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Research Article
Long-Term Ketogenic Diet Induces Metabolic Acidosis, Anemia,
and Oxidative Stress in Healthy Wistar Rats
Aryadi Arsyad ,
1
Irfan Idris,
1
Andi A. Rasyid,
2
Rezky A. Usman,
2
Kiki R. Faradillah,
2
Wa Ode U. Latif,
2
Zidni I. Lubis,
3
Aminuddin Aminuddin,
4
Ika Yustisia,
5
and Yulia Y. Djabir
6
1
Department of Physiology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
2
Biomedical Science Study Program, Postgraduate School, Hasanuddin University, Makassar, Indonesia
3
Department of Physiotherapy, Faculty of Health Science, University of Muhammadiyah Malang, Malang, Indonesia
4
Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
5
Department of Biochemistry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
6
Laboratory of Clinical Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
Correspondence should be addressed to Aryadi Arsyad; aryadi.arsyad@gmail.com
Received 13 December 2019; Revised 19 April 2020; Accepted 21 May 2020; Published 29 June 2020
Academic Editor: Phillip B. Hylemon
Copyright ©2020 Aryadi Arsyad 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. Ketogenic diet has been used as supportive therapy in a range of conditions including epilepsy, diabetes mellitus, and
cancer. Objective. is study aimed to investigate the effects of long-term consumption of ketogenic diet on blood gas, he-
matological profiles, organ functions, and superoxide dismutase level in a rat model. Materials and Methods. Fifteen male Wistar
rats were divided into control (n�8) and ketogenic (n�7) groups. Controls received standard diet contained 52.20% of car-
bohydrates, 7.00% fat, and 15.25% protein; meanwhile, the ketogenic group received a high-fat-low-carbohydrate diet which
contained 5.66% of carbohydrate, 86.19% fat, and 8.15% protein. All rats were caged individually and received 30g of either
standard or high-fat-low-carbohydrate pellets. e experiment was carried out for 60 days before the blood samples were taken
and analyzed to obtain blood gas, cell counts, organ biomarkers, and plasma antioxidant superoxide dismutase (SOD) levels.
Results. e rats subjected to ketogenic diet experienced a marked decrease in body weight, blood sugar, and increased blood
ketones (p<0.05). e average blood pH was 7.36 ±0.02 and base excess was −5.57 ±2.39 mOsm/L, which were significantly
lower than controls (p<0.05). Hematological analysis showed significantly lower erythrocyte, hemoglobin, and hematocrit levels.
No significant changes were found in alanine aminotransferase, aspartate aminotransferase, urea, and creatinine levels, indicating
normal liver and kidney functions. Nevertheless, plasma SOD level significantly reduced with ketogenic diet. Conclusion. Long-
term ketogenic diet induces metabolic acidosis, anemia, and reduced antioxidant enzyme level in rats following 60 days of
consuming high-fat-low-carbohydrate diet.
1. Introduction
e ketogenic diet is a food regimen which consists of a high
concentration of fat, with moderate/low protein and very
low carbohydrate content. is type of diet triggers high
production of ketone bodies derived from the breakdown of
fat to produce energy [1]. Some studies show that the ke-
togenic diet has therapeutic benefits in a range of illnesses. It
has been recommended as a supplementary therapy for
polycystic ovary syndrome, acne, cancer, and respiratory
distress [2]. It is also beneficial as anticonvulsant therapy to
reduce the frequency of seizures in people with epilepsy
[3, 4]. Ketogenic diet may also help to reduce HbA1C levels
in people with type 2 diabetes, maintaining mood stability
for people with bipolar disorder, and reducing cholesterol
levels in obese patients [5].
A clinical study has demonstrated that a short-term
ketogenic diet for 14 days might increase the concentration
Hindawi
Journal of Nutrition and Metabolism
Volume 2020, Article ID 3642035, 7 pages
https://doi.org/10.1155/2020/3642035
of ketone bodies in the blood, but it also improved the
antioxidant capacity of the blood that contributes to reduced
oxidative stress [6]. Another clinical trial has shown that
consuming ketogenic diet for 20 days significantly reduced
carbon dioxide deposits in the body, which may find clinical
benefit in patients with increased PaCO
2
due to respiratory
failure [2].
