol/L in therapy [10, 11].
Journal of Nutrition and Metabolism
Volume 2018, Article ID 9812806, 8 pages
e human organism has two nutrition-related ways of
reaching ketosis. e first is starvation and the second is
a high fat and at the same time low carbohydrate (HFLC)
diet which is also known as a ketogenic diet [8, 12]. Ketosis
can also be reached by an energy deficit caused by prolonged
exercise [13]. In all cases, the organism reacts by an in-
creasing ketone body production because of the decreased
availability of glucose and therefore making the alternative
fuel, ketone bodies, necessary as brain fuel or as energy
substrate for other tissues, especially muscle [1, 8]. e main
difference between the two nutrition-related states of ketosis
is that in starvation fat reserves are used for ketone body
synthesis and in HFLC fat from daily nutrition [8, 12]. Aside
from the nutritional trend of low-carb diets with a maximal
βHB serum concentration of 0.4 mmol/L, ketone bodies and
specific diet forms like the ketogenic diet are of high sci-
entific interest [14, 15].
ere are different types of clinically relevant ketogenic
diets. e milder forms are the low glycaemic index diet
(LGID) and the modified Atkins diet (MAD) where carbo-
hydrate intake is limited to 15 grams per day. More stringent
are the medium chain triglycerides (MCT) diet as well as the
3 : 1 and the 4 : 1 classical ketogenic diets. e ratio depicts the
fat contents in relation to the sum of carbohydrates and
proteins based on their weight [16]. A well-known problem of
ketogenic diets is limited patient compliance [17]. e daily
intake of high amounts of fat is not tasty and has negative
effects on the quality of life. Carbohydrate restriction is often
even more difficult to adhere to. Adverse effects, especially
soon after starting the diet, are often recorded and lead to
dropouts. Typical undesirable side effects of the traditional
ketogenic diet are gastrointestinal discomfort, weight loss, and
negative changes in lipid profiles [18]. e application of
moderate (50 g carbohydrates per day) ketogenic diets for
weight loss show partially different effects when compared to
clinically applied ketogenic diets. Positive effects on blood
lipids, blood pressure, and weight are reported in obese
subjects [19]. ere are various very low carbohydrate and
ketogenic trend diets that are milder than medical diets be-
cause trend diets have a lower fat content. e palatability of
food in medical or trend diets increases strongly with the
introduction of more carbohydrates and protein to the daily
nutrition [20, 21].
e ketogenic diet has proven to be an effective therapy
for epilepsy, although not only the anticonvulsive effect is
used in medicine. In addition, some inherited metabolic
diseases of glucose uptake or metabolism, for example, the
GLUT1 or pyruvate dehydrogenase deficiency, are treated
using ketogenic diets to ensure sufficient energy supply [22].
In special severe metabolic diseases of β-oxidation, like
multiple acyl-CoA dehydrogenase deficiency (MADD),
a direct intake of ketone bodies for energy supply is nec-
essary. Inducing ketogenesis using normal food products is
not possible due to the impairment of fatty acid oxidation.
e genetic defect in the electron transport flavoprotein or
the electron transport flavoprotein oxyreductase causes a dys-
function of all acyl-CoA dehydrogenases in β-oxidation by the
impaired oxidation of FADH
to FAD [23]. For this disease,
direct ketone body therapy using D,L-3-hydroxybutyrate
sodium salt can be life-saving. Ketone body therapy in MADD
is documented in some case reports. In treated patients, an
increase of D-βHB in serum was detectable within one hour of
intake and led to dramatic clinical improvements. After 2 and
9 months, MRI investigations showed a progressive decrease
of leukodystrophy, a typical problem in MADD patients [24].
In cases of hypoglycemia caused by hyperinsulinisim, treat-
ment with βHB as a supplement has been used without any
adverse side effects and increased the serum concentration of
D-βHB [25].
Good efficacy of ketogenic diets is clouded by poor
practicability and the necessity of maintaining a constant
ketosis during the day. erapeutic levels can be achieved
more easily through oral intake of βHB [10]. e direct oral
intake of ketone body salts or acid, as described in some case
reports, may not be totally free of health risks. Possible
adverse side effects are cation overload or acidosis/alkalosis
[26]. Newer publications on ketone body salts concentrate
on their application in sports [27, 28]. However, available
knowledge is still very limited. To manage potential prob-
lems, researchers are concentrating on synthesizing ketone
body esters consisting of the primary ketone βHB and an
alcohol, for example 1,3-butanediol [29].
Supplements containing ketone bodies have potential
applications in cases of severe metabolic diseases, cancer,
neurodegenerative disease, and many more. Apart from the
medical use, such supplements are also of interest for life-
style applications such as weight loss [30].
In an Internet search of the worldwide supplement
market, a lot of products with βHB as the main ingredient
are available since 2015. e first available product was
a simple mixture of calcium and sodium βHB salt with an
added flavor. ere is currently no scientific opinion or
direct testing published about products with a calcium and
sodium βHB salt as the main ingredient. e aim of this
study is to provide additional scientific information for an
easily available ketone body salt mixture and discuss the
potential benefit of such products in clinical application.
2. Materials and Methods
2.1. Subjects. A total of six healthy adult subjects (3 males
and 3 females) aged between 18 and 57 years (40 ±15.9
years) were selected for this study. e participants, 4–
normal, 1–overweight, and 1–obese, had an average BMI of
25.44 ±5.99 kg/m
. e criteria for inclusion were absence of
metabolic diseases (like diabetes), not pregnant, medically
healthy with a normal medical history, and no intake of
drugs (excluding oral contraceptives) or nutritional sup-
plements in the previous 30 days prior to the start of the
study. Subjects were excluded if they suddenly got ill or
consumed a restrictive diet, low carb, or ketogenic diet, in
the 60 days before the day of testing. Recruitment was done
by putting up a notice on a board at the University Hospital
of Muenster. After filling in a precheck questionnaire,
a short clinical examination was performed by a medical
doctor. On the day of testing, those that had qualified for
inclusion had to appear with an empty stomach. e intake
of food and caloric beverages was not allowed for 12 hours,
2Journal of Nutrition and Metabolism
24 hours for alcoholic beverages, before testing began. Black
unsweetened coffee and water were allowed on the testing
day. All subjects were informed in detail about the study and
signed the consent before they participated in the study. e
study was conducted in accordance with the Declaration of
Helsinki, and the protocol was approved by the Ethics
Committee of the Medical Association of Westfalen-Lippe
and the University of M¨
unster (project identification code:
2.2. Procedure. A single-center one-dose kinetic study was
conducted at the Muenster University Hospital, Germany, in
accordance with the guidelines of good clinical practice. e
present design of a one-dose kinetic study does not require
randomisation, placebo-control, and blinding of the medical
staff or subjects. e subjects fasted from 6 pm on the day
before the test until the test began at 8 am. After weighing,
placing a venous access and drawing the first blood sample
), the subjects ingested the prepared test solution. e
solution was prepared for each subject by using the formula
0.5 grams of βHB-salt supplement per kilogram body weight
dissolved in 250 milliliters (8.45 fl oz) of water. is
translated to 30–57.5 g of the supplement per subject
depending on their bodyweight. e taste of the beverage
was recorded in a sensory interview after intake. Blood
samples were drawn every 30 minutes over a period of
5.5 hours. roughout testing, subjects were free to drink
mineral water without gas and black unsweetened coffee or
tea as well as move within the building. Each subject
recorded observed side effects in a predetermined protocol.
