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ORGINAL ARTICLE
IRANIAN JOURNAL OF DIABETES AND OBESITY, VOLUME 11, NUMBER 4, WINTER 2019
257
The Aerobic Training and Berberine Chloride Intervention on
Pancreatic Tissue Antioxidant Enzymes and Lipid Peroxidation in Type
1 Diabetic Rats
Javad Ramezani1, Mohammad Ali Azarbayjani2*, Maghsoud Peeri3
Introduction
ype 1 diabetes is an autoimmune
disease that most often occurs in young
people. In this disease, pancreatic beta
cells, which produce insulin, are degraded and
ultimately lead to lower insulin secretion(1).
Oxidative stress is associated with almost all
pathological conditions, especially in the
T
1. Ph.D. Student, Department of Exercise
Physiology, Central Tehran Branch, Islamic
Azad University, Tehran, Iran.
2. Professor Department of Exercise
Physiology, Central Tehran Branch, Islamic
Azad University, Tehran, Iran.
3. Professor Department of Exercise
Physiology, Central Tehran Branch, Islamic
Azad University, Tehran, Iran.
*Correspondence:
Mohammad Ali Azarbayjani, Professor
Department of Exercise Physiology,
Central Tehran Branch, Islamic Azad
University, Tehran, Iran.
Tel: (98) 912 317 2908
Email: Ali.azarbayjani@gmail.com
Received: 20 June 2019
Accepted: 21 November 2019
Published in April 2020
Abstract
Objective:
Aerobic training and berberine chloride include
antioxidant characteristics. In this study, aerobic training and berberine
chloride intervention on the activity of antioxidant enzymes and lipid
peroxidation of pancreatic tissue were investigated in type 1 diabetic
male wistar rats.
Materials and Methods:
In the current study, 56 Wistar male rats
were randomly assigned to seven different groups (n= 8), these groups
include healthy control, diabetic control, Berberine-treated diabetes
(15&30 mg/kg), aerobic training-treated diabetes, Diabetes treated with
Berberine and aerobic training (15&30 mg/kg). The aerobic training
schedule consisted of 6 weeks treadmills with a frequency of 5 sessions
per week. The Berberine was also fed a specific dose every day and a
half before training. The superoxide dismutase, glutathione peroxidase,
catalase, and malondialdehyde were assessed using ELISA method.
Results:
The results showed that aerobic training, as well as the
intervention of Aerobic Training and Berberine chloride, had a
significant effect on the increase of antioxidant enzymes SOD and CAT
in the pancreatic tissue groups (P-value< 0.05), but did not significantly
affect the GPX level (P-value> 0.05). There was a significant decrease
in MDA level in all treatment groups (P-value< 0.05). In diabetic groups
that received both treatments at the same time, the MDA level more
decreased (P-value< 0.0005).
Conclusion:
The aerobic training and berberine chloride concurrent
intervention have a greater effect on the antioxidant enzymes in the
pancreatic tissue of diabetic specimens. Therefore, it is recommended
that aerobic training be done with berberine chloride.
Keywords:
Type 1 diabetes, Aerobic training, Berberine chloride,
Antioxidant enzymes
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258
IRANIAN JOURNAL OF DIABETES AND OBESITY, VOLUME 11, NUMBER 4, WINTER 2019
inflammatory process. (2). Oxidative stress is
characterized by increasing the production of
cellular oxidants (including superoxide,
hydrogen peroxide and nitric oxide), or
decreasing the concentration of antioxidants
enzymes, including glutathione peroxidase
(GPX), superoxide dismutase (SOD) and
catalase (CAT). The fact that increased
oxidative stress is an important factor in the
development of diabetes is accepted (3,4).