Despite its popular use, some concerns arise on how
ketogenic diet will affect the whole-body system. Since ke-
togenic diet replaces glucose with fat as the main source of
energy, the body is forced to activate a series of fat metabolic
processes to acquire energy [7]. Fat metabolic processes
form acetyl coenzyme A (acetyl-CoA) as the main product,
which then enters the citric acid cycle and is oxidized to
produce ATP [8]. Acetyl-CoA that exceeds the availability of
oxaloacetate and/or the activity of the citric acid cycle leads
to an increase in ketone bodies (acetoacetate, β-hydrox-
ybutyrate, and acetone). is process is called ketogenesis
[9]. e ketone bodies formed from ketogenic diets are
acidic; therefore, excessive excretion of these acids through
kidneys may cause a decrease in alkaline reserves or bi-
carbonate ions (HCO
3-
) [10]. As a result, the implication of
ketogenic diet reduced blood pH, leading to ketoacidosis
[11].
Several animal models have been used to learn about the
effect of a high-fat diet on the function of vital organs, such
as the kidneys and liver [12, 13]. High-fat diet is more likely
to trigger a reduction in mitochondrial quinone pool and is
associated with increased mitochondrial reactive oxygen
species (ROS) formation in the rat liver [14]. A high-fat diet
has been shown to induce alteration in renal lipid meta-
bolism in mice, especially the balance between lipogenesis
and lipolysis, leading to the accumulation of lipid in the
kidneys and, consequently, renal dysfunction [15].
To obtain more comprehensive data on how ketogenic
diet may affect the whole-body system, this present study
aimed to investigate the effects of long-term consumption of
ketogenic diet on blood gas profiles, hematological pa-
rameters, organ functions, and antioxidant level in a rat
model.
2. Materials and Methods
2.1. Preparation of Standard and Ketogenic Diet.
Standard food was obtained from a manufacturer as stan-
dard pellets for rodents (AD2®, Indonesia), while the ke-
togenic food was prepared in our laboratory by involving a
nutritionist. e ketogenic pellets contain 30% of nonpure
fat mixed with 70% of goat fat (Table 1), which is formulated
based on NutriSurvey®software to calculate the calorie
intake and the percentage of macro and micronutrients per
gram pellet. All ingredients were liquefied and mixed using a
hand mixer and then frozen for 24 hours with the tem-
perature of −20°C. e solidified material was then pul-
verized and molded into pellets. e standard and ketogenic
pellets were then examined for their fat, protein, and car-
bohydrate contents at the Laboratory of Animal Food
Chemistry, Faculty of Animal Science, Universitas
Hasanuddin.
2.2. Experimental Protocols. Male Wistar rats weighing
200–330 g age 3–4 months (n�15) were acclimated for 7 days
in the laboratory before starting the experiment. At this stage, all
rats received standard pellets and water ad libitum. Rats were
cared for according to the standard for laboratory animal care,
and all animal protocols have been approved by the Animal
Ethics Committee of the Faculty of Medicine, Universitas
Hasanuddin. Rats were divided into two groups. e first group
(n�8) received a standard diet, while the second group received
the ketogenic diet for 60 days. is 60-day period of adult rat life
is equivalent to ∼4 years of human life [17]. Each rat was caged
individually and offered 30 g of food per day ad libitum and not
subjected to calorie restriction.e remaining food was weighed
every morning to record the calorie intake of each rat. e blood
samples were withdrawn following 60 days of treatments and
prepared for further analysis.
