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Int J Diabetes & Metabolism (2007) 15: 108-115
108
Anti-diabetic and hypolipidaemic properties of garlic (Allium sativum) in
streptozotocin-induced diabetic rats
Martha Thomson, Zainab M. Al-Amin, Khaled K. Al-Qattan, Lemia H. Shaban and Muslim Ali
Department of Biological Sciences, Faculty of Science, Kuwait University, , Kuwait.
____________________________________________________________________________________
Abstract
In this study the hypoglycaemic, hypocholesterolaemic and hypotriglyceridaemic effects of garlic were studied in
streptozotocin (STZ)-induced diabetic rats. Compared to normal (non-diabetic) rats, STZ-induced diabetic rats had
approximately 200% higher serum glucose, 50% higher serum cholesterol and 30% higher serum triglyceride levels as well
as 86% higher urinary protein levels. Daily treatment of STZ-induced diabetic rats with an extract of raw garlic (500mg/kg
intraperitoneally) for seven weeks significantly lowered serum glucose, cholesterol and triglyceride levels. Compared to
control diabetic rats, garlic-treated rats had 57% less serum glucose, 40% lower serum cholesterol levels and 35% lower
triglyceride. In addition, urinary protein levels in garlic-treated diabetic animals were 50% lower compared to the diabetic
controls. In contrast, the increased urine output and water intake of diabetic rats were not affected by garlic treatment. These
results indicate that raw garlic possesses a beneficial potential in reversing proteinuria in addition to reducing blood sugar,
cholesterol and triglycerides in diabetic rats. Therefore, garlic could be of great value in managing the effects and
complications of diabetes in affected individuals.
Key words: Diabetes, Garlic, hypoglycaemic activity, hypolipidaemic activity, proteinuria
Introduction
Garlic (Allium sativum) is one of the most popular herbs
used worldwide to reduce various risk factors associated
with cardiovascular diseases. Garlic, a member of the
Liliaceae family, is a common food for flavour and spice
and it is one of the herbs most commonly used in modern
folkloric medicine. Garlic was an important medicine to the
ancient Egyptians as listed in the medical text Codex Ebers
(ca. 1550 BC) especially for the working class involved in
heavy labour because it was an effective remedy for many
aliments such as heart problems, headache, bites, worms
and tumours.
Garlic is stated to possess many therapeutic benefits.
Garlic’s strong odour is largely due to sulphur-containing
compounds (e.g. S-allylcysteine sulphoxide), which are
believed to account for most of its medicinal properties.
1
Actually, garlic contains a variety of effective compounds
that exhibit anticoagulant (anti-thrombotic),
2,3,4,5,6
antioxidant,
7,8
antibiotic,
9,10,11
hypocholesterolaemic,
12
hypoglycaemic,
1
as well as hypotensive activities.
12-13
As mentioned above, although a large number of sulphur-
____________________________________
Received on: 16/3/2007
Accepted on: 18/10/2007
Correspondence to: Prof. Muslim Ali, Dept of Biological
Sciences, Faculty of Science, Kuwait University, P.O. Box
5969, 13060-Safat, Kuwait. Tel.: +965-498 5706; Fax:
+965-484 7054; email: alimuslim@hotmail.com
thiosulphinates are present in sufficient quantities at normal
consumption levels (3-5 g per day). Allicin has been shown
to be important in many health effects of garlic.
14
However,
the anti-cancer effect of garlic might be shared between
allicin and other unidentified compounds.
15
Garlic contains
about 1% alliin, which is converted enzymatically by
allicinase to allicin, and other sulphur-containing
compounds.
16
Garlic has been found to be effective in lowering serum
glucose levels in STZ-induced as well as alloxan-induced
diabetic rats and mice. Most of the studies showed that
garlic can reduce blood glucose levels in diabetic mice, rats
and rabbits.
14
Augusti and Sheela consistently showed that
S-allyl cysteine sulphoxide, (allicin), a sulphur-containing
amino acid in garlic (200 mg/kg body weight), had a
potential to reduce the diabetic condition in rats almost to
the same extent as did glibenclamide and insulin.
17-18
Aged
garlic extract was also effective in preventing adrenal
hypertrophy, hyperglycaemia and elevation of
corticosterone in mice made hyperglycaemic by
immobilization stress.
