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

Authors:
  • University of Applied Sciences Muenster

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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.
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Research Article
Effect of a Sodium and Calcium DL-β-Hydroxybutyrate Salt in
Healthy Adults
Tobias Fischer ,
1
Ulrike Och,
2
Ira Klawon,
2
Tim Och,
2
Marianne Gr¨
uneberg,
2
Manfred Fobker,
3
Ursula Bordewick-Dell,
1
and Thorsten Marquardt
2
1
Department of Food, Nutrition, and Facilities, FH M¨
unster-University of Applied Sciences Muenster, Corrensstraße 25,
48149 Muenster, Germany
2
Department of Pediatrics, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany
3
Center of Laboratory Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany
Correspondence should be addressed to Tobias Fischer; tobias.fischer@fh-muenster.de
Received 8 December 2017; Revised 1 February 2018; Accepted 12 February 2018; Published 12 April 2018
Academic Editor: Jos´
eMar´
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].
Hindawi
Journal of Nutrition and Metabolism
Volume 2018, Article ID 9812806, 8 pages
https://doi.org/10.1155/2018/9812806
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
2
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
2
. 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:
2017-402-f-S).
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
(t
0
), 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
+
,
K
+
, and Ca
2+
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
2+
) 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
Muenster.
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
+
was
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
0
). 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
1
0.2; μ
2
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
0
to the maximal mean
value of 0.598 ±0.300 mmol/L at t
6
. 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
2
, pO
2
, 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
max
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
60,000
80,000
100,000
120,000
140,000
0 30 60 90 120 150 180 210 240 270 300 330
Glucose (mg/dL)
Time (min)
Glucose (mg/dL)
(a)
0.000
0.100
0.200
0.300
0.400
0.500
0.600
0.700
0.800
0.900
1.000
Serum D-βHB (mmol/L)
D-βHB (mmol/L)
0 30 60 90 120 150 180 210 240 270 300 330
Time (min)
(b)
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
further.
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
+
and
Ca
2+
) 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
2
, 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.
Acknowledgments
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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... Several studies have reported circulating [R-βHB] of ~ 0.4 to ~ 1.0 mM in response to ingestion of racemic and nonracemic KS at doses ranging from ~ 10 to ~ 40 g of βHB [21,34,36,45,46,51,52,62,85] The majority of commercially available KS being racemic makes them less effective at elevating the R-βHB enantiomer, yet they produce larger (~ twofold greater than R-βHB) and sustained (~ 2.0 mM at 90-120 min) increases in [S-βHB] [34] Medium chain fatty acids co-ingested with ketone salts (MCFA + KS) MCFA + KS is most typically a combination of the respective compounds in 1:1 or 2:1 ratios Rodent data suggest this method results in a more sustained induction of nutritional ketosis because KBs are delivered directly in the form of KS, while ketogenesis is stimulated by MCFAs [103] This approach allows for lower dosing of individual components, with lesser potential for side effects from high intake of individual EKS or minerals Such formulations are available in popular commercialised EKS, but have not been extensively evaluated in human trials Two studies have reported whole blood [R-βHB] of ~ 0.6 mM 60 min after ingestion of a ~ 7 to ~ 9 g R,S-βHB salt with ~ 7 g MCFA [37,64] Whole blood [R-βHB] was ~ 0.1 mM higher after ingestion of double the above dose [37] Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
... Broadly speaking, GI disturbances during exercise are proposed as physiological, mechanical, or nutritional in nature, and have the potential to negatively impact performance through distraction, discomfort, and/or the attenuation of substrate delivery from exogenous fuel sources [202]. Some concerns exist around EKS because of incidences of GI symptoms reported in several studies after acute ingestion of EKS at rest [52,65], or prior to exercise [35,36,38,49,57,72,86], and include flatulence, diarrhoea, cramping, belching, heartburn, nausea, and vomiting. ...
... Greater incidences of GI symptoms with the ingestion of KS compared with control conditions have been observed at rest with ~ 30-58 g of racemic R,S-βHB salts [52], and during exercise with ~ 48 g R,S-BD (2 × ~ 24 g) provided prior to and during 85 min of steady-state cycling exercise followed by a 7 kJ.kg −1 TT [57], and ~ 36 g of racemic R,S-βHB salts (2 × ~ 18 g) in the 60 min prior to 48 min of graded cycling exercise [36]. ...