e concentrations of βHB and glucose were determined;
blood gas analyses (BGA) in a two-sample series was per-
formed every 2.5 hours, and the content of the minerals Na
, and Ca
in serum was quantified. A medical doctor was
available all the time and monitored the course of the study.
2.3. Nutritional Supplement. e supplement, with the trade
name KetoCaNa Orange, is produced by a manufacturer in
the USA (Ketosports) and was purchased from an online
shop in the Netherlands. e main ingredient is a combi-
nation of sodium and calcium βHB-salt (racemic mixture;
D-/L-βHB). Additional ingredients are citric acid, natural
flavor, and stevia as sweetener. e supplement facts are
shown in Table 1. All calories in the product are derived from
the contained ketones. e producer recommends a serving
size of 19 g powder dissolved in 236ml (8 fl oz) of cold water
that can be consumed up to three times a day. e producer
mentions that the product properties praised have not been
approved by the Food and Drug Administration (FDA) and
the product is not intended for use in diseases.
2.4. Sampling and Analysis
2.4.1. Blood Sampling. At the start of study, a venous
catheter was placed and the first blood sample was drawn.
For further sampling, the catheter was flushed with physi-
ological saline. To avoid dilution of the sample, five
milliliters of blood were discarded up front each blood
sample. In case of a blocked venous access, a new catheter
was placed. e samples were immediately cooled at 20°C
for analysis on the same day. Otherwise, storage temperature
was 80°C.
2.4.2. βHB, Glucose, and Minerals in Serum. Serum levels of
D-βHB were determined by using an enzymatic assay kit
produced by Sigma-Aldrich (St. Louis, USA). e kit is
designed to produce a compound whose colorimetric in-
tensity, determined at a wavelength of 450 nm, is pro-
portional to the concentration of D-βHB. Glucose and
mineral (K
, Na
, and Ca
) content in serum were de-
termined using the analyzer Cobas 8000 manufactured by
Roche Diagnostics (Mannheim, Germany) and carried out
in the clinical laboratory of the university hospital in
2.4.3. Blood Gas Analyses. Blood samples were transported
in a cooling box to the central laboratory immediately after
sampling. e fully automated blood gas analyzer ABL800
Flex manufactured by Radiometer (Krefeld, Germany) was
used to measure pH, electrolytes, and metabolites.
2.4.4. Food Chemistry Analysis. Content of citric acid was
determined using an enzymatic test kit for food, manu-
factured by Boehringer Mannheim (Darmstadt, Germany).
e amount of oxidized NADH is stoichiometric to the
citrate content. Difference between NADH and NAD
determined photometrically at 340 nm. Determination of
pH was done using a pH meter and an electrode manu-
factured by Mettler Toledo (Giessen, Germany), after per-
forming a three-point calibration. e quantification of
minerals was carried out by a certified food laboratory. For
sodium, potassium, calcium, and magnesium, ICP-MS and
ICP-OES according to DIN EN ISO 11885/DIN EN ISO
17294-2 were used.
2.4.5. Sensory Interview. e taste of the beverage was
recorded in a face-to-face interview. All subjects had to
describe the flavor and mouth-feel of the product in their
own words supported. e questions of the interview were
“Please describe as accurately as possible the taste of the
beverage” followed by “How is the mouth-feel?” and “How
Table 1: Nutritional information and caloric content per serving
size (19 g) and in 100 grams of the supplement.
19 g (serving size) 100 g
Calories 68 358
Macronutrients and minerals Grams Grams
Fat 0 0
Carbohydrate 0 0
Protein 0 0
Sodium 1.30 6.84
Calcium 1.15 6.05
βHB 11.70 61.57
Journal of Nutrition and Metabolism 3
would you describe the aftertaste?.” e last question was
“Did you notice anything else?.” e test person was not to be
interrupted when answering the questions, and the in-
terviewer was prompted to interrupt only when responses
were ambiguous or it was unclear what the test person meant.
Especially positive or negative statements were examined
more closely. e interview was recorded in its entirety.
2.5. Statistical Analysis. Data preparation was performed by
using Microsoft Excel 2016, and for the data analysis, IBM
SPSS Statistics 24 was used. Kolmogorov–Smirnov test,
Shapiro–Wilk test, and graphical analyses were used to
evaluate normal distribution. All data were first analyzed
using descriptive statistics such as mean value, median, and
standard deviation.
e basis for comparison was the first blood sample
drawn from the subjects (t
). To calculate the difference
between the results, a t-test for paired groups or Wilcoxon
test was used. e level of significance was set at p0.05. For
relation among different sample series, the area under curve
(AUC) was calculated.
In order to detect a clinical relevant change in the main
outcome variable βHB (μ
0.2; μ
0.5; SD 0.2; effect size
dz 1.5) with power of 80% and two-sided alpha of 0.05,
a total of 5 participants were required. For security in case of
dropout, one more subject (20%) was recruited.
3. Results
One of the subjects (female, obese) dropped out directly after
imbibing the solution due to a severe reaction to the intake.
ese reactions included severe vomiting, nausea, and upper
abdominal pain. All other volunteers (n5) successfully
completed testing.