Usually, diabetes is associated with increased
production of free radicals (4,5) or antioxidant
deficiency (6,7). Reducing oxidative stress
may protect cells from damage caused by
oxidants, especially ROSs. The GPX enzyme
is found in cells that metabolize peroxide to
water (8). Any change in their levels makes
the cells susceptible to oxidative stress and
thus cell damage. CAT enzyme regulates
H2O2 metabolism, which is a major cause of
serious damage to fats, RNA, and DNA. The
formation of H2O2 can suppress the metabolic
activity of β-cells unless it is rapidly
eliminated (9,10). CAT, converts H2O2 to
water and oxygen and neutralizes it. In the
case of catalase disorder, the pancreatic β-
cell, which contains a large number of
mitochondria, is caused by over-exposure to
ROS under the influence of oxidative stress,
which leads to dysfunction of β-cells and
ultimately diabetes (11). The SOD enzyme is
the first line of defense against ROSs that
cause cell damage. This enzyme catalyzes
superoxide into oxygen and peroxide. It can be
argued that SOD also decomposes superoxide
into other components that are less toxic (12).
Since ancient times, herbal medicines have
been widely used to treat diabetes (13).
Among these anti-diabetic herbal medicines,
berberine chloride (BC) is an isoquinoline
alkaloid, potentially potent anti-inflammatory
and anti-oxidant (14) and hypoglycemic
effects (15). It is found in many herbs such as
berberis aquifolium, berberis vulgaris, and
berberis aristata.
On the other, there is evidence that exercise
inhibits progress in glucose tolerance (16) and
may also reduce hyperglycemia in type 1
diabetic patients (17-19). In addition, evidence
suggests that exercise can repair the mass of
β-cells in type 1 diabetic rodents (20,21). The
study also examined the effect of different
Aerobic Training intensities on preventing
damage to pancreatic β-cells in STZ-diabetic
rats. Moderate intensity exercises had the best
effect on the preservation of β-cells of the
pancreas, which is one of the most important
reasons for the anti-inflammatory and anti-
oxidant effects of this intensity of exercise
(21,22).
In this study, we sought to answer the question
whether concurrent intervention of aerobic
training with moderate intensity and berberine
chloride has an effect on antioxidant enzymes
and lipid peroxidation in Type 1 Diabetic Rats
or not?
Materials and Methods
This was a laboratory trial on 56 adult male
wistar rats from the Pasteur Institute of Iran,
Tehran. The rats were taken to an animal room
located on the International Campus of Shahid
Sadoughi University of Medical Sciences in
Yazd. All standard items including
temperature conditions (24 ± 1 ° C), relative
humidity (55 ± 3%), free access to water and a
standard special diet of mice (made by
Behparvar, Iran) as well as the dark/light cycle
(12/12 hours). Also, the ethical guidelines for
working with laboratory animals were met in
accordance with the Helsinki Statement of
2008 (23). And before the study began, the
code of ethics in the research was obtained
with the identifier IR.PNU.REC.1397.033.
Animals were placed in special cages of
polycarbonate for two weeks to adapt to the
new environment. In the course of two weeks,
in order to get acquainted with the treadmill,
the animals walked on a treadmill five days a
week and each session for 5-10 minutes at a
speed of 4-5 m/min.
The rats were randomly assigned into seven
groups of eight. In the healthy control group,
instead of STZ, a saline solution was injected.
In other groups, diabetes was induced by
intraperitoneal injection (IP) of fresh
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IRANIAN JOURNAL OF DIABETES AND OBESITY, VOLUME 11, NUMBER 4, WINTER 2019
259
streptozotocin solution (Sigma, S0130) with
pH=4.5 and at 60 mg/kg dissolved in 0.1 M
citrate buffer(24). After the injection of STZ, a
5% glucose solution was used instead of water
for 48 hours to reduce mortality in rats(25).