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... Most commonly, these are sodium, potas sium, and calcium salts ( Figure 18). In studies in rats fed a normal diet and supplemente with these salts, a small increase in ketone body concentration in the blood was observed Mineral salts of β-hydroxybutyrate can induce ketosis, but the amounts required can lea to negative gastrointestinal effects and issues due to high levels of sodium [99]. The use of synthetic ketogenic compounds to supplement a normal diet has not onl shown the capability to induce ketosis, but also consequently decreases blood glucos concentration without affecting triglyceride or cholesterol levels [6]. ...
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... One approach of supplementing ketone bodies is the use of calcium and sodium salts of a racemic mixture of βOHB which resulted in a modest increase of circulating levels, to about 0.5 mmol/l. There were gastrointestinal problems and possible long-term risks because of high sodium intake [112]. Much more effective are βOHB esters such as (R)-3-hydroxybutyl (R)-3hydroxybutyrate which can be given per os to reach > 4 mmol/l of βOHB and was well tolerated during a 28-day trial, except for bitter taste [113,114]. ...
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Objectives Exogenous ketone (monoester or salt) supplements are increasingly being employed for a variety of research purposes and marketed amongst the general public for their ability to raise blood beta-hydroxybutyrate (β-OHB). Emerging research suggests a blood glucose-lowering effect of exogenous ketones. Here, we systematically review and meta-analyze the available evidence of trials reporting on exogenous ketones and blood glucose. Methods We searched 6 electronic databases on December 13, 2021 for trials of any length that reported on the use of exogenous ketones compared to a placebo. We pooled raw mean differences (MD) in (i) blood β-OHB and (ii) blood glucose using random-effects models, and explored differences in the effects of ketone salts compared to ketone monoesters. Publication bias and risk of bias were examined using funnel plots and Cochrane's risk-of-bias tool, respectively. Results Twenty-eight trials including a total of 332 participants met inclusion criteria. There was no evidence for publication bias. Four trials were judged to be at low risk of bias with some concern for risk of bias in the remaining trials. Compared to placebo, consumption of exogenous ketones raised blood β-OHB (MD = 1.98 mM; 95% CI: 1.52 mM, 2.45 mM; P < 0.001) and decreased blood glucose (MD = −0.47 mM; 95% CI: −0.57 mM, −0.36 mM; P < 0.001) across the post-supplementation period of up to 300 minutes. Across both analyses, significantly greater effects were found following ingestion of ketone monoesters compared to ketone salts (P < 0.001). Conclusions Consumption of exogenous ketone supplements leads to acutely increased blood β-OHB and decreased blood glucose. Ketone monoesters exert a more potent β-OHB-raising and glucose-lowering effect as compared to ketone salts. Funding Sources Michael Smith Foundation for Health Research (MSFHR) Scholar Award.
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Nutritional ketosis is a state of mildly elevated blood ketone concentrations resulting from dietary changes (e.g., fasting or reduced carbohydrate intake) or exogenous ketone consumption. In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, double-blind, placebo-controlled, parallel trial (NCT04707989). Healthy adults (n = 59, mean (SD), age: 42.8 (13.4) y, body mass index: 27.8 (3.9) kg/m2) were randomized to consume a beverage containing 12.5 g (Days 0–7) and 25 g (Days 7–28) of BH-BD or a taste-matched placebo daily with breakfast. Tolerability, stimulation, and sedation were assessed daily by standardized questionnaires, and blood and urine samples were collected at Days 0, 7, 14, and 28 for safety assessment. There were no differences in at-home composite systemic and gastrointestinal tolerability scores between BH-BD and placebo at any time in the study, or in acute tolerability measured 1-h post-consumption in-clinic. Weekly at-home composite tolerability scores did not change when BH-BD servings were doubled. At-home scores for stimulation and sedation did not differ between groups. BH-BD significantly increased blood ketone concentrations 1-h post-consumption. No clinically meaningful changes in safety measures including vital signs and clinical laboratory measurements were detected within or between groups. These results support the overall tolerability and safety of consumption of up to 25 g/day BH-BD.
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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.
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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.
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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.
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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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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.
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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.