3.1. βHB and Glucose Levels. e 0.5 g/kg BW dose corre-
sponded to 0.31 g D-/L-βHB/kg BW (3 mmol D-/L-βHB/kg
BW) was calculated using the information provided by the
manufacturer. e free D-βHB in serum increased after 2.5
hours from 0.232 ±0.177 mmol/L at t
to the maximal mean
value of 0.598 ±0.300 mmol/L at t
. e differences between
0 min, 150 min (maximum), and 180 min after treatment
were significant (p0.033;p0.043). e first effect of the
βHB salt intake was noted 2 hours later in the form of an
increased concentration of serum D-βHB. Directly after
reaching a maximum, the concentration declined continuously
to near the baseline. ere were large differences in D-βHB
concentrations between the test persons as depicted in the
rather large standard deviation in AUC (1.917 ±0.811; n4).
Serum glucose concentrations in the serum of the test subjects
remained constant almost right through the study period with
an increase at the maximum of D-βHB concentration and after
4-5 hours. Both differences in serum glucose were not sig-
nificant (t5p0.741;t10p0.689; Figure 1).
3.2. BGA and Serum Minerals. Blood gas analysis showed no
difference in pH, pCO
, pO
, cations, and lactate concentration.
An increase was detected in base excess (cBase; 2.350 ±1.909 to
5.450 ±0.071 mmol/L) and anion gap (1.450 ±0.778 to 2.350 ±
1.061 mmol/L). e measured electrolytes sodium and calcium
presented no difference during the study period. Potassium
increased, and the increase was directly proportional to D-βHB
levels in tested subjects. Determination of significance was not
possible due to the small number of cases.
3.3. Side Effects. One of the subjects dropped out directly
after solution intake due to severe vomiting, nausea, and
upper abdominal pain. All other volunteers (n5) finished
the test successfully. One proband reported feeling of full-
ness directly after beverage intake, which was caused by the
volume of the solution. Two others had nausea and slightly
upset stomach in the first 30 minutes of testing. One of the
subjects developed stomach cramps, diarrhea, and severe
nausea after one hour, and a metoclopramide medication
was necessary. In further course, one person felt hyperactive
and three reported not feeling hungry over the complete
study period.
3.4. Sensory Tasting. All subjects described the fragrance of
the product as fruity and appetizing. One participant found
the aroma unnatural and was reminded of medicine. e
optical impression was neutral as the beverage had no color
and was clear in appearance. Two test subjects found a color,
corresponding to the fruit aroma, missing. One person
reported a tolerable sour taste and four an extensive sour
taste after solution intake. e flavor was pushed to the
background by the high acidity. One subject additionally
described the beverage as salty and soapy. Overall, the testers
described the product as not being tasty and hard to drink
especially in such a high volume.
3.5. Food Chemistry. Determination of citric acid showed
a content of 0.286 g/g amounting to 5.434g per serving size
(19 g) with a mean pH of 4.32 when prepared according to the
recommendation made by the manufacturer. An intake of
0.5 g/kg of the product corresponds to 0.7 mmol/kg citric acid.
e content of minerals was analogous to the specifications on
the product package. For magnesium and potassium, possible
contaminations causing slight deviation were detectable
(Table 2). e chosen dose of 0.5 g/kg in this study amounts to
1.3 mmol/kg sodium and 0.8 mmol/kg calcium. A three-times
daily supplement intake of 0.5 g/kg would lead to an intake of
0.44 g/kg (2.2 mmol/kg) citric acid, 0.09 g/kg (3.9 mmol/kg)
sodium, and 0.09 g/kg (2.3 mmol/kg) calcium.
4. Discussion
e results show a slow and moderate increase of D-βHB
serum levels with a slow decline in healthy humans. Intake of
a high concentration of D-/L-βHB supplement caused an
average maximum increase of 0.366 mmol/L. Interpersonal
variation of ketone body levels in humans is a well-known
fact, a publication from 1958 determined a difference of 30
4Journal of Nutrition and Metabolism
percent in healthy young men after fasting overnight [31]. In
a collection of normal weight and overweight subjects, the
standard deviation of βHB concentration was around 50
percent which is similar to our findings [32].
A direct comparison with other data is not possible due
to absence of publications on the mixture of sodium and
calcium D-/L-βHB salt. Only some case reports on the usage
of sodium D-/L-βHB in severe metabolic diseases in children
and studies testing different sodium and potassium D-/L-
βHB salts are available. Van Hove et al. described a peak
between 0.19mmol/L and 0.36 mmol/L after 30 minutes to 1
hour caused by intake of 0.150g/kg BW D-/L-βHB [24].
Gautschi et al. found a D-βHB concentration increase of
0.055 mmol/L within 1-2 h (150 mg/kg BW) and a measured
maximum of 0.343 mmol/L after 2 h (200 mg/kg BW) [33].
Another group did not observe any rise in D-βHB con-
centration after the intake of 0.9 g/kg BW, and only after
increasing the intake to 2.6 g/kg BW was there a measurable
change in D-βHB levels [34]. All presented data originated
from children with MADD and cannot be transfered to
healthy adult subjects. ere was an almost 10-fold increase
in blood D-βHB within 0.5–3 h measured in two children
with hyperinsulinism [25]. Especially, the second case report
from Gautschi et al. shows in part a similar absorption of
βHB salt when compared to our data [33]. In all case reports
with children, no adverse effects were reported after the
intake of sodium βHB [24, 25, 33, 34].
Testing of a ketone body ester consisting of D-1,3-
butanediol and D-βHB (3-hydroxybutyl-3-hydroxybutyrate)
exhibited a concentration peak between 1,5 and 2.5 h into
testing. e recorded c
D-βHB was 1.00 mmol/L achieved
using 357 mg/kg BW of ester; this value corresponds to
2.80 mmol/L achieved using 1 g/kg BW of ester. In the single
intake study, no adverse effects using a maximum dose of
714 mg/kg BW were reported. Only in a repeated dose study
with a concentration of 2142 mg/kg BW per day did gas-
trointestinal side effects like vomiting, nausea, diarrhea, or
abdominal pain occur [35]. A study with male athletes as test
subject showed a rapid rise of D-βHB concentration in 10
minutes after drinking a solution made using 573 mg/kg BW
of the 3-hydroxybutyl l-3-hydroxybutyrate ketone ester.
In different experimental setups with young athletes, no
adverse effects of βHB were reported [36]. In healthy sub-
jects, Stubbs et al. showed a maximum increase of D-βHB
concentration after 1.5 h to 1.00 ±0.1 mmol/L after the intake
Table 2: Measured content in grams of selected minerals per
serving size (19g) and in 100 grams of the supplement.