2.3. Analysis of Blood Gas, Hematological Parameters, Organ
Biomarkers, and Superoxide Dismutase Level. e blood gas
analysis was performed on rat whole blood immediately
following blood sampling with the use of the i-Stat®analyzer
(Abbott®). For hematological analysis, blood samples were
collected using a BD®vacutainer with EDTA, centrifuged
for 20 min with the rate of 3000 rpm before analyzed using a
hematology analyzer (ermo Scientific®). e organ bio-
markers, such as alanine aminotransferase (ALT), aspartate
aminotransferase (AST), creatinine, and urea were measured
using Humalyzer 3500 (Human Global Diagnostic®)
according to the instruction on the reagent kits (Human®).
To measure plasma superoxide dismutase (SOD) level, the
plasma was prepared based on instruction in Rat SOD for
ELISA kit (Abbexa®) and analyzed with the enzyme-linked
immunosorbent assay (ELISA) reader (ermo Scientific®).
2.4. Analysis of Lipid Peroxidation Activity in Liver and Renal
Tissues. At the end of the experiment, rats were anes-
thetized, euthanized, and laparotomy was performed. e
Table 1: Composition of standard and ketogenic diet.
Composition Percentage
Standard diet
a
Water 12
Protein 15
Palm oil 7
Fiber 6
Calcium 7
Phosphor 0.7
Enzyme 0.1
Corns 52.2
Ketogenic diet
b
Water —
Avocado 5.69
Chicken egg yolk 19.45
Roasted peanuts 4.86
Goat fat 70
a
Formula is obtained from the commercial rodent chow label.
b
Formula is
prepared based on ketogenic diet for rats, with the ratio of 8.6 : 1 portion of
fat:(carbohydrate + protein) [16].
2Journal of Nutrition and Metabolism
liver and the kidneys of the rats were removed and im-
mediately immersed in liquid nitrogen. Organs were
weighed 400 mg and homogenized before adding 2mL of
phosphate buffer solution pH 7.4. e mixture is centrifuged
at 3000 rpm for 20 minutes. e supernatant (0.5 mL) was
mixed with 1 mL of 1% thiobarbituric acid and 1 mL of 1%
trichloroacetic acid and heated to 100°C for 20 minutes. e
mixture was then centrifuged at 3000 rpm for 10 minutes to
separate the residue. Organ lipid peroxidation was measured
as malondialdehyde (MDA) level (λ�530 nm) using a UV-
VIS spectrophotometer (Agilent®).
2.5. Statistical Analysis. e data obtained were analyzed
using the SPSS IBM 23 software. Data distribution was
examined using Kolmogorov–Smirnov to determine
whether the data were normally distributed or not. e data
that were normally distributed were subsequently analyzed
using an independent t-test, while data that were not nor-
mally distributed were analyzed using the Mann–Whitney U
test. A significant difference was achieved if p<0.05 or very
significant difference if p<0.01. All data were presented in
mean ±SEM.
3. Results
3.1. Long-Term Ketogenic Diet on Rats Causes Significant
Weight Loss, Reduced Blood Glucose, and Increased Blood
Ketone Levels. e food composition of the ketogenic pellet
has far less carbohydrate (5.66% vs 52.20%) and much higher
fat content (86.19% vs 7.00%) compared to the standard diet
(Table 2). e calorie of the standard chow is 5.85 kCal/g,
while that of the ketogenic pellet is 8.29 kCal/g. e average
of daily calorie intake per rat in each week is depicted in
Table 3. It is found that the standard group consumed more
amount of food than the ketogenic group; hence, the calorie
intakes of both groups are quite similar despite the difference
in calories per gram food.
e difference in the diet composition was found to
significantly affect the body weight, blood glucose, and blood
ketone levels in the male rats after 60-day intake. Table 4
shows the impact of ketogenic diet on rat body weight after
60 days. While all rats fed with standard diet gained weight
after 2 months (on average ∼25% increase from baseline
weight), the ketogenic-fed rats experienced a weight loss by
around 100 g from their baseline body weight (∼40% loss).
Apart from weight loss, the blood glucose level of ke-
togenic-fed rats was significantly lower compared to the
standard diet group (Figure 1). At this stage, the value of
blood glucose was 57 ±5.69 mg/dl, suggesting a hypogly-
cemic condition of the ketogenic diet group. Meanwhile, the
level of blood ketone markedly elevated in the ketogenic
group, about 8 times higher than the standard rats
(7.97 ±0.15 vs 0.34 ±0.02 mmol/L).
