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Metabolic impact of a ketogenic diet compared to a hypocaloric diet in obese children and adolescents

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The effects of carbohydrate-restricted (ketogenic) diets on metabolic parameters in children have been incompletely assessed. To compare the efficacy and metabolic impact of ketogenic and hypocaloric diets in obese children and adolescents. Fifty-eight obese subjects were placed on one of the two diets for 6 months. Anthropometric measurements, body composition, oral glucose/insulin tolerance test, lipidemic profile, high molecular weight (HMW) adiponectin, whole-body insulin sensitivity index (WBISI), and homeostatic model assessment-insulin resistance (HOMA-IR) were determined before and after each diet. Both groups significantly reduced their weight, fat mass, waist circumference, fasting insulin, and HOMA-IR (p = 0.009 for ketogenic and p = 0.014 for hypocaloric), but the differences were greater in the ketogenic group. Both groups increased WBISI significantly, but only the ketogenic group increased HMW adiponectin significantly (p = 0.025). The ketogenic diet revealed more pronounced improvements in weight loss and metabolic parameters than the hypocaloric diet and may be a feasible and safe alternative for children's weight loss.
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J Pediatr Endocr M et 2012;25(7–8):697–704 © 2012 by Walter de Gruyter • Berlin • Boston. D OI 10.1515/jpem -2012-0131
*Corresponding author: Bessie E. Spiliotis, Division of Pediatric
Endocrinology and Diabetes, Department of Pediatrics, University
of Patras School of Medicine, Patras, Achaea, Greece
Phone: + 30-2613-603-741, Fax: + 30-2610-994-533,
E-mail: besspil@endo.gr
Received April 24, 2012; accepted May 27, 2012;
previously published online July 5, 2012
Metabolic impact of a ketogenic diet compared to a
hypocaloric diet in obese children and adolescents
Ioanna Partsalaki, Alexia Karvela and
Bessie E. Spiliotis *
Research Laboratory of the Division of Pediatric
Endocrinology and Diabetes , Department of Pediatrics,
University of Patras School of Medicine, Patras, Achaea ,
Greece
Abstract
Background: The effects of carbohydrate-restricted (keto-
genic) diets on metabolic parameters in children have been
incompletely assessed.
Objective: To compare the effi cacy and metabolic impact
of ketogenic and hypocaloric diets in obese children and
adolescents.
Subjects: Fifty-eight obese subjects were placed on one of
the two diets for 6 months.
Methods: Anthropometric measurements, body composition,
oral glucose/insulin tolerance test, lipidemic profi le, high
molecular weight (HMW) adiponectin, whole-body insulin
sensitivity index (WBISI), and homeostatic model assess-
ment-insulin resistance (HOMA-IR) were determined before
and after each diet.
Results: Both groups signifi cantly reduced their weight, fat
mass, waist circumference, fasting insulin, and HOMA-IR
(p = 0.009 for ketogenic and p = 0.014 for hypocaloric), but the
differences were greater in the ketogenic group. Both groups
increased WBISI signifi cantly, but only the ketogenic group
increased HMW adiponectin signifi cantly (p = 0.025).
Conclusions: The ketogenic diet revealed more pronounced
improvements in weight loss and metabolic parameters than
the hypocaloric diet and may be a feasible and safe alternative
for children s weight loss.
Keywords: adiponectin; adolescents; children; hypocaloric
diet; insulin sensitivity; ketogenic diet; obesity.
Introduction
Many studies report a signifi cant increase in adiposity among
children and adolescents in most parts of the world (1, 2) , and
these trends have also been confi rmed in the Greek popula-
tion (3, 4) .
Childhood obesity is a serious public health issue that is
associated with the development of metabolic risk factors,
such as dyslipidemia, endothelial dysfunction, hypertension,
insulin resistance, and type 2 diabetes mellitus during ado-
lescence (5, 6) . In addition, the presence of obesity during
childhood also increases the risk of cardiovascular disease
later in life (7, 8) . Adipose tissue seems to be a key factor in
the development of the complications of obesity because it
plays an important role in systemic metabolic homeostasis via
the secretion of adipokines (9) . Evidence suggests that adi-
ponectin, an adipokine derived from adipose tissue, is criti-
cal in sustaining insulin sensitivity, and it decreases in obese
individuals, thus depriving the body of its vast benefi ts on
the metabolism of carbohydrates and lipoproteins (10, 11) . In
adults, high molecular weight (HMW) adiponectin appears
to represent the most bioactive isoform of adiponectin (12) ;
therefore, it seems to be a more useful marker of insulin sen-
sitivity and endothelial dysfunction than total adiponectin
(13) . In children and adolescents, it has recently been shown
that adiponectin concentrations are inversely associated to the
amount of visceral adipose tissue present (14) .
The treatment of obesity is theoretically straightforward
and is thought to be merely the maintenance of energy intake
lower than the energy expenditure. For that purpose, fat- and
calorie-restricted diets have traditionally been recommended
in overweight and obese children and adolescents (15) .
Recently though, low-carbohydrate diets have emerged as an
important alternative to low-fat diets in adult obesity man-
agement and seem to have more benefi cial effects on glyce-
mic control, triglyceride levels, and high-density lipoprotein
(HDL)-cholesterol levels in many obese adults than low-fat
diets (16 18) . A very low-carbohydrate diet ( < 20 – 50 g/d car-
bohydrates) leads to a chronic state of mild ketosis, deriving
the majority of calories from fat and protein sources (19) while
providing proteins and calories for adequate growth (20, 21) .