Minerals 19 g (serving size) 100 g
Sodium (g) 1.140 6.000
Potassium (g) 0.003 0.016
Magnesium (g) 0.006 0.031
Calcium (g) 1.178 6.200
0 30 60 90 120 150 180 210 240 270 300 330
Glucose (mg/dL)
Time (min)
Glucose (mg/dL)
Serum D-βHB (mmol/L)
D-βHB (mmol/L)
0 30 60 90 120 150 180 210 240 270 300 330
Time (min)
Figure 1: (a) Mean, standard deviation of blood glucose (mg/dL) and (b) mean, standard deviation of D-βHB (mmol/L) level in serum of all
subjects (n5) within a time period of 5.5 h after intake of βHB salt mixture (0.5 g/kg BW).
Journal of Nutrition and Metabolism 5
of 282 mg/kg BW of a sodium and potassium D-/L-βHB salt.
At the same time, tested βHB-ester leads to higher values at
the same concentration (2.8 ±0.2 mmol/L) [36]. Two further
studies evaluated the adminstration of supplements con-
taining D-/L-βHB salts to athletes during exercise. e levels
of D-βHB concentration were between 0.60 and 1.00 mmol/L
after the intake of the supplements [27, 28]. In all studies, no
direct side effects were reported in healthy adults [27, 28, 37].
One publication reported a potential risk of gastrointestinal
distress for high doses of βHB [27]. e tested product
showed some gastrointestinal side effects directly after or
within 2 h of solution intake. In comparison to these data, the
intake of βHB was not high enough for specific side effects
caused by ketone bodies. A possible reason is the high content
of cations and citric acid in this product, causing the intense
sour taste. As a whole, use of combination of calcium and
sodium βHB salt is not free from adverse effects and exhibits
a slow resorption kinetic. Just like in other supplements, such
as the ester of 1,3-butandiol and βHB, the combined sodium
and calcium salt exhibits a fast decrease in serum concen-
tration. A direct comparison between the salts and the ester
is not possible due to the structural differences and the
metabolization of 1,3-butanediol being unclear. ere are
indications that 1,3-butandiol is metabolized to ketone
bodies. is and the hydrolysis to D-βHB, not D-/L-βHB as
in the salts, are possible explanations for the reported high
βHB concentration in subjects after intake of this ester
[35, 38, 39]. e sodium and potassium salt exhibits an
earlier increase of D-βHB concentration in serum and
a higher maximum using nearly the same dose when
compared to our testing [37]. Likewise, the ester compound
predominantly showed a faster increase of serum D-βHB
concentration [35, 37, 40]. It seems that the salt combi-
nation affected the resorption of βHB. e results of ath-
letes during exercise are not comparable to our population
[27, 28].
A limitation of the measurements is the usage of an
enzymatic assay specific for clinically relevant D-βHB.
D-βHB acts as the main energy substrate in fasting humans
and is therefore of high therapeutic relevance [8]. L-βHB,
acetoacetate, and acetone were not analyzed in this study.
Accordingly, an underestimation of total ketone bodies is
possible. e effect of active substrates is considered to be
low because there was an intake of βHB without longer
fasting time period and a resulting short-time increase of
βHB in serum. L-βHB is the nonphysiological enantiomer of
D-βHB. ere is an indication that L-βHB can be converted
to physiological active ketone bodies (acetoacetate and
D-βHB) and lipids in animal models but only in a limited
amount [41, 42]. In humans, L-βHB showed a much lower
metabolic rate and conspicuously higher elimination in
urine than the D-βHB after intake of a D-/L-βHB salt [37].
More research is necessary to get more information about
the metabolization of L-βHB in humans.
A one dose intake did not result in an increase of calcium
and sodium. e relatively high amounts of both salts had no
direct effect on their serum levels. In an example, a person
weighing 70 kg would take around 2.100 g (91 mmol) sodium
and 2.170g (54 mmol) calcium with one dose (0.5g/kg) of
the supplement. e three-times daily dosage of 19 g product
recommended by the manufacturer would lead to an intake
of 3.420 g (149 mmol) sodium and 3.534 g (88 mmol) calcium.
e calculated loads of both elements are above the tolerable
upper intake level (UL) for adults recommended by the Institute
of Medicine (IOM) (sodium 2.3 g/d (100 mmol/d); calcium
2.5 g/d (62 mmol/d)) [43, 44]. In comparison to the physio-
logical need of sodium for body function, estimated at 500 mg/d
(22 mmol/d), an estimated 47-fold increased ingestion takes
place [45]. e high intake of sodium is combined with nu-
merous adverse effects like thirst, fluid retention, hypertension,
and higher risk for cardiovascular disease. Furthermore, a high
sodium load has an effect on calcium metabolism expressed by
higher calcium loss with a potential risk for urinary tract stones
and bone demineralization [4648]. An excessive ingestion of
calcium leads to gastrointestinal side effects, renal stones, and
a potential increase in cardiovascular events [49, 50]. e impact
on cardiovascular diseases is still under discussion [50]. In case
of an overload of sodium and calcium, a cumulative effect
cannot be excluded. Long-term intake of high dosage of both
elements could lead to side effects and have to be investigated
e finding of a similar increase between D-βHB and
potassium levels needs further research. In our testing, we can
exclude the influence of the test product (16mg K
/100 g) or
a pseudo hyperkalaemia by venous catheter.
e excessive intake of ketone body salt or acid could
have consequences for the acid-base balance. According to
a theory by Stewart, a shift of the strong ion difference (SID)
can cause alkalosis or acidosis. On one hand, a high SID
generated by intensive resorption of cations (e.g., Na
) is a potential risk factor for alkalosis. On the other
hand, a low SID and at the same time high strong ion gap
(SIG) triggered by ketoacids can cause a metabolic acidosis
[51, 52]. Stubbs et al. detected an increase of pH after intake
of a sodium and potassium D-/L-βHB mixture, but no
similar effect in a corresponding test using βHB-ester. Both
products had a mild influence to the acid-base balance [37].
In an earlier study in the 1980s, a rise in pH after ketone
body salt infusion was detected [53]. Surveillance of blood
parameters, like the pH, pCO
, and product specific cations,
are necessary to avoid adverse metabolic effects.
ere are suggestions in the literature of an impact of
increased βHB on reducing food intake. e mechanisms for
this are not clear [54]. In our study, the majority of par-
ticipants reported a loss of appetite and hunger beyond the
testing time of 5.5 h. us, βHB may have an effect on the
regulation of hunger and satiety. Further research with
a double-blinded test design is needed to eliminate the
influence of a known product ingredient.