3.2. Long-Term Ketogenic Diet Significantly Lowered Blood pH
and Reduced Base Excess Level. e analysis of blood gas
values demonstrates that the administration of the ketogenic
diet for 60 days causes a significant alteration in blood gas
homeostasis (Table 5). It was found there was a very sig-
nificant decrease in blood pH of rats following 2 months of
having a ketogenic diet compared to those fed with a
standard diet (p<0.01). e decrease in blood pH was not
accompanied by significant changes in carbon dioxide
pressure (pCO
2
), oxygen pressure (pO
2
), total carbon di-
oxide (TCO
2
), and hemoglobin oxygen saturation (SO
2
).
Although the blood bicarbonate (HCO−
3) level of the ke-
togenic group insignificantly decreased (19.74 ±2.54 vs
22.75 ±0.79 mmol/L), it was found that the group’s base
excess level was significantly lower compared to the standard
group (p<0.05).
3.3. Long-Term Ketogenic Diet Induces Anemia in Male Rats.
e result of hematological analysis after receiving standard
and ketogenic diets for 60 days is presented in Table 6. e
ketogenic group appears to have slightly lower red blood cell
(RBC) counts, significantly lower hemoglobin, and hemat-
ocrit, as well as significantly smaller mean corpuscular
volume (MCV) and mean corpuscular hemoglobin (MCH)
indices. ese hematological abnormalities indicate that rats
fed with the ketogenic diet were anemic.
3.4. Long-Term Ketogenic Diet Does Not Significantly Alter the
Functions of Liver and Kidney. is study also measured the
effect of a long-term ketogenic diet in rats on liver and renal
functions. e result is presented in Figure 2. From the data,
it is revealed that the levels of liver biomarkers, the alanine
aminotransferase (ALT) and aspartate aminotransferase
(AST), were not significantly different between the standard
and ketogenic groups. However, when comparing the renal
function test, a slight increase in plasma creatinine and urea
levels was found in the ketogenic group compared to
standard, although the difference was not statistically
significant.
3.5. Long-Term Ketogenic Diet Increases Lipid Peroxidation
and Reduces the Antioxidant Level. e level of lipid per-
oxidation and antioxidant activity could be a good indi-
cator to reveal oxidative stress level in the system. In this
study, it was found that the ketogenic diet in rats for 60 days
may induce an increase in malondialdehyde (MDA) level in
the liver and kidney (Figure 3). e increase of MDA level
in both vital organs was very significant in the ketogenic
group compared to standard (p<0.01). e increase of
MDA level in the ketogenic group was accompanied by a
reduced level of antioxidant superoxide dismutase (SOD),
which was ∼80% lower compared to that of standard
(p<0.01).
Table 2: e comparison of carbohydrate, fat, and protein contents
of standard and ketogenic diets obtained from food analysis.
Type of diet Carbohydrate (%) Fat (%) Protein (%)
Standard 52.20 7.00 15.25
Ketogenic 5.66 86.19 8.15
Journal of Nutrition and Metabolism 3
4. Discussion
e ketogenic diet has gained public attention since it is first
introduced as an alternative therapy for pharmacoresistant
epilepsy [18]. Nowadays, the use of ketogenic diet has ex-
panded beyond epileptic therapy; indeed, its use in healthy
individuals has become more popular, especially to those
who wish to lose weight. Unfortunately, the benefits of
ketogenic diet may come with side effects. is study ex-
amined the long-term effects of ketogenic diet in a healthy
male rat model to obtain more information about the po-
tential complications of this type of diet.
Standard food with its high carbohydrate content allows
the body to use glucose as the main source of energy. When
carbohydrate intake is more than sufficient to meet the needs
of ATP, the body will physiologically convert glucose into
glycogen as energy stores in tissues. Consumption of a diet
rich in carbohydrates will also cause an increase in the
Table 3: e average of daily calorie intake per rat each week in standard and ketogenic diet groups.