The ketogenic diet was primarily developed to treat refractory
epilepsy in children for at least 2 years with no detrimental
effects on their short- or long-term growth or on their bio-
chemical parameters (22) . Currently, carbohydrate-restricted
diets have also been used in managing type 2 diabetes (23) .
From a practical perspective, weight control poses an over-
whelming challenge for many children, and the optimal pre-
scription still remains elusive. We attempted to explore the
effectiveness of a very low-carbohydrate (ketogenic) diet in
comparison to a low-fat, calorie-restricted (hypocaloric) diet,
on metabolic parameters relating to insulin sensitivity, adi-
ponectin levels, and their lipidemic profi le, in obese children
and adolescents.
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698 Partsalaki et al.: Impact of ketogenic diet in obesity
Subjects and methods
Participants selection and study design
Fifty-eight obese [ > 95th percentile body mass index (BMI) for gen-
der and age] (24, 25) children and adolescents (aged 8 18) were
randomly recruited from the outpatient clinic of the Division of
Pediatric Endocrinology and Diabetes of the University Hospital of
Patras, Greece. The protocol was approved by the Ethics Committee
of the University Hospital of Patras. Informed parental consent and
children s assent were obtained in all cases.
During recruitment, the children and adolescents underwent a full
medical examination and the pediatric endocrinologist confi rmed their
suitability for participation in the study. The inclusion criteria speci-
ed that all subjects were not following any specialized diet and had
normal liver, respiratory, kidney, and gastrointestinal functions. All
children with thyroid dysfunction were on treatment with thyroxine
and were euthyroid during the entire study. Individuals with diabetes
or genetically associated obesity syndromes were excluded from the
study. The enrolled participants were randomly assigned to either a
ketogenic diet or a hypocaloric diet with a goal to lose at least 10 % of
their initial body weight. The duration of the study was 6 months. All
measurements, except for anthropometric measurements that were
taken at every visit, were assessed at baseline and after a weight loss
of 10 % from the initial body weight.
Twenty-nine children and adolescents were assigned randomly
to each diet. The dietitian met with them individually at baseline
and weekly for the fi rst month and biweekly thereafter in order for
the appropriate education and counseling on the diets to take place.
Each participant was given written and oral instructions throughout
the sessions. Common household measuring cups, spoons, and food
scales were used to measure portion size whenever such a practice
was necessary.
Ketogenic diet
The ketogenic diet group aimed for < 20 g/day carbohydrates, with a
gradual increase towards 30 40 g/day, if the measurements of urinary
ketones continued to indicate ketosis. To ensure this, urinary ketone
concentrations were measured daily with dipsticks (KETOSTIX
2880, Bayer, Portland, OR, USA). On this basis, all children and
adolescents were in mild ketosis for the majority of the trial period.
There were no restrictions on caloric intake or the type of fat or
cholesterol concentration of the foods. Food commonly preferred was
poultry, beef, pork, fi sh, cheese, eggs, vegetable oils (especially olive
oil), a limited amount of various nuts/seeds, moderate amounts of
vegetables, water, tea, or occasionally low-carbohydrate diet drinks.
Due to the fact that the ketogenic diet is not a well-balanced diet,
as far as micronutrient composition is concerned, the children s diet
was supplemented daily by sugar-free multivitamins with minerals,
appropriate for the participant s age (26) .
Hypocaloric diet
The children and adolescents on the hypocaloric diet were instructed
to reduce their caloric intake by 500 calories daily while deriving
28 % – 33 % and 50 % – 55 % of these calories from fat and carbohy-
drates, respectively, which is in accordance with the dietary guide-
lines for children and adolescents of the American Heart Association
(27) . Like the ketogenic group, the hypocaloric diet group was also
supplemented with the same multivitamin supplement daily.
Both groups were encouraged to have at least 1 h daily of vigor-
ous exercise. Detailed quantitative data on physical activity were not
obtained, but all subjects reported 1 h of play or exercise at least 5
days a week. Last but not least, the participants of the study, or their
caregivers, completed food diaries, which allowed the determination
of eating behavior in terms of quality, frequency, and composition.
Anthropometric measurements and body
composition
Body weight was measured at each visit using a calibrated electronic
digital scale (Tanita, TBF-300, Arlington Heights, IL, USA) to the
nearest 0.1 kg, with subjects wearing light clothing and no foot-
wear. Height was measured using a stadiometer (Seca, model 222,
Hamburg, Germany) to the nearest 0.5 cm. These measurements
were used for weight (kg)/height (m
2 ) and BMI % determination.
Waist circumference was determined at the narrowest region between
the costal margin and iliac crest. On a monthly basis, a bioelectrical
impedance analyzer (Tanita, TBF-300) was used to assess fat, water,
and fat-free mass. Blood pressure was monitored at the beginning
and at each follow-up session during the dietary intervention period.
Oral glucose tolerance test
All subjects underwent an oral glucose tolerance test (OGTT) with
simultaneous measurements of insulin concentrations before and
after their participation in the ketogenic or hypocaloric regimen.