In conclusion, the tested product cannot be recom-
mended for an intake of 0.5 g/kg BW and leads to adverse
gastrointestinal effects. e high acidity and general taste
were not well accepted by the subjects making the product
unsuitable for long-term application. Clinically, the high
content of sodium, calcium, and the release of potassium is
crucial and requires further research to establish short-term
as well as long-term effects on the human organism. An
additional aspect is that a higher intake is necessary to reach
6Journal of Nutrition and Metabolism
a ketosis sufficient for therapeutic purposes. us, an intake
of 1 g/kg BW of the product would lead to a maximum of, in
average, around 1.2 mmol/L (0.598 mmol/L at 0.5 g/kg BW).
No interpersonal factors have been included in this simple
calculation of our results. In combination with a higher
intake, the cation load and proportion of additives increases,
therefore increasing the potential risk of side effects. For
treatment with high doses of external ketone bodies, further
clinical trials on healthy adults are needed to gather more
information on metabolic utilization.
Conflicts of Interest
e authors declare no conflicts of interest.
e human kinetic study was funded by the Department of
Congenital Metabolic Disorders of the University Hospital,
Muenster. Sensory and food chemistry analyses were funded
by the Department of Food, Nutrition, Facilities of the
University of Applied Sciences, Muenster.
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... Ketone bodies can be endogenous where they are produced by the body in the liver, or exogenous, where they are taken in the form of a supplement [4] . Ketone body supplements are commonly composed of β-hydroxybutyrate (βHB) combined with a salt, such as potassium, calcium or sodium (Na-βHB) [4] , which are then known as ketone salts. ...
... Ketone bodies can be endogenous where they are produced by the body in the liver, or exogenous, where they are taken in the form of a supplement [4] . Ketone body supplements are commonly composed of β-hydroxybutyrate (βHB) combined with a salt, such as potassium, calcium or sodium (Na-βHB) [4] , which are then known as ketone salts. A ketone ester, otherwise known as a ketone monoester, such as (R)-3-hydroxybutyl (R)-3hydroxybutyrate, is salt-free [5] and not commercially available. ...
... Modern ketone supplement manufacturers claim to cut out this nutritional manipulation period with the ingestion of a supplement containing on average 12g βHB [4] . This amount can be supported by studies [1][2][3] showing that by ingesting a ketone supplement, can result in ketosis in 30 minutes. ...
Full-text available
Background: There is a keen interest in performance-enhancing supplementation and the associated benefits, despite reports of incorrect label claims made by manufacturers and the questionable efficacy of the supplements. The use of ketone body supplements as a source of fuel during exercise and sporting performance, in particular, is of interest to sportspeople. By increasing blood ketone body levels, with an accompanying decrease in blood glucose, may indicate a state of nutritional ketosis, whereby the body no longer relies on glucose metabolism but rather the metabolism of ketone bodies. This could be beneficial for long, slow steady-state endurance exercise. Discussion: There are numerous ketone body supplements on the market manufactured in South Africa and internationally. However, unlike medicines, the sports supplementation industry is poorly regulated. Furthermore, ketone body supplementation with regard to its effects on improving exercise and athletic performance is still unconvincing. Conclusion: Within the ever-changing sports supplementation industry, ketone body supplements are being used despite controversies regarding the accuracy and scientific merit of label claims. The ingredients and their quantities, as well as the performance benefits, need to be objectively validated.
... Ketone salts are comprised of a BHB or AcAc molecule bound to an inorganic anion, commonly sodium, potassium, or calcium. The limitations of ketone salts include the relatively low circulating BHB levels (approx. 1 mM) that are achieved with current oral formulations [40,41], issues with oral tolerability [40,41], and concerns over the long-term effects of a high mineral load. However, infusions of BHB and AcAc salts can provide sustained elevation of both AcAc and BHB, depending on the formulation used [22][23][24]. ...
... Ketone salts are comprised of a BHB or AcAc molecule bound to an inorganic anion, commonly sodium, potassium, or calcium. The limitations of ketone salts include the relatively low circulating BHB levels (approx. 1 mM) that are achieved with current oral formulations [40,41], issues with oral tolerability [40,41], and concerns over the long-term effects of a high mineral load. However, infusions of BHB and AcAc salts can provide sustained elevation of both AcAc and BHB, depending on the formulation used [22][23][24]. ...
Full-text available
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.
... During our manuscript preparation, two human studies that included an objective similar to ours were published. 12,13 In one of the experiments published by Stubbs et al., 12 15 participants ingested a dose of a combination of sodium and potassium βHB providing ~12g βHB, similar to our full dose, and the circulating βHB levels reached 1.0±0.1mmol/L (mean±SE) during the first hour. ...
... Although in our study the peak concentration occurred sooner; at 15minutes (or at 30minutes excluding data from the potential outlier), our AUC data were similar to theirs, and the βHB levels returned to baseline after 2hours in both studies. In the second publication, 13 6 healthy adults ingested one dose of a combination of sodium and calcium βHB salts providing 30-57.5g depending on their bodyweight, but one subject immediately dropped out due to severe vomiting. ...
... Numerically, implementing KD can raise serum β-OHB levels above 2 mM, prolonged fasting can have β-OHB levels reach 6-8 mM, and 90 min of intense exercise can elevate β-OHB to 1-2-mM levels [30]. Similar to KD being utilized as a therapeutic for NAFLD and neuronal disorders, exogenous supplementation of sodium β-OHB is the only therapeutic available for those with multiple acyl-CoA dehydrogenase deficiency, which is a severe form of inborn errors of metabolism with impaired mitochondrial fatty acid oxidation [31,32]. Administration of exogenous β-OHB has also been shown to boost global histone acetylation and, thus, expression of oxidative-stressrelieving genes due to its histone deacetylase (HDAC) inhibitory property [33,34]. ...