Diet e calorie intake (kCal/day)
Week I Week II Week III Week IV Week V Week VI Week VII Week VIII
Standard 83.11 81.24 81.13 82.83 80.62 78.29 76.19 75.57
Ketogenic 88.77 84.78 82.86 83.45 86.70 84.78 88.77 98.24
Table 4: Changes in rat body weight after receiving standard and ketogenic diets for 60 days.
Type of diet NBody weight Mean ±SEM (g) pvalue
Standard 8 Baseline 252 ±20.61 0.001∗
Posttreatment 319 ±19.35
Ketogenic 7 Baseline 260 ±12.60 0.01∗
Posttreatment 157 ±06.40
0
20
40
60
80
100
120
140
160
Standard Ketogenic
Blood glucose (mg/dl)
∗∗
(a)
0.00
2.00
4.00
6.00
8.00
10.00
Standard Ketogenic
Blood ketone (mmol/L)
∗∗
(b)
Figure 1: e level of blood glucose and blood ketone of rats consuming standard and ketogenic diet for 60 days. e symbol ∗∗ implies a
very significant difference (p<0.01) between groups.
Table 5: e comparison of blood gas profiles of rats receiving
standard and ketogenic diets for 60 days.
Blood gas NDiet Mean ±SEM pvalue
pH 8 Standard 7.52 ±0.01 0.001∗
7 Ketogenic 7.36 ±0.02
pCO
2
(mmHg) 8 Standard 27.63 ±1.34 1.00
7 Ketogenic 35.72 ±5.96
pO
2
(mmHg) 8 Standard 107.75 ±2.93 0.32
7 Ketogenic 88.14 ±12.14
HCO
3-
(mmol/l) 8 Standard 22.75 ±0.79 0.48
7 Ketogenic 19.74 ±2.54
Base excess (mmol/l) 8 Standard 1.08 ±0.43 0.04∗
7 Ketogenic 0.32 ±0.11
TCO
2
(mmol/l) 8 Standard 23.63 ±0.84 0.56
7 Ketogenic 20.86 ±2.77
SO
2
(%) 8 Standard 98.63 ±0.18 0.20
7 Ketogenic 90.29 ±6.18
Table 6: e comparison of hematology profiles of rats receiving
standard and ketogenic diets for 60 days.
Hematology parameters NDiet Mean ±SEM pvalue
RBC (10
6
/μL) 8 Standard 8.04 ±0.24 0.33
7 Ketogenic 7.65 ±0.29
Hemoglobin (g/dl) 8 Standard 13.76 ±0.33 0.02∗
7 Ketogenic 11.98 ±0.54
Hematocrit (%) 8 Standard 39.90 ±0.97 0.001∗
7 Ketogenic 32.77 ±1.69
MCV (fL) 8 Standard 49.78 ±1.40 0.001∗∗
7 Ketogenic 42.67 ±0.89
MCH (pg) 8 Standard 17.15 ±0.37 0.01∗
7 Ketogenic 15.62 ±0.19
4Journal of Nutrition and Metabolism
amount of fat deposited in adipose tissue under the skin or in
the abdominal cavity. is is the main reason for the increase
in body weight of rats fed with a standard diet.
On the other hand, rats treated with the ketogenic diet
had a significant weight loss as a result of induced ketosis.
Ketogenic diet with high fat, low protein, and low carbo-
hydrate composition renders the body depends on the
process of gluconeogenesis, the formation of non-
carbohydrate glucose, to produce energy [19]. When the
fatty acids (fat content) are mainly used to produce energy, it
will induce the formation of ketone bodies, such as ace-
toacetate, beta-hydroxybutyrate, and acetone. e presence
of ketosis in the ketogenic group was confirmed by a sig-
nificantly higher level of blood ketone (∼8 mmol/L) and a
significantly low blood sugar level (<60 mg/dl). Apart from
weight loss, the rats also experience a decrease in pH or
acidosis, which occurs as a result of increased blood ketone
level [11]. e ketone bodies are acidic; thus, an increase in
ketone bodies in circulation may induce acidosis [11, 20].