This test involved the following requirements: (a) overnight fasting
and (b) ingestion of a dextrose solution containing 1.75 g/kg body
weight dextrose (up to a maximum of 75 g) immediately after the
0 min time point. Venous blood samples were obtained at 0, 30, 60,
90, 120, and 180 min for the determination of plasma glucose and
insulin concentrations. Insulin sensitivity was calculated from the
glucose and insulin values during the OGGT using the whole-body
insulin sensitivity index (WBISI) [WBISI = 10,000/square root of
[(fasting glucose × fasting insulin) × (mean glucose × mean insulin dur-
ing OGTT)]], which has been shown to be highly correlated (r = 0.73,
p < 0.0001) to the rate of whole-body glucose disposal during the eu-
glycemic insulin clamp (28) . Insulin resistance was assessed using
the homeostasis model assessment (HOMA) on modeling of fasting
insulin and glucose [HOMA-IR = fasting insulin ( μ U/mL) × fasting
glucose (mmol/L)/22.5)] (29) .
Fasted blood samples were also collected at two time points: at the
start (baseline) and at the end of each dietary intervention. All blood
samples were collected into EDTA and serum separator Vacutainer
tubes, briefl y placed on ice, and then centrifuged at 4 ° C for 10 min
at 1881.6 × g. The separated serum and plasma were stored at 80 ° C
until further utilization.
Biochemical analyses
Serum total cholesterol, HDL-cholesterol, triglycerides, low-density
lipoprotein (LDL)-cholesterol, and uric acid were measured using
standard methods. Insulin was determined using an automated ana-
lyzer (Elescys 2010) with a commercial kit based on electrochemilu-
minescence immunoassay (Roche Diagnostics GmbH, Indianapolis,
IN, USA). HMW adiponectin levels were determined using a spe-
cifi c sandwich ELISA kit [Adiponectin (Multimeric) EIA (ALPCO
Diagnostics, Salem, NH, USA)].
Statistical analysis
For all characteristics (age, height, weight, BMI, fat mass, waist
circumference, fasting glucose, fasting insulin, total cholesterol,
HDL-cholesterol, LDL-cholesterol, triglycerides, systolic blood
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Partsalaki et al.: Impact of ketogenic diet in obesit y 699
pressure, diastolic blood pressure, WBISI, uric acid, urea, crea-
tinine, HOMA-IR, and HMW adiponectin), the mean value and
standard deviation were calculated for all participants initially in
the study (n = 29 for each subgroup) and participants who com-
pleted the study (i.e., n = 21 for the ketogenic subgroup and n = 17
for the hypocaloric subgroup). Furthermore, the mean value and
standard deviation of the same parameters after 6 months (except
for age and height) were also calculated for all participants who
completed the study for both dietary subgroups. Statistically sig-
nifi cant differences between the two dietary groups (ketogenic vs.
hypocaloric) were tested with a non-parametric test (two-tailed
Mann-Whitney U-test for two independent unpaired data) for all
participants initially in the study and also for those who completed
the study.
In order to assess if sample reduction affects values of baseline
characteristics, statistically signifi cant differences between partici-
pants initially in the study and participants who completed the study
for both dietary subgroups were also tested with a non-parametric
test (two-tailed Mann-Whitney U-test for two independent unpaired
data).
Furthermore, statistically signifi cant differences between baseline
characteristics from participants who completed the study and their
characteristics after 6 months (for the ketogenic and hypocaloric
subgroups) were also tested with a non-parametric test (two-tailed
Wilcoxon signed-ranks test for paired data).
In all cases, derived values of p < 0.05 were considered to indicate
statistically signifi cant differences. Statistical analysis was performed
using the IBM SPSS Statistics software package (SPSS Release 19.0,
SPSS, Inc., Chicago, IL, USA).
Results
The anthropometric and metabolic characteristics of the par-
ticipants included in the study are summarized in Table 1
.
There were no signifi cant differences between the baseline
characteristics of the two diet subgroups for participants ini-
tially in the study.
Out of the 29 subjects who were recruited for each diet
subgroup, 21 (75 % ) and 17 ( 60 % ) children completed both
baseline and weight loss testing in the ketogenic and hypoca-
loric diet groups, respectively; therefore, only those were
included in the analyses. The comparison between those chil-
dren who achieved the 10 % weight loss in the two diet sub-
groups revealed again the non-signifi cant differences in their
baseline characteristics (Table 1).
Over the 6-month period of the study (Table 2
), the chil-
dren and adolescents in both diet groups signifi cantly reduced
their weight (mean: 8 kg for the ketogenic, p = 0.001 and
5.7 kg for the hypocaloric, p = 0.001) and their BMI (mean:
– 3.7 kg/m 2 for the ketogenic, p = 0.001 and – 3.3 kg/m 2 for the
hypocaloric, p = 0.001). After both ketogenic and hypocaloric
diets, there was a signifi cant fat mass reduction (mean: 7 kg
for the ketogenic, p = 0.001 and 5.1 kg for the hypocaloric,
p = 0.003). All individuals signifi cantly reduced their waist
circumference (mean: 9.2 cm for the ketogenic, p = 0.002
and 7.4 cm for the hypocaloric diet, p = 0.003, respectively).
Also, all of the above parameters showed non-signifi cant
Table 1 Baseline characteristics (mean ± standard deviation) of all participants initially in the study and participants who completed the study
for both diet subgroups.