After 72 hours of STZ injection, blood glucose
concentrations were measured after 12 hours
of fasting overnight, with a small lacrimal
injury in the rat's tail area using Japan's
glucocard-01 device. Rats with the blood
glucose level above 300 mg/dl were included
in the study as diabetic animals. Experimental
groups included:
1. The healthy control group (Normal Ctr)
2. The diabetic control group (D)
3. Diabetic + Berberine chloride (D-BBr 15
mg/kg)
4. Diabetic + Berberine chloride (D-BBr 30
mg/kg)
5. Diabetic + Aerobic Training (D-AT)
6. Diabetic + Aerobic Training + Berberine
chloride (D-AT-BBr 15 mg/kg)
7. Diabetic + Aerobic Training + Berberine
chloride (D-AT-BBr 30 mg/kg)
The berberine used in this study was
manufactured by Sigma Aldrich (with code
number: 14050). The administration of
berberine was done by gavage. In this study,
doses of 15 and 30 mg/kg were used, and this
dose was determined based on the EC50
berberine used in previous studies. The
Berberine drug was given to specimens at all
times and at a specific time. In groups that
performed aerobic training, an hour before the
start of the exercise. The drug was given to the
specimens even on rest days and 48 hours after
the last exercise session and after 12 hours of
fasting, sampling was performed from control
and treatment groups (27). To collect the
specimens, animals were initially anesthetized
by intraperitoneal injection (IP) with a
combination of ketamine (30-50 mg/kg) and
xylazine (3-5 mg/kg) based on rat weight(28).
The chest of animals was then split and blood
samples were taken directly from the heart of
the rats. Blood was immediately poured into
tubes containing ethylene diamine tetraacetic
acid (EDTA). The samples were then
centrifuged at a speed of 3000 rpm for 15
minutes, and their topical solution was stored
inside labeled microtubules and kept until the
test day at -80 °C. After the blood collection,
the animals were sacrificed and the pancreatic
tissue was carefully removed from the body of
the rats and immediately labeled with
microtube and transferred to tank containing
liquid nitrogen to freeze, then transferred to a
freezer -80. On the test day, place a small
piece of pancreatic tissue at about 100 mg in 1
ml of PBS buffer (pH=7.4) and homogenizer
(T10 Basic, IKA model, Germany) on ice for 5
minutes Completely solved. Then the solution
was centrifuged for 20 minutes at 4 ° C with
6000 RPM. The supernatant was transferred to
a 1 cc micro tube and finally concentrated on
the Bradford method.
To measure the SOD enzyme in pancreatic
tissue, a ZellBio Germany (Cat No: ZB-SOD-
96A) kit with a sensitivity of 1 U/mL was
used. To measure the GPX enzyme from a
specific kit manufactured by ZellBio Germany
(Cat No: ZB- GPX-96A) with a sensitivity of
5 U/mL. To measure the enzyme CAT from a
specific kit manufactured by ZellBio Germany
(Cat No: ZB-CAT-96A) kit with a sensitivity
of 0.5 U / mL and to measure the MDA
enzyme from the ZellBio proprietary kit
Germany (Cat No: ZB-MDA-96A) was used
by ELISA method. Glucoskeletan was also
measured by Japan's glucocard-01 device.
The Kolmogorov-Smirnov test was used to
determine the normality of the samples .We
also used the two-way analysis of variance test
and the Tukey's post hoc test to analyze the
data. The results were presented as mean ±
standard deviation and the significance level
was considered as P-value< 0.05. Data were
analyzed with SPSS software version 25.
Table 1. Aerobic Training program (26)
Practice variables
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Speed (m/min)
10
10
14-15
14-15
17-18
17-18
Duration (min)
10
20
20
30
30
40
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IRANIAN JOURNAL OF DIABETES AND OBESITY, VOLUME 11, NUMBER 4, WINTER 2019
Ethical considerations
The study began, the code of ethics in the
research was obtained with the identifier
IR.PNU.REC.1397.033.
Results
The results of changes in body weight (BW),
body mass index (BMI) and fast blood glucose
(FBS) concentrations are presented in Table 2.
FBS concentration were significantly
decreased in the intervention groups (P-value=
0.015, 0.003), but no significant changes were
observed in other treatment groups (P-value>
0.05).