19
In addition, Liu and co-workers
reported that both garlic oil and diallyl trisulphide improved
glycaemic control in STZ-induced diabetic rats.
20
Ingestion
of garlic juice resulted in better utilization of glucose in
glucose tolerance tests performed in rabbits, while allicin at
a dose of 250 mg/kg was 60% as effective as tolbutamide in
alloxan-induced diabetic rabbits.
21
In contrast, garlic powder intake (6.25% by weight in diet)
for 12 days reduced hyperphagia and polydipsia, but did not
Thomson et al
109
alter either hyperglycaemia or hypoinsulinaemia in STZ-
induced diabetic mice.
22
Similarly, Baluchnejadmojarad and
Rohgani found no hypoglycaemic effect of an aqueous
extract of garlic in rats with STZ-induced diabetes although
they did observe a significant effect of garlic on vascular
reactivity.
23-24
Liu and co-workers have speculated that
these inconsistent results are at least partly due to the use of
different preparations or derivatives of garlic in the different
studies.
20
Staba and coworkers have established that the
chemicals present in a garlic product are largely dependent
on the processing conditions, such as temperature, duration
of preparation, and extraction solvents used.
25
In humans, the hypoglycaemic effect of garlic is not well
documented. Most reports have shown a significant effect of
garlic on blood glucose of normal healthy individuals but
not in diabetic patients. Thus the role of garlic in diabetes
treatment/prevention in humans is yet to be confirmed.
13
The aim of the present study was to investigate the efficacy
of an aqueous extract of raw garlic in controlling serum
glucose, cholesterol, triglyceride and urine protein levels in
STZ-induced diabetic rats treated daily intraperitoneally
(IP) for a period of 7 weeks. Since there have been variable
reports about the use of different preparations of garlic, as
discussed above, an aqueous extract of raw garlic was used
in the present study. Use of this preparation is also
consistent with our previous work with garlic.
4-5, 26, 27,28
Materials and Methods
Extract preparation
Aqueous garlic extract was prepared from locally available
garlic bulbs. The garlic bulbs were peeled on crushed ice.
Then 50 g of the peeled garlic was cut into small pieces and
homogenized in 70 ml of cold, sterile 0.9% NaCl in the
presence of some crushed ice. The homogenization was
carried out in a blender at high speed using 30 second bursts
for a total of 10 minutes. The homogenized mixture was
filtered 3 times through cheesecloth, the filtrate was
centrifuged at 2000 RCF for 10 minutes and the clear
supernatant was diluted to 100 ml with normal saline. The
concentration of this garlic preparation was considered to be
500 mg/ml on the basis of the weight of the starting material
(50 g/100 ml). The aqueous extract of garlic was stored in
small aliquots at -20°C until use. The stability of the
preparation during storage has been previously established
in platelet aggregation studies (unpublished observations).
Treatment of Diabetic Rats
Male Sprague-Dawley rats weighing 250-280 g (parents
purchased from Laboratory Animals Inc., England) and
maintained on a normal diet and filtered tap water ad
libitum were used in the experiment. For baseline data,
blood was drawn from all animals by cardiac puncture
under ether anaesthesia and allowed to clot. Immediately,
the clotted blood was centrifuged at 3500 RPM for 30
minutes. The serum was separated and stored at –80
o
C for
later analysis.
The animals were randomly divided into a healthy group (8
rats) and a streptozotocin (STZ)-treated group (initially 20
rats). The STZ-treated rats were injected IP with 60 mg
streptozotocin/kg body weight in a volume of 0.5 ml saline
following an overnight fast.
29
After a period of three days,
blood was drawn from the fasting STZ-treated animals and
serum was prepared and stored for later analysis as
described above. Serum glucose levels were determined
immediately and the STZ-treated rats determined to be
diabetic due to a high serum glucose level (>350 mg/dl)
were randomly divided into two groups containing 8
animals each: Group 1, the control diabetic group, was
injected IP daily with saline for the treatment period, and
Group 2, the garlic-treated group, was injected IP daily with
500 mg/kg of the garlic extract. After periods of two, five
and seven weeks, blood was drawn from the fasting rats by
cardiac puncture, and serum was prepared and stored for
later analysis as described above.