Characteristics Initial Completed
Ketogenic diet
(n = 29)
Hypocaloric
diet (n = 29)
p-Value Ketogenic diet
(n = 21)
Hypocaloric
diet (n = 17 )
p-Value
Male/female 14/15 13/16 10/11 7/10
Age, years 13.6 ± 2.5 12.3 ± 2.7 0.082 12.8 ± 2.1 12.7 ± 2.8 0.927
Tanner, I/II/III/IV/V 5/4/6/7/7 8/4/4/8/5 3/2/4/5/7 5/2/2/3/5
Height, cm 157.1 ± 11.1 153.8 ± 11.7 0.33 5 156. 2 ± 8.3 152.1 ± 12.4 0.662
Weight, kg 77.7 ± 28.0 66.9 ± 15.6 0.116 73.7 ± 14. 9 65.7 ± 14 .2 0.113
BMI, kg/ m
2 30.8 ± 8.1 28.0 ± 4.2 0.246 30.0 ± 4.3 28.1 ± 3.1 0.182
Fat mass, kg 26.8 ± 11. 3 2 2.2 ± 9.0 0.2 04 26.0 ± 8.1 21.8 ± 8.2 0.198
Waist circumference, cm 94.6 ± 18 .0 88.9 ± 10.2 0.187 93.0 ± 7. 8 89. 2 ± 9.3 0 .298
Fasting glucose, mmol/L
(mmol/L)
4.67 ± 0.54
(84.3 ± 9.8 )
4.45 ± 0.97
(80.2 ± 17.6 ) 0.133 4.52 ± 0.61
(81.6 ± 11.1)
4.25 ± 0.55
(76.7 ± 10.0 ) 0.594
Fasting insulin, pmol/L
( μ U/mL)
113. 89 ± 90.97 82.64 ± 92.59 0.133 125.01 ± 63.89 77.08 ± 60.42 0.058
(16.4 ± 13.1) (11.9 ± 9.6) (18.0 ± 9.2) (11.1 ± 8.7)
Total cholesterol, mmol /L 4.24 ± 0.85 4.26 ± 0.95 0.693 4.4 ± 0.85 4.05 ± 0.94 0.559
HDL-cholesterol, mmol/L 1.28 ± 0.36 1.16 ± 0.20 0.243 1.27 ± 0.26 1.13 ± 0.20 0.222
LDL-cholesterol, m mol/ L 2.59 ± 0.66 2.7 ± 0.82 0.516 2.72 ± 0.69 2.6 ± 0.83 0.687
Triglycer ide s, mmol/L 0.85 ± 0.42 1.0 ± 0.53 0.301 0.83 ± 0.35 0.89 ± 0.57 0.878
Systolic blood pressure, m m Hg 110 ± 13 107 ± 90.654108 ± 13 106 ± 11 0. 815
Diastolic blood pressure, mm Hg 66 ± 10 65 ± 10 0.764 68 ± 862 ± 11 0.2 4 0
Uric acid, μmol/L 291.45 ± 83.27 303.35 ± 59.48 0.447 291.45 ± 59.48 309.29 ± 59.48 0.748
Urea, mmol/ L 10.31 ± 2.85 9.85 ± 1.75 0.725 8.6 4 ± 1.43 10.1 ± 1.25 0.121
Creatinine, μmol/L 53.38 ± 7.62 53.3 8 ± 7.6 2 0. 811 45.9 7 ± 7.6 2 53.3 8 ± 7.62 0.38 6
WBISI 5.4 ± 4.0 6.3 ± 4.8 0.448 4.4 ± 2.8 6.0 ± 2.6 0.178
HOMA-IR 3.4 ± 3.0 2.3 ± 2.0 0.096 3.6 ± 2.0 2.2 ± 1.9 0.053
HMW adiponectin, μ g/mL 2.5 ± 1.7 2. 3 ± 2.0 0.384 1.9 ± 1.1 2.1 ± 2.3 0.594
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700 Partsalaki et al.: Impact of ketogenic diet in obesit y
AB
CD
0
2
4
6
8
10
12
14
16
Weight loss, kg
0
2
4
6
8
10
12
14
Ketogenic Hypocaloric Ketogenic Hypocaloric
Ketogenic Hypocaloric Ketogenic Hypocaloric
Fat mass loss, kg
0
4
8
12
16
20
Waist circumference reduction, cm
0
1
2
3
4
5
6
BMI reduction, kg/m2
Figure 1 Comparison of the weight loss (a), BMI reduction (b), fat mass loss (c), and waist circumference reduction (d) between the keto-
genic diet and the hypocaloric diet groups, in box-plot representation, for the subjects who completed the study.
Table 2 Characteristics after 6 months (mean ± standard deviation) from participants who completed the study for both diet groups.