The level of SOD in the diabetic control group
was significantly lower than the healthy
control group (P-value< 0.0002).
CAT levels in the D-AT group and D-
BBr30mg/kg group showed a significant
increase compared to the diabetic control
group (P-value= 0.007, 0.030). There was no
significant difference in other treatment groups
compared to the diabetic control group.
The descriptive statistics of the variables in
table 3. Data are presented as mean ± standard
deviation.
The concentration of MDA enzyme was
measured as a lipid peroxidation index in
pancreatic tissue (Figure 1). The MDA level in
the diabetic control group was significantly
higher than the healthy control group (P-
value= 0.0001). In all treatment groups, MDA
had a significant reduction than the diabetic
control group (P-value= 0.005, 0.001 and
0.003). Also, the levels of this enzyme in the
D-AT, D-AT-BBr (15 mg/kg) and D-AT-BBr
(30 mg/kg) groups were significantly lower
than the D-BBr (15 mg/kg) group.
The correlation coefficient between variables
is shown in Table 4. Between CAT with SOD
and GPX, there is a significant and direct
relationship (P-value= 0.003, 0.039). There is
reverse and significant relationship between
MDA with CAT and SOD (P-value= 0.004,
Table 2. Mean ± standard deviation of BW, BMI and Blood Glucose in the research groups. (BW):
Bodyweight, (BMI): Body mass index, (FBS): Fast Blood Glucose.
Variable
week
Group
Normal Ctr
D
D-BBr
(15 mg)
D-BBr
(30 mg)
D-AT
D-AT-BBr
(15 mg)
D-AT-BBr
(30 mg)
BW (gr)
1
283.63
(±18.20)
285.12
(±13.37)
283.81
)±21.84(
281.57
(±14.04)
281.78 ±3.01
283.63
(±5.79)
282.78
(±17.05)
6
343.87
(±21.48)
198.57
(±4.47)
228.81
(±10.65)
283.88
(±10.05)*
205.36
(±11.59)
289.63
(±7.95)
*
323.85
(±18.07)
*
P-value
0.032
0.021
0.001
BMI (g/cm2)
1
0.63 (±0.02)
0.61 (±0.02)
0.60 (±0.01)
0.62 (±0.03)
0.61 (±0.01)
0.60 (±0.01)
0.60 ±0.02
6
0.64 (±0.0)
0.46 (±0.03)
0.45 (±0.03)
0.50 (±0.03)
0.48 (±0.06)
0.61 (±0.01)†
0.62 ±0.02†
P-value
0.002
0.001
FBS (mg/dl)
6
96.25 (±2.76)
601.62
(±17.27)
584.75
(±23.87)
559.62
(±8.43)
583.87
(±10.58)
410.62
(±20.28)#
356.75
(±37.12)#
P-value
0.015
0.003
Values include means ±SD assayed by two-way ANOVA and Tukey's post hoc test; significant differences were seen between the experimental
groups; (*, †( Indicate significantly increased compare to Diabetic control group. (#) Indicate significant decreased compare to the Diabetic control
group. In a row P-value that nothing is written, the P-value is greater than 0.05.
Table 3. Mean (± standard deviation) of SOD, GPX, CAT and MDA in the research groups.
Variable
Group
Normal Ctr
D
D-BBr
(15 mg)
D-BBr
(30 mg)
D-AT
D-AT-BBr
(15 mg)
D-AT-BBr
(30 mg)
SOD
P-value
4.29 (±0.20)
1.95 (±0.50)
3.05 (±0.11)
3.05 (±0.50)
3.92 (±0.23)*
0.018
4.59 (±0.86)*
0.0001
3.87 (±0.41)*
0.001
GPX
P-value
21.13 (±1.63)
18.23 (±0.34)
19.00 (±2.64)
21.76 (±3.07)
24.60 (±11.54)
21.55 (±0.92)
19.29 (±2.12)
CAT
P-value
2.94 (±0.59)
1.63 (±0.28)
2.97 (±0.51)
2.50 (±0.54)
3.62 (±1.01)*
0.007
2.68 (±0.50)
3.77 (±0.91)*
0.030
MDA
P-value
2.01 (±0.19)
8.57 (±1.52)
4.60 (±0.46)
3.57 (±1.19)
1.98 (±0.75)#
0.0005
1.60 (±0.72)#
0.0001
1.94 (±0.13)#
0.0003
(*) Indicate significant difference compare to the diabetic control group. (#)Indicate significant decreased compare to the Diabetic control group. In
a row p-value that nothing is written, the p-value is greater than 0.05.