The metabolism of macro and micronutrients is a complex and highly regulated biological process. An imbalance in the metabolites and their signaling networks can lead to non-resolving inflammation and consequently to the development of chronic inflammatory-associated diseases. Therefore, identifying the accumulated metabolites and altered pathways during inflammatory disorders would not only serve as ‘real time’ markers, but also help in the development of nutritional therapeutics. In this review, we explore recent research that has delved into elucidating the effects of carbohydrate/calorie restriction, protein malnutrition, lipid emulsions and micronutrient deficiencies on metabolic health and inflammation. Moreover, we describe the integrated stress response in terms of amino acid starvation and lipemia, and how this modulates new age diseases such as inflammatory bowel disease and atherosclerosis. Lastly, we explain the latest research on metaflammation and inflammaging. This review focuses on multiple signaling pathways, including, but not limited to, the FGF21-β-hydroxybutryate-NLRP3 axis, the GCN2-eIF2α-ATF4 pathway, the von Hippel-Lindau/Hypoxia-inducible transcription factor pathway and the TMAO-PERK-FoxO1 axis. Additionally, throughout the review, we explain how the gut microbiota responds to altered nutrient status and also how antimicrobial peptides generated from nutrient-based signaling pathways can modulate the gut microbiota. Collectively, it must be emphasized that metabolic starvation and inflammation are strongly regulated by both environmental (i.e. nutrition, gut microbiome) and non-environmental (i.e. genetics) factors, which can influence the susceptibility to inflammatory disorders.
... Exogenous D-BHB is directly absorbed into the circulation, with some of it being converted to AcAc by the liver, and both ketones being distributed throughout the body. Until recently, only racemic mixtures of dextro (D) and levo (L) BHB (D+L-BHB) were available and oral human studies with them have been reported (9,(11)(12)(13)(14). As L-BHB is not metabolized significantly into energy intermediates and is slowly excreted in the urine (9,15), D+L-BHB would be anticipated to be less ketogenic than pure D-BHB. ...
Full-text available
There is growing interest in the metabolism of ketones owing to their reported benefits in neurological and more recently in cardiovascular and renal diseases. As an alternative to a very high fat ketogenic diet, ketones precursors for oral intake are being developed to achieve ketosis without the need for dietary carbohydrate restriction. Here we report that an oral D-beta-hydroxybutyrate (D-BHB) supplement is rapidly absorbed and metabolized in humans and increases blood ketones to millimolar levels. At the same dose, D-BHB is significantly more ketogenic and provides fewer calories than a racemic mixture of BHB or medium chain triglyceride. In a whole body ketone positron emission tomography pilot study, we observed that after D-BHB consumption, the ketone tracer 11 C-acetoacetate is rapidly metabolized, mostly by the heart and the kidneys. Beyond brain energy rescue, this opens additional opportunities for therapeutic exploration of D-BHB supplements as a "super fuel" in cardiac and chronic kidney diseases.
... There have been stable isotope studies in neonates utilising and measuring metabolism of the D-stereoisomer. Similarly clinical studies typically measure the D-isomer even when the racemic mixture has been administered [36]. ...
Full-text available
Background: Ketone bodies form a vital energy source for end organs in a variety of physiological circumstances. At different times, the heart, brain and skeletal muscle in particular can use ketones as a primary substrate. Failure to generate ketones in such circumstances leads to compromised energy delivery, critical end-organ dysfunction and potentially death. There are a range of inborn errors of metabolism (IEM) affecting ketone body production that can present in this way, including disorders of carnitine transport into the mitochondrion, mitochondrial fatty acid oxidation deficiencies (MFAOD) and ketone body synthesis. In situations of acute energy deficit, management of IEM typically entails circumventing the enzyme deficiency with replenishment of energy requirements. Due to profound multi-organ failure it is often difficult to provide optimal enteral therapy in such situations and rescue with sodium DL-3-hydroxybutyrate (S DL-3-OHB) has been attempted in these conditions as documented in this paper. Results: We present 3 cases of metabolic decompensation, one with carnitine-acyl-carnitine translocase deficiency (CACTD) another with 3-hydroxyl, 3-methyl, glutaryl CoA lyase deficiency (HMGCLD) and a third with carnitine palmitoyl transferase II deficiency (CPT2D). All of these disorders are frequently associated with death in circumstance where catastrophic acute metabolic deterioration occurs. Intensive therapy with adjunctive S DL-3OHB led to rapid and sustained recovery in all. Alternative therapies are scarce in these situations. Conclusion: S DL-3-OHB has been utilised in multiple acyl co A dehydrogenase deficiency (MADD) in cases with acute neurological and cardiac compromise with long-term data awaiting publication. The use of S DL-3-OHB is novel in non-MADD fat oxidation disorders and contribute to the argument for more widespread use.
... There are a number of studies that highlight the limitations to ketone salt and ketone esters that are available commercially or for research applications. These limitations are primarily due to gastrointestinal symptoms associated with aversive taste or osmotic load in the GI tract (Leckey et al., 2017;Fischer et al., 2018). Future studies need to assure that the ketone supplement formulations are well tolerated and provide an ideal pharmacokinetic profile of sustained ketone elevation before such supplements are evaluated in humans (Stubbs et al., 2018b). ...
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The ketogenic diet (KD) is a high-fat, low-carbohydrate treatment for medically intractable epilepsy. One of the hallmark features of the KD is the production of ketone bodies which have long been believed, but not yet proven, to exert direct anti-seizure effects. The prevailing view has been that ketosis is an epiphenomenon during KD treatment, mostly due to clinical observations that blood ketone levels do not correlate well with seizure control. Nevertheless, there is increasing experimental evidence that ketone bodies alone can exert anti-seizure properties through a multiplicity of mechanisms, including but not limited to: (1) activation of inhibitory adenosine and ATP-sensitive potassium channels; (2) enhancement of mitochondrial function and reduction in oxidative stress; (3) attenuation of excitatory neurotransmission; and (4) enhancement of central γ-aminobutyric acid (GABA) synthesis. Other novel actions more recently reported include inhibition of inflammasome assembly and activation of peripheral immune cells, and epigenetic effects by decreasing the activity of histone deacetylases (HDACs). Collectively, the preclinical evidence to date suggests that ketone administration alone might afford anti-seizure benefits for patients with epilepsy. There are, however, pragmatic challenges in administering ketone bodies in humans, but prior concerns may largely be mitigated through the use of ketone esters or balanced ketone electrolyte formulations that can be given orally and induce elevated and sustained hyperketonemia to achieve therapeutic effects.
... One reason forthe use of a racemic mixture of βHBaffects the physiological use [16]. Overall, the bioavailability and the maximum intake of D/L-βHB salt seem to be limited [16,19]. More human studies, especially long-term studies are necessary to improve the understanding of the application of βHB-based products. ...