Characteristics Ketogenic diet (n = 21) Hypocaloric diet (n = 17 )
6 months p-Value 6 months p-Value
Weight, kg 65.7 ± 13.6 0.001 60.0 ± 12.8 0.001
BMI, kg/ m
2 26.3 ± 3.9 0.001 24.8 ± 3.0 0.001
Fat mass, kg 19.0 ± 8.0 0.001 16.7 ± 7. 4 0.003
Waist circumference, cm 83.8 ± 8.7 0.002 81.8 ± 7.7 0.003
Fasting glucose, mmol/L
(mg/d L)
4.51 ± 0.29 0.929 4.5 ± 0.5 0.906
(81.3 ± 5.3) (81.6 ± 9.1)
Fasting insulin, pmol/L
(µU/mL)
65.97 ± 45.83 0.017 39.58 ± 22.91 0.009
(9.5 ± 6.6) (5.7 ± 3.3)
Total cholesterol, mmol /L 4.63 ± 0.75 0.272 4.03 ± 0.89 0.859
HDL-cholesterol, mmol/L 1.38 ± 0.25 0.344 1.23 ± 0.23 0.202
LDL-cholesterol, m mol/ L 2.86 ± 0.65 0.133 2.55 ± 0.77 0.721
Triglycer ide s, mmol/L 0.81 ± 0.39 0.937 0.80 ± 0.40 0.306
Systemic blood pressure, mm Hg 103 ± 10 0.283 102 ± 10 0.475
Diastolic blood pressure, mm Hg 67 ± 80.78866 ± 70.423
Uric acid, µmol/L 285.5 ± 83.27 0.734 2 49.81 ± 41.63 0.022
Urea, µmol/L 10.92 ± 2.35 0.118 9.31 ± 1.21 0.154
Creatinine (µmol/ L) 53.38 ± 7.62 0. 630 53. 38 ± 7.62 0.222
WBISI 8.7 ± 6.0 0.032 10.0 ± 3.9 0.009
HOMA-IR 1.8 ± 1.4 0.014 1.2 ± 0.6 0.014
HMW adiponectin, μ g/mL 2.7 ± 1.5 0.025 1.8 ± 2.3 0.906
Statistically signifi cant differences between baseline characteristics and characteristics after 6 months are marked as boldfaced p-values for
both diet subgroups.
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Partsalaki et al.: Impact of ketogenic diet in obesit y 701
differences between the two diet groups after the intervention
(Figure 1 ).
There were no signifi cant differences between or within the
groups in the total, HDL, or LDL cholesterol and triglycerides
concentration (which were within the normal ranges for both
groups) nor was there a signifi cant change in either group
before or after the weight loss. HDL-cholesterol concentration
though did show a relative increase that tended to be greater
in the ketogenic group than in the hypocaloric group.
The levels of fasting insulin signifi cantly decreased after
the weight loss in both diets (p = 0.017 for the ketogenic and
p = 0.009 for the hypocaloric diet). Nevertheless, WBISI sig-
nifi cantly increased for the ketogenic diet (p = 0.032) and for
the hypocaloric diet (p = 0.009), and their HOMA-IR index
decreased signifi cantly (p = 0.014 and p = 0.014, respectively)
after the weight loss. Also, the HMW adiponectin increased
signifi cantly only in the ketogenic group after intervention
(p = 0.025) (Table 2), because the subjects on the ketogenic diet
initially had much lower concentrations than the hypocaloric
group, whereas there was no signifi cant difference between
the two diet groups (Figure 2 ). In addition, the response of
glucose and insulin sensitivity, as assessed by HOMA-IR
and WBISI, was not signifi cantly different between the diet
groups (Figure 3 ).
Systolic and diastolic blood pressure did not change sig-
nifi cantly in either group during the study nor were there sig-
nifi cant differences found between them.
At baseline, when the entire study population was con-
sidered, an apparent correlation was found between the fat
mass and the HOMA-IR (r = 0.369, p = 0.026) and the WBISI
(r = – 0.541, p = 0.001). Also, HDL-cholesterol was posi-
tively correlated with WBISI, whereas LDL-cholesterol was
negatively correlated with WBISI (r = 0.421, p = 0.016 and
r = – 0.490, p = 0.005, respectively).
All children had normal growth for their age and pubertal
status during the 6-month period of the study. The statistical
0
0.5
1.0
1.5
2.0
2.5
3.0
A
B
Ketogenic Hypocaloric
Ketogenic Hypocaloric
HOMA-IR decrease
-4
-2
0
2
4
6
8
10
12
WBISI increase
Figure 3 Box-plot representation for the changes observed in
HOMA-IR (a) and WBISI (b) indexes between the ketogenic diet
and the hypocaloric diet groups in the subjects who completed the
study. No signifi cant differences were observed between the two
groups in those indexes.
-1.0
-0.5
0
0.5
1.0
1.5
2.0
2.5
3.0
HMW adiponectin increase, μg/mL
Ketogenic Hypocaloric
Figure 2 Box- plot representation for the changes observed in the
levels of HMW adiponectin for the ketogenic diet and the hypocaloric
diet groups in the subjects who completed the study. No signifi cant
difference was found between them.
analysis did not reveal any signifi cant differences between
prepubertal and pubertal subjects and also when the subjects
were grouped according to their pubertal stage.
Discussion
In this randomized, controlled trial, we investigated the
effects of a very low-carbohydrate ketogenic diet and a low-
fat, hypocaloric diet on serum lipoprotein concentrations, glu-
cose, and insulin sensitivity and resistance parameters and on
HMW adiponectin levels in obese children and adolescents
and compared these effects between the two diet subgroups.
The children and adolescents on both diets were able to
achieve a weight loss of 10 % of their initial body weight,
but those on the ketogenic diet experienced a signifi cantly
greater reduction in body weight, as seen in many other stud-
ies conducted in adults (16, 30) and obese adolescents (31
33) . Both diet groups showed a signifi cant reduction in their
fat mass and waist circumference after dieting, but they both
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702 Partsalaki et al.: Impact of ketogenic diet in obesity
did not show a change in the fat-free mass, which consists
of skeletal muscle, bone, and water. The literature contains
confl icting results regarding the body composition changes
on low-carbohydrate, high-protein diets. Volek et al. (34) ,
relying upon dual-energy X-ray absorptiometry (DEXA),
concluded that low-carbohydrate diets favor a loss of fat
and preserve lean body mass. In contrast, Krebs et al. (31)
reported that their high-protein, low-carbohydrate adolescent
dieting group lost not only more fat mass than the low-fat
group but also marginally signifi cantly more lean body mass
despite the greater dietary protein intake. They also found
no signifi cant changes in the mean bone mineral density of
their subjects over the intervention period. In another study,
Willi et al. (32) reported that the calcium balance in adults
was affected by the ketogenic diet by increasing urinary cal-
cium excretion and decreasing bone mineral content during
the 8-week period of the diet. However, these changes were
reversed, returning to the normal range after the introduction
of more carbohydrates into the diet. As far as the lean body
mass changes are concerned, as assessed by DEXA and uri-
nary creatinine, they concluded that they were not signifi cant
over the term of the diet.