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IRANIAN JOURNAL OF DIABETES AND OBESITY, VOLUME 11, NUMBER 4, WINTER 2019
261
0.001). There was no significant relationship
between other enzymes (table 4).
Discussion
In this study, we evaluated the effect of
simultaneous Aerobic Training and
supplementary Berberine chloride (15 and 30
mg/kg) on the activity of antioxidant and lipid
peroxidation in pancreatic tissue of STZ-
induced diabetic rats. Given that oxidative
stress in diabetic individuals increases with
free radical production, it can be suggested as
one of the factors contributing to the
progression of diabetes mellitus (29). It is
believed that, in response to oxidative stress,
antioxidant enzymes should protect cellular
function in maintaining hemostasis (30).
The high levels of MDA, which are lipid
peroxidation products, represent the oxidative
stress of diabetes. The results of this study
showed that the Induction of diabetes
increases the multifold of MDA. According to
the results of this study, antioxidant defense of
the pancreatic tissue has been reduced against
the oxidative stress in STZ-induced diabetes in
rats, which is accompanied by a significant
increase in MDA in the diabetic control group.
Aerobic Training, Berberine with doses of 15
and 30 mg/kg, all alone reduced MDA
significantly in pancreatic tissue of diabetic
specimens. The concurrent aerobic and
Berberine intervention resulted in a further
reduction in MDA. According to the results, in
groups with decreased MDA (especially
interventional groups), BW and FBS levels
were better than the diabetic control group and
significant changes were observed. The
relationship between MDA and BW was
inversely and significant, and the relationship
between MDA and FBS was direct and
significant. G. Chandirasegaran et al. (2017)
obtained similar results on diabetic rats (25).
In this study, the lipid peroxidation of rats
treated with Berberine (50 mg/kg) was
significantly lower than the diabetic control
group. In another study, it was shown that
consumption of Berberine with doses of 150
and 300 mg/kg had a significant effect on
MDA reduction in diabetic specimens (31).
Berberine has reduced the amount of MDA in
the pancreas of diabetic specimens, suggesting
the protective effect of berberine in the
pancreas due to its protective effect on lipid
Figure 1. Malondialdehyde changes in the study groups.
†
†
#
# †
# †
*
●
Table 4. Pearson correlation coefficient between
the variables.
Variable
Variable
Pearson correlation
Significance
CAT
SOD
0.622
0.003 *
CAT
GPX
0.453
0.039 *
CAT
MDA
- 0.600
0.004 *
SOD
MDA
- 0.809
< 0.001 *
BW
MDA
- 0.581
0.006 *
FBS
MDA
0.508
0.019 *
(*) Indicates that there is a relationship between variables.
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IRANIAN JOURNAL OF DIABETES AND OBESITY, VOLUME 11, NUMBER 4, WINTER 2019
peroxidation damage.
During exercise, increased levels of oxidative
stress promote antioxidant defense
mechanisms in various tissues. This slight to
moderate increase in radical oxygen species is
part of the "hormesis" that triggers the optimal
biological response to small amounts of toxins
and stressors. (32). Also, this increase in
exercise results in adaptations that include
increased activity of antioxidant / oxidative-
boosting enzymes, increased resistance to
oxidative stress, and ultimately reduced
oxidative damage. But overproduction of
radical oxygen species is accompanied by
harmful factors (22).