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Objectives: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a severe inborn disorder of mitochondrial fatty acid oxidation. The only treatment option for MADD is the use of exogenous ketone bodies, like sodium β-hydroxybutyrate (NaβHB). However, the use of ketone body salts leads to a high intake of accompanying minerals, which can lead to additional side effects. The use of mineral-free formulations could improve tolerability. Methods: In this report, the use of a βHB acid (βHBA) in a patient with MADD is described. The production of D/L-βHBA was carried out using ion exchange chromatography (IEX) and using a precipitation method. During two inpatient treatment intervals, the tolerability as well as clinical and metabolic effects were monitored. D-βHB in serum, blood gas analysis, and standard blood measurements (like minerals) were used as control parameters. Results: Production of D/L-βHBA using the precipitation method was more effective than using IEX. The tube feed solution used had a minimum pH of 3.5. Capillary D-βHB measurements were between 0.1 and 0.4 mmol/L and venous were at 0.1 mmol/L or below. Minerals and serum pH were within the normal range. During application of D/L-βHBA, gastrointestinal discomfort occurred and no clinical improvement was observed. Conclusions: The use of D/L-βHBA in the therapy of severe MADD could be a good addition to the use of classical ketone body salts. The observed gastrointestinal side effects were of a mild nature and could not be specifically attributed to the D/L-βHBA treatment. In short-term application, no clinical benefit and no substantial increase of D-βHB in serum were noted. No tendency towards acidosis or alkalosis was observed during the entire period of treatment.
... Concerns have been raised about the practical use of exogenous ketone supplements by athletes due to the high rates of occurrence of GI distress in previous work using BD (26), KS (7,17), KDE (12), and KME (4). However, in the present study, incidences of GI distress were similar between conditions, and this is consistent with previous work using KME (5). ...
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Purpose Pre-exercise ingestion of exogenous ketones alters the metabolic response to exercise, but effects on exercise performance have been equivocal. Methods On two occasions in a double-blind, randomized crossover design, eight endurance-trained runners performed 1 h of submaximal exercise at ~65% VO2max immediately followed by a 10-km self-paced TT on a motorized treadmill. An 8% carbohydrate-electrolyte solution was consumed before and during exercise, either alone (CHO+PLA), or with 573 of a ketone monoester supplement (CHO+KME). Expired air, heart rate (HR), and rating of perceived exertion (RPE) were monitored during submaximal exercise. Serial venous blood samples were assayed for plasma glucose, lactate and β-hydroxybutyrate concentrations. Results CHO+KME produced plasma β-hydroxybutyrate concentrations of ~1.0 to 1.3 mM during exercise (P < 0.001), but plasma glucose and lactate concentrations were similar during exercise in both trials. VO2, running economy, respiratory exchange ratio, HR and RPE were also similar between trials. Performance in the 10-km TT was not different (P = 0.483) between CHO+KME (mean = 2402 s; 95% confidence interval [CI] = 2204, 2600 s) and CHO+PLA (mean = 2422 s; 95% CI = 2217, 2628 s). Cognitive performance, measured by reaction time and a multi-tasking test, did not differ between trials. Conclusion Compared with carbohydrate alone, co-ingestion of KME by endurance-trained athletes elevated plasma β-hydroxybutyrate concentrations, but did not improve 10-km running TT or cognitive performance.
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The ketone body D-β-hydroxybutyrate (DBHB) has gained attention owing to its cellular signalling function; however, its effect on the human colonic microbiota remains unclear. Here, DBHB dynamics in the human colon were investigated using an in vitro colonic microbiota model, which maintained most of the operational taxonomic units detected in the original faeces. Over 54% of 0.41% (w/v) DBHB was metabolised by microbiota models originating from seven faecal samples after 30 h of fermentation (regarded as DBHB utilisers); however, <19% of DBHB was metabolised by microbiota models from five faecal samples (regarded as non-utilisers of DBHB). In utilisers, DBHB administration increased the relative abundance of the genus Coprococcus, correlated with increased butyrogenesis. Increased butyrogenesis was not observed in DBHB non-utilisers. Based on PICRUSt analysis, the relative abundance of β-hydroxybutyrate dehydrogenase was maintained in microbiota models from DBHB utilisers following DBHB administration; however, it decreased in microbiota models from non-utilisers. After 21 h of fermentation, the intracellular glutamate concentration, which is indicative of growth, showed a positive correlation with DBHB utilisation (R2 = 0.70). Human colonic microbiotas with high growth activity demonstrate efficient utilisation of DBHB for increased butyrate production, which affords health benefits.
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Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate “ketogenic” diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3–4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3–1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.
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The purpose of the present study was to examine the effects of an oral β-hydroxybutyrate (BHB) supplement on cycling performance. Using a double-blind, placebo-controlled, crossover design, 12 highly-trained cyclists (mean ± SD: age; 35 ± 8 y, mass; 74.5 ± 7.6 kg, VO2peak; 68.0 ± 6.7 ml.min-1kg-1) were supplemented with two 30 ml servings of an oral BHB supplement or placebo formula (PLA) prior to and during exercise. Participants cycled at a submaximal intensity (80% of second ventilatory threshold) for 90-min, followed by a 4-min maximal cycling performance test (4PT). The difference in 4PT power output between trials was not statistically significant (p > 0.05) and was associated with a trivial effect (ES ±90%CI = 0.19 ±0.37). Ingestion of the BHB supplement was associated with a large increase in blood BHB concentrations when compared to PLA for the 4PT (ES = 1.75 ±0.50, p < 0.01). The increased BHB concentration was accompanied by a moderate increase in the respiratory exchange ratio (RER) during the submaximal exercise phase (ES = 0.54 ±0.45, p = >0.05) and a moderate increase during the 4PT (ES = 0.78 ±0.57, p = 0.03). Submaximal VO2 did not differ between trials, however, VO2 was higher during the 4PT phase in the BHB trial (ES = 0.28 ±0.32; small). In conclusion, BHB supplementation altered blood BHB concentrations, RER and VO2 values during steady state sub-maximal exercise, but did not improve 4-minute cycling performance.
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Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease.
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Despite the successful use of a ketogenic diet in pediatric epilepsy, its application in adults has been limited. The aim of this meta-analysis was to summarize the findings of relevant published studies in order to identify the efficacy of and compliance with a ketogenic diet and its main subtypes (i.e., classic ketogenic diet and modified Atkins diet) in adults with intractable epilepsy, and to provide useful information for clinical practice. Electronic searches of PubMed, EMBASE, Google Scholar, and the ISI Web of Science were conducted to identify studies of the efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy; the included studies were reviewed. Meta-analyses were performed using STATA to determine combined efficacy rates and combined rates of compliance with the ketogenic diet and its main subtypes. In total, 12 studies qualified for inclusion, and data from 270 patients were evaluated.The results of the meta-analysis revealed combined efficacy rates of all types of ketogenic diet, a classical ketogenic diet, and a modified Atkins diet were 42%, 52%, and 34%, respectively; the corresponding combined compliance rates were 45%, 38%, and 56%. The results indicate that a ketogenic diet is a promising complementary therapy in adult intractable epilepsy, and that while a classical ketogenic diet may be more effective, adult patients are likely to be less compliant with it than with a modified Atkins diet.