The ketogenic diet provides a very low-carbohydrate sup-
ply, thus favoring fatty acid oxidation and the formation of
ketone bodies that are used as an alternative energy substrate.
One of the proposed mechanisms for the greater weight loss
in the very low-carbohydrate ketogenic diets is that they
result in an improved satiety, thus allowing better compliance
(35) . Given that the brain is a major regulator of appetite, the
provision of an alternative fuel supply (ketone bodies) seems
to affect the motivation to eat (36) . Johnstone et al. (37) sup-
ported this hypothesis in a crossover trial that showed a greater
decrease in ad libitum energy intake with a high-protein,
low-carbohydrate ketogenic diet than with the high-protein,
medium-carbohydrate (non-ketogenic) diet. Ketone bodies
produced by the ketogenic diet also seem to have a neuro-
protective effect in the central nervous system by enhanc-
ing ATP production and decreasing reactive oxygen species
production, which help to preserve mitochondrial integrity in
the brain (38) . Interestingly, in a recent study, Farres et al.
reported that the ketone bodies of diet-induced ketosis block
the proinfl ammatory cytokine macrophage migration inhibi-
tory factor and in this way reduce insulin resistance (39) .
In the present study, although total cholesterol, LDL-
cholesterol, and triglycerides concentration did not differ sig-
nifi cantly between the two groups, HDL-cholesterol tended to
increase more favorably in individuals assigned to the keto-
genic diet and these results are in accordance with previous
studies (16, 18, 30) . It is of importance though to mention that
the children in both groups had lipidemic profi les within the
normal range; therefore, any changes observed were benefi cial.
Furthermore, the aforementioned studies demonstrate little or
no change in total or LDL-cholesterol in the low-carbohydrate
groups. Recent trials explored a more detailed lipoprotein
assessment and reported shifts in lipoprotein subclasses that
tend to differ according to the carbohydrate content of the diet.
Several lines of evidence indicate that subclasses of very low-
density lipoproteins (VLDL), LDL, and HDL cholesterol may
provide a more complete cardiovascular risk profi le than tradi-
tionally determined lipid values (40) .
Westman et al. (41) found that a ketogenic diet supple-
mented with low doses of ω -3 fatty acids led to greater reduc-
tions in triglyceride and VLDL subclass levels and greater
increases in HDL-cholesterol and large LDL levels compared
with a low-fat, reduced calorie diet over a 6-month period.
Similarly, Seshadri et al. (42) , in a 6-month study, without
supplementation, found an average change from small LDL-
cholesterol to large LDL-cholesterol. Some of these favorable
results seem to persist beyond the period of weight loss and
during a weight maintenance phase with reduced dietary car-
bohydrate consumption (43) .
In obesity, there is also a milieu of factors that contribute
to cardiometabolic risks, some of which are found to be
deregulated in states of excess and expanded adipose tissue
(9, 44, 45) . One of the most important adipokines secreted
from adipose tissue with anti-infl ammatory and insulin-
sensitizing properties is adiponectin, which is normally
found decreased in states of increased adiposity. Recently,
Martos-Moreno et al. (46) demonstrated that obesity in pre-
pubertal children results in decreased HMW adiponectin
and S A (the ratio of HMW oligomers to total adiponectin
levels), whereas total adiponectin was higher. They also
found a negative correlation between HMW adiponectin
with the HOMA index and the BMI in the whole cohort and
that both total and HMW adiponectin levels and S A were
more highly correlated with the carbohydrate metabolism
status than with BMI. In the same study, a reduction in
body fat increased total and HMW adiponectin. Our study
demonstrated that the levels of serum HMW adiponectin
were signifi cantly increased after the ketogenic diet, pos-
sibly demonstrating the study group s improvement in BMI
and in their carbohydrate metabolism, because the load in
carbohydrates remained minimal. There is also a possibil-
ity that the increased serum HMW adiponectin in the keto-
genic diet group may refl ect a decrease in visceral adipose
tissue because they showed a signifi cant decrease in waist
circumference and a tendency towards decreased fat mass
after their weight loss. Such changes possibly contribute
to their insulin sensitivity, as observed by the signifi cant
decreases in their fasting insulin levels and their HOMA
index, together with the signifi cant increase observed in the
WBISI after the ketogenic diet. In the hypocaloric diet, insu-
lin also decreased and WBISI increased, but these changes
were not followed by an increase in HMW adiponectin and a
decrease in their HOMA index, demonstrating a higher and
more signifi cant impact of the ketogenic diet on the insulin
sensitivity of these children.