Anemia is not uncommon side effects of high-fat diets.
is study also found reduced hematological indices, such as
RBC, hemoglobin, hematocrit, MCV, and MCH in rats fed
with ketogenic diet for 60 days. Studies on epileptic children
have revealed that ketogenic diet is more likely to cause
anemia, which may occur due to dietary restriction, leading
to copper deficiency [21, 22]. However, this complication of
the ketogenic diet can be managed with copper
supplementation.
In this study, the administration of ketogenic diet in rats
for 60 days did not significantly alter liver and kidney
function. Nevertheless, the plasma creatinine and urea of the
ketogenic-fed rats were somewhat higher than standard-fed
rats, which may suggest a minor effect of the ketogenic diet
on renal function. is effect could be more striking if the
duration of the ketogenic diet administration is prolonged.
It is interesting that although the liver and renal function
were not significantly altered, the lipid peroxidation activity
in both organs significantly increased. is was indicated by
a significantly higher MDA level of liver and renal tissues in
ketogenic-fed rats compared to those with a standard diet.
Increased activity of lipid peroxidation could be triggered by
the elevation of reactive oxygen species (ROS) in the organs
and incapability of the antioxidant enzyme activity to protect
cell membranes from ROS-induced damage. is result
could emerge as a potential threat to both organs should the
diet be sustained longer than the period investigated. In line
with this, the plasma concentration of superoxide dismutase
(SOD) significantly reduced in ketogenic-fed animals
(p<0.01), suggesting the presence of oxidative stress in-
duced by long-term ketogenic diet in rats.
0.00
20.00
40.00
60.00
80.00
100.00
120.00
140.00
160.00
Standard Ketogenic
AST (U/L)
(a)
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
Standard Ketogenic
ALT (U/L)
(b)
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
Standard Ketogenic
Creatinine (mg/dl)
(c)
0.00
10.00
20.00
30.00
40.00
50.00
60.00
Standard Ketogenic
Urea (mg/dl)
(d)
Figure 2: e level of aspartate aminotransferase (a), alanine aminotransferase (b), plasma creatinine (c), and plasma urea (d) in rats
consuming standard and ketogenic diet for 60 days.
Journal of Nutrition and Metabolism 5
e reason why a ketogenic diet may induce oxidative
stress has been explained in several studies. Ketone bodies
are known to stimulate the mitochondria to produce more
ATP compared to glucose [23–25]. However, fat metabolism
requires more complex processes, such as reduction, oxi-
dation, hydroxylation, and conjugation, which may elevate
the production of reactive oxygen species (ROS) in the liver
cells [26, 27]. If the release of ROS is in balance with the
body’s antioxidant activities, the occurrence of oxidative
stress can be prevented. In contrast, if ROS formation has
exceeded antioxidant levels, the free radicals will attack
macromolecules, such as, proteins, polysaccharides, DNA,
and cell membranes that contain polyunsaturated fatty acids,
leading to cellular damage [28]. is study shows an increase
in liver and renal MDA levels, which is accompanied by a
decrease in plasma SOD after 60-day consumption of ke-
togenic diet. is might implicate a precaution on the long-
term use of the ketogenic diet.
5. Conclusions
Despite the weight loss, low blood sugar, and high blood
ketone, sustainable consumption of keto diet for 60 days in
rats also instigated some concerning effects such as meta-
bolic acidosis, anemia, and decreasing plasma antioxidant
enzyme level. It is interesting that albeit a significant increase
in lipid peroxidation activity on the liver and kidney, both
organ functions were remained intact, at least during the
period investigated.
Data Availability
e data used to support the findings of this study are
available from the corresponding author upon request.
Conflicts of Interest
e authors declare no conflicts of interest.
Acknowledgments
is publication was made possible by a block grant from the
Faculty of Medicine, Hasanuddin University, Indonesia.
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34.00
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36.00
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6Journal of Nutrition and Metabolism
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