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Background: Multiple acyl-CoA dehydrogenase deficiency- (MADD-), also called glutaric aciduria type 2, associated leukodystrophy may be severe and progressive despite conventional treatment with protein- and fat-restricted diet, carnitine, riboflavin, and coenzyme Q10. Administration of ketone bodies was described as a promising adjunct, but has only been documented once. Methods: We describe a Portuguese boy of consanguineous parents who developed progressive muscle weakness at 2.5 y of age, followed by severe metabolic decompensation with hypoglycaemia and coma triggered by a viral infection. Magnetic resonance (MR) imaging showed diffuse leukodystrophy. MADD was diagnosed by biochemical and molecular analyses. Clinical deterioration continued despite conventional treatment. Enteral sodium D,L-3-hydroxybutyrate (NaHB) was progressively introduced and maintained at 600 mg/kg BW/d (≈ 3% caloric need). Follow up was 3 y and included regular clinical examinations, biochemical studies, and imaging. Results: During follow up, the initial GMFC-MLD (motor function classification system, 0 = normal, 6 = maximum impairment) level of 5-6 gradually improved to 1 after 5 mo. Social functioning and quality of life recovered remarkably. We found considerable improvement of MR imaging and spectroscopy during follow up, with a certain lag behind clinical recovery. There was some persistent residual developmental delay. Conclusion: NaHB is a highly effective and safe treatment that needs further controlled studies.
This study investigated the impact of raising plasma beta-hydroxybutyrate (β-OHB) through ingestion of ketone salts on substrate oxidation and performance during cycling exercise. Ten healthy adult males (age, 23 ± 3 years; body mass index, 25 ± 3 kg/m(2), peak oxygen uptake, 45 ± 10 mL/(kg·min)(-1)) were recruited to complete 2 experimental trials. Before enrollment in the experimental conditions, baseline anthropometrics and cardiorespiratory fitness (peak oxygen uptake) were assessed and familiarization to the study protocol was provided. On experimental days, participants reported to the laboratory in the fasted state and consumed either 0.3 g/kg β-OHB ketone salts or a flavour-matched placebo at 30 min prior to engaging in cycling exercise. Subjects completed steady-state exercise at 30%, 60%, and 90% ventilatory threshold (VT) followed by a 150-kJ cycling time-trial. Respiratory exchange ratio (RER) and total substrate oxidation were derived from indirect calorimetry. Plasma glucose, lactate, and ketones were measured at baseline, 30 min post-supplement, post-steady-state exercise, and immediately following the time-trial. Plasma β-OHB was elevated from baseline and throughout the entire protocol in the ketone condition (p < 0.05). RER was lower at 30% and 60% VT in the ketone compared with control condition. Total fat oxidation was greater in the ketone versus control (p = 0.05). Average time-trial power output was ∼7% lower (-16 W, p = 0.029) in the ketone condition. Ingestion of ketone salts prior to exercise increases fat oxidation during steady-state exercise but impairs high-intensity exercise performance.
The ketogenic diet is an effective treatment for drug-resistant epilepsies in children. In addition, it is the first-line treatment for some metabolic disorders, such as glucose transporter 1 deficiency syndrome. This article discusses the proposed mechanisms of a ketogenic diet’s antiseizure action, its clinical indications, and its contraindications. The steps involved in ketogenic diet initiation, monitoring, and management of its side effects are also discussed. This review provides general pediatricians with the necessary skills to provide comprehensive care of children using the ketogenic diet and counsel their families and caregivers.
Background: The ketogenic diet (KD) is an established, effective non-pharmacologic treatment for drug resistant childhood epilepsy. For a long time, the KD was not recommended for use in infancy (under the age of 2 years) because this is such a crucial period in development and the perceived high risk of nutritional inadequacies. Indeed, infants are a vulnerable population with specific nutritional requirements. But current research shows that the KD is highly effective and well tolerated in infants with epilepsy. Seizure freedom is often achieved and maintained in this specific patient group. There is a need for standardised protocols and management recommendations for clinical use. Method: In April 2015, a project group of 5 experts was established in order to create a consensus statement regarding the clinical management of the KD in infants. The manuscript was reviewed and amended by a larger group of 10 international experts in the KD field. Consensus was reached with regard to guidance on how the diet should be administered and in whom. Results: The resulting recommendations include patient selection, pre-KD counseling and evaluation, specific nutritional requirements, preferred initiation, monitoring of adverse effects at initiation and follow-up, evaluation and KD discontinuation. Conclusion: This paper highlights recommendations based on best evidence, combined with expert opinions and gives directions for future research.
Calcium is an essential element in the diet, but there is continuing controversy regarding its optimal intake, and its role in the pathogenesis of osteoporosis. Most studies show little evidence of a relationship between calcium intake and bone density, or the rate of bone loss. Re-analysis of data from the placebo group from the Auckland Calcium Study demonstrates no relationship between dietary calcium intake and rate of bone loss over 5 years in healthy older women with intakes varying from <400 to >1500 mg day(-1) . Thus, supplements are not needed within this range of intakes to compensate for a demonstrable dietary deficiency, but might be acting as weak anti-resorptive agents via effects on parathyroid hormone and calcitonin. Consistent with this, supplements do acutely reduce bone resorption and produce small short-term effects on bone density, without evidence of a cumulative density benefit. As a result, anti-fracture efficacy remains unproven, with no evidence to support hip fracture prevention (other than in a cohort with severe vitamin D deficiency) and total fracture numbers are reduced by 0-10%, depending on which meta-analysis is considered. Five recent large studies have failed to demonstrate fracture prevention in their primary analyses. This must be balanced against an increase in gastrointestinal side effects (including a doubling of hospital admissions for these problems), a 17% increase in renal calculi and a 20-40% increase in risk of myocardial infarction. Each of these adverse events alone neutralizes any possible benefit in fracture prevention. Thus, calcium supplements appear to have a negative risk-benefit effect, and so should not be used routinely in the prevention or treatment of osteoporosis. © 2015 The Association for the Publication of the Journal of Internal Medicine.