In conclusion, the results of our study show that the keto-
genic diet elicited a greater improvement in weight loss, adi-
ponectin concentrations, the lipidemic profi le, and metabolic
parameters concerning insulin sensitivity and resistance in
the obese children and adolescents in the study in compari-
son to the hypocaloric diet. This is a study with a few limi-
tations, because we recognize that the long-term safety and
maintenance of weight loss in any diet protocol is an impor-
tant issue. Further follow-up studies need to be conducted in
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Partsalaki et al.: Impact of ketogenic diet in obesit y 703
order to confi rm whether these benefi cial effects will con-
tinue in the long-term. Nonetheless, our results support the
view that the ketogenic diet may be a feasible alternative for
weight loss and metabolic improvement in obese children
and adolescents.
Acknowledgments
We would like to express our appreciation to the children and ado-
lescents who volunteered to this study and their families and to the
physicians and nurses of the Division of Pediatric Endocrinology and
Diabetes for their assistance with blood collection.
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... A total of 25 publications were excluded, due to the following reasons: no data on measures of interest (n = 6), BMI < 30 (n = 1), article not available (n = 2), caloric restriction (n = 8), other diet or carbohydrate intake > 50 g per day (n = 5) and same cohort from another article (n = 4). Finally, the systematic research resulted in 20 studies that met the inclusion criteria [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Of these, 19 focused on weight loss, 8 on BMI, 8 on systolic and diastolic blood pressure, 14 on fasting glucose levels, 10 on fasting insulin levels, 5 on HOMA-IR, 7 on HbA1c level, 9 on total cholesterol, 15 on HDL and LDL levels, 16 on TG levels, 4 on AST levels, 5 on ALT levels, 1 on left hepatic lobe volume and 1 on liver biopsy histopathological characteristics ( Table 1). ...
... Weight loss is the main recommendation of health-care guidelines to reduce the risk of complication development [69,70] in the context of MetS. Interestingly, the majority of the studies have demonstrated a significant weight loss induced by KD [50][51][52][54][55][56][57][58][59][60][61][62][63][64][65][66]68]. In the eight studies which also investigated the effects of KD on the BMI, the significant weight loss was systematically associated with a significant decrease of the BMI [50,56,58,60,61,63,65]. ...
... Interestingly, the majority of the studies have demonstrated a significant weight loss induced by KD [50][51][52][54][55][56][57][58][59][60][61][62][63][64][65][66]68]. In the eight studies which also investigated the effects of KD on the BMI, the significant weight loss was systematically associated with a significant decrease of the BMI [50,56,58,60,61,63,65]. Among the 19 papers, only 2 showed no significant effect of the KD on weight loss [49,53]. ...
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Metabolic syndrome (MetS) is a major societal concern due to its increasing prevalence and its high risk of cardiovascular complications. The ketogenic diet (KD), a high fat, low carbohydrate, and non-caloric restrictive diet, is a new popular weight loss intervention but its beneficial effects are controversial. This study aims to gather all of the relevant studies using KD for metabolic disease treatment to determine its beneficial effects and evaluate its safety and efficacy for patients. Following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 20 articles in the final review. Overall, most of the studies showed a significant effect of KD on weight loss (17/19 articles), BMI (7/7), glucose levels (9/13), insulin levels (7/9), HOMA-IR (4/5), HbA1c (7/7), total cholesterol (6/9), TG (13/15), AST (3/4), and ALT (3/5), and no major side effects. The results heterogeneity seems to be explained by a difference of diet composition and duration. In conclusion, KD is a safety diet which seems to be a promising approach for obesity and MetS treatment, even if the optimal carbohydrate proportion and diet duration must be explored to enhance the beneficial effects of KD.
... Hay pocos ensayos clínicos en adolescentes con dietas con bajo contenido de hidratos de carbono, a las que se describen como cetogénicas, por contener hasta 20 g de hidratos de carbono por día. En su mayoría, la duración de los ensayos es de 12 semanas, aunque uno de ellos alcanzó los seis meses 57 . Todos los ECAs reportan disminución significativa del peso (de 4 a 9 k en promedio), disminución en parámetros antropométricos como perímetro de cintura y una mejoría de los parámetros bioquímicos analizados, como la sensibilidad insulínica, los valores de adiponectina y la disminución de los valores de triglicéridos 58,59 . ...
... En el estudio de mayor seguimiento, los autores reportaron que todos los niños tuvieron un crecimiento normal para su edad y su estado puberal durante los 6 meses que duró el estudio 57 . No se encontraron estudios que reporten seguridad a largo plazo con estas dietas en esta población. ...
... In studies that compared two methods of dietary macronutrient manipulation, such as low carbohydrate versus low fat, within-group analyses show both to be equally effective in reducing childhood adiposity indicators. [56][57][58] Across five RCTs, a low glycaemic index (GI) diet reduced adiposity outcomes compared to iso-caloric [59,60] or hypocaloric (but higher GI) dietary interventions [61]. In the context of broader lifestyle interventions, low glycaemic load interventions are as effective as interventions that modify macronutrient proportions and hypocaloric diets. ...
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... Although previous meta-analyses and systematic reviews have demonstrated the efficacy of a ketogenic diet in body weight control [12,13], conflicting findings have been reported with regard to changes in glycemic and lipid profiles of T2DM patients under this dietary intervention. A randomized controlled trial (RCT) reported that a ketogenic diet could mitigate insulin resistance and reduce glycemic responses, thereby improving the glycemic profiles of T2DM patients [14]. Conversely, other evidence indicates that a low-carbohydrate and high-fat diet is associated with deteriorated lipid profiles [15,16]. ...