SOD catalyzes and removes superoxide
radicals, converting them to water and oxygen
molecules, thereby protecting tissues against
free radicals. The reduction of SOD in diabetic
specimens can be due to inactivation by H2O2
or glycation enzymes (33). In this study, SOD
significantly increased in D-AT, D-AT-BBr
(15, 30 mg/kg) groups compared to the
diabetic control group. Therefore, Aerobic
Training alone, as well as the intervention of
Aerobic Training and Berberine chloride, may
reduce the production of free radicals and also
increase the activity of SOD antioxidant
activity in pancreatic tissue, but Berberine
chloride alone with selected doses (15 and 30
mg/kg) has no significant effect on SOD. In a
study was shown that intake of Berberine
chloride with a dose of 50 mg/kg in diabetic
rats caused a significant increase in the SOD
antioxidant enzyme (25). The results of
another study showed that the consumption of
Berberine with doses of 75, 150 and 300
mg/kg significantly increased the SOD
enzyme (34). By comparing the results of this
study with other studies, it can be concluded
that Berberine with doses of less than 50
mg/kg cannot have a significant effect on the
number of SOD enzymes. In a study,
moderate-intensity exercise was shown to
increase the activity of the SOD enzyme in
mice (32).
Also, according to the results of this study, the
level of CAT in the D-AT group and D-AT-
BBr (30 mg/kg) group compared to the
diabetic control group significantly increased.
There were no significant changes in other
treatment groups compared to the diabetic
control group. In one study, CAT levels in the
pancreas of diabetic rats treated with
Berberine chloride increased significantly,
which was probably prevented from forming
hydroxyl radicals due to the antioxidant
properties of Berberine chloride (25). The
results of another study showed that physical
exercise increases the amount of enzyme CAT
in serum (35). H2O2 is one of the metabolic
products that should be eliminated quickly,
which is done by antioxidants such as CAT,
otherwise, it can lead to dysfunction of β-cells
and ultimately diabetes (11). Aerobic Training
and Berberine chloride medications can
prevent further damage to the pancreatic cells
caused by oxidative stress, given their
antioxidant properties.
GPX reduces its toxicity through the oxidation
of glutathione (GSH) and the conversion of
H2O2 to water (22). Decreased activity of
GPx in tissues during diabetes may lead to
harmful effects due to the accumulation of
toxic products (36). In the present study, GPX
increased in treatment groups, but this increase
was not statistically significant. One study
showed that treatment of diabetic rats with
Berberine at a dose of 50 mg/kg significantly
increased GPX activity in the pancreas(25).
Therefore, the doses used in our research are
likely to be less than those that have a
significant effect on GPX. Also, the
simultaneous intervention of Aerobic Training
and Berberine chloride with selected doses did
not have a significant effect on the GPX of
pancreatic tissue.
Conclusions
Administration of Berberine chloride at doses
of 15 and 30 mg/kg has no effect on the
antioxidant enzymes of the pancreatic tissue of
the rats, but simultaneous administration of
Berberine chloride with Aerobic Training has
a positive and significant effect on the
antioxidant enzymes of the pancreatic tissue
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IRANIAN JOURNAL OF DIABETES AND OBESITY, VOLUME 11, NUMBER 4, WINTER 2019
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(SOD and CAT). Also, Berberine chloride
alone with selected doses has a significant
effect on MDA in the pancreatic tissue, but the
simultaneous presentation of Berberine
chloride and Aerobic Training has a more
pronounced effect on MDA. Therefore, the
simultaneous intervention of Aerobic Training
and Berberine chloride can be used as an
effective way to increase the antioxidant
defense and decrease MDA in the pancreatic
tissue of type 1 diabetes mellitus.
Acknowledgements
We wish to thank Dr. Fatemeh Zare Mehrjerdi
who helped us in all steps of this study.
Funding
This study was the result of a doctorate thesis
in Exercise's Physiology approved by the
epartment of Exercise's Physiology, Islamic
Azad University, Central Branch, Tehran, Iran.
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