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... Fifty-eight subjects followed either of the two diets for 6 months. Greater differences in fat mass, weight, waist circumference, and fasting insulin were observed in the KD group as compared to the HCD group and only KD group showed significantly increased high molecular weight (HMW) adiponectin (34). The mechanism behind successful weight loss by KD is still a scientific debate. ...
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... Feeding mice with a KD for 4 weeks only ameliorated pathological cardiac remodeling without improving cardiac function during heart failure, but infusion of 3-hydroxybuytrate or ketone ester showed significant protective effects [10,11]. Additionally, the results of clinical studies designed to test the benefits of KD for cardiac disease or cardiovascular disease risk factors are still inconclusive [16][17][18][19]. The underlying mechanism of a poor cardioprotective effect of KD feeding during heart failure remains unknown. ...
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There is a need for a detailed understanding of effective dietary interventions for children with obesity. This systematic review examined the effectiveness of diets of varying energy content as a component of weight treatment in children and adolescents with obesity, severe obesity and obesity‐related comorbidity. A systematic search of six databases, from 2000 to 2021, for intervention studies of targeted dietary treatment for obesity in children aged 2–18 years identified 125 studies. Dietary interventions were grouped according to diet type and energy target. Risk of bias was assessed using the Effective Public Healthcare Panacea Project assessment tool. Meta‐analysis examined change in body mass index (BMI) at intervention end. A broad array of diet types were effective at reducing BMI in children with obesity. When dietary types were considered by energy target, a gradient effect was observed. Very‐low energy diets were most effective with a − 4.40 kg/m2 (n = 3; 95% CI –7.01 to −1.79). While dietary interventions with no specified energy target were ineffective, resulting in a BMI gain of +0.17 kg/m2 (n = 22; 95% CI 0.05 to 0.40). Practical definitions of dietary energy target in the management of obesity and severe obesity are urgently required to ensure treatment seeking children have timely access to efficacious interventions.
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Cardiovascular disease (CVD) is caused by risk factors that can present at all ages, including early life. Healthy lifestyle practices can delay or prevent the onset of CVD risk factors. Consistent evidence demonstrates that a healthy dietary pattern in childhood prevents the early onset of CVD risk factors and lowers CVD risk in adulthood. Healthy dietary patterns are abundant in fruits, vegetables, whole grains and lean animal- or plant-protein foods, and limit foods and beverages higher in added sugars, saturated fat, and sodium. Meeting dietary recommendations in childhood reduces the risk of CVD risk factors including overweight/obesity, high blood pressure, dyslipidemia, and elevated fasting plasma glucose, thereby decreasing CVD risk in adulthood. Health professionals should screen and monitor lifestyle behaviors, including diet, throughout childhood. Teaching children and their caregivers about implementing a heart-healthy dietary pattern early in life could benefit primordial prevention and decrease CVD risk later in life.
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Prescribing a ketogenic diet (KD) is a century-old dietary intervention mainly used in the context of intractable epilepsy. The classic KD and its variants regained popularity in recent decades, and they are considered potentially beneficial in a variety of neurological conditions other than epilepsy. Many patients with multiple sclerosis have attempted diet modification for better control of their disease, whereas evidence thus far remains insufficient to recommend a specific diet for these patients. The results of three pilot clinical trials of KD therapy for multiple sclerosis, as well as several related studies, have been reported in recent years. The preliminary findings suggest that KD is safe, feasible, and potentially neuroprotective and disease-modifying for patients with multiple sclerosis. Research on corresponding rodent models also lent support to the efficacy of KD in the prevention and treatment of experimental autoimmune encephalomyelitis and toxin-induced inflammatory demyelinating condition in the brain. Furthermore, the animal studies yielded mechanistic insights into the molecular mechanisms of KD action in relevant situations, paving the way for precision nutrition. Herein we review and synthesize recent advances and also identify unresolved issues, such as the roles of adipokines and gut microbiota, in this field. Hopefully this panoramic view of current understanding could inform future research directions and clinical practice with regard to KD in MS and related conditions.
Article
To determine the efficacy of the ketogenic diet in multiple centers. A prospective study of the change in frequency of seizures in 51 children with intractable seizures who were treated with the ketogenic diet. Patients were enrolled from the clinical practices of 7 sites. The diet was initiated in-hospital and the patients were followed up for at least 6 months. Fifty-one children, aged 1 to 8 years, with more than 10 seizures per week, whose electroencephalogram showed generalized epileptiform abnormalities or multifocal spikes, and who had failed results when taking at least 2 appropriate anti-epileptic drugs. The children were hospitalized, fasted, and a 4:1 ketogenic diet was initiated and maintained. Frequency of seizures was documented from parental calendars and efficacy was compared with prediet baseline after 3, 6, and 12 months. The children were categorized as free of seizures, greater than 90% reduction, 50% to 90% reduction, or lower than 50% reduction in frequency of seizures. Eighty-eight percent of all children initiating the diet remained on it at 3 months, 69% remained on it at 6 months, and 47% remained on it at 1 year. Three months after initiating the diet, frequency of seizures was decreased to greater than 50% in 54%. At 6 months, 28 (55%) of the 51 initiating the diet had at least a 50% decrease from baseline, and at 1 year, 40% of those starting the diet had a greater than 50% decrease in seizures. Five patients (10%) were free of seizures at 1 year. Age, sex, principal seizure type, and electroencephalogram were not statistically related to outcome. The ketogenic diet is effective in substantially decreasing difficult-to-control seizures and can successfully be administered in a wide variety of settings.