Rats were weighed before the start of the experiment and
then weekly during the experimental period. Animals were
monitored for general health during the treatment period.
Twenty-four hour water intake was measured daily.
Twenty-four hour urine output was measured in each
treatment group before STZ administration and at two, five
and seven weeks by housing the animals in metabolic cages
and collecting the urine in a calibrated 250 ml attached
container. The collected urine was centrifuged at 3000
RPM for 10 min to remove any particulate material. Urine
samples were then stored at -80°C for protein determination.
At the end of the experiment, the rats were sacrificed under
sodium pentobarbitone anaesthesia according to the
guidelines for euthanasia in the Guide for the Care and Use
of Laboratory Animals.
30
Assays
Serum glucose, cholesterol and triglyceride were
determined spectrophotometrically using kits supplied by
CARO Co., Germany. Urinary protein was determined by
the Coomassie Blue dye binding method of Bradford.
31
Statistical Analysis
The data are expressed as mean ± SEM. Readings within a
group were compared using the one-way ANOVA analysis
and readings between groups were compared using the
independent sample test. Statistical analysis was performed
using SPSS (Version 14). A level of p <0.05 was considered
to be significant.
Results
Figure 1 shows changes in the serum glucose levels in STZ-
induced diabetic rats in response to 500 mg/kg garlic extract
administration. It is clear from the data that the serum
glucose levels of the control diabetic animals continued to
increase during the 7 weeks of the experiment compared to
the post-STZ injection level. In contrast, the garlic-treated
diabetic rats showed significantly reduced serum glucose
levels during the treatment period when compared to the
control diabetic rats. At weeks 2, 5 and 7 of garlic extract
treatment, the serum glucose levels of the garlic-treated
diabetic rats were reduced by 29%, 68% and 57%,
respectively in comparison to control diabetic rats.
Anti-diabetic effects of garlic
110
0
100
200
300
400
500
600
700
800
blood glucose (mg/dl)
control diabetic garlic treated diabetic normal
a
post-STZ 2 wks 5 wks 7 wks
b
c
a
b
c
a
b
c
Figure 1: Serum glucose levels in STZ-induced diabetic rats treated with aqueous extract of garlic. Glucose levels were
measured in serum of normal rats, STZ-induced diabetic rats (control diabetic) and garlic-treated STZ-induced diabetic rats
(garlic-treated diabetic). Normal glucose levels were averaged over the experimental period and are depicted as a broken
line. Analysis was done after STZ injection (post-STZ), and after 2, 5 and 7 weeks of treatment.
a: Significantly increased compared to normal (p<0.05), b: Significantly decreased compared to control diabetic (p<0.05).
c: Significantly decreased compared to post-STZ (p<0.05).
0
20
40
60
80
100
120
140
160
180
weight % with weeks during the experiment
normal control diabetic garlic treated diabetic
a
a
b
pre-STZ post-STZ 1
23456 7
Figure 2: Weights of normal and STZ-induced diabetic rats over the garlic treatment period. Weights were measured in
normal rats, STZ-induced diabetic rats (control diabetic) and garlic-treated STZ-induced diabetic rats (garlic treated
diabetic). The animals were weighed before STZ injection (pre-STZ), one week after STZ-injection (post-STZ), and then
weekly during the treatment period of 7 weeks. Weights are plotted as percentiles with the starting weights all standardized to
100%. a: Significantly decreased compared to normal at week 7 (p<0.05), b Significant difference between control diabetic
and garlic treated diabetic rats (p<0.05).
However, garlic treatment did not reduce serum glucose of
diabetic animals to normal levels.
Normal rats gained weight significantly throughout the
experimental period, while both the control diabetic and
garlic-treated diabetic animals had significantly lower body
weights when compared to normal animals (Figure 2).
However, garlic-treated diabetic rats maintained their initial
weights during the 7-week treatment period although at the
end of the experiment their body weights were significantly
less than those of normal rats. In contrast, the control
diabetic rats showed significant weight loss when compared
to both the normal rats and the garlic-treated diabetic rats at
the end of the 7-week experiment.
Thomson et al
111
0
20
40
60
80
100
120
140
160
180
Blood cholesterol (mg/dl)
control diabetic garlic treated diabetic normal
post-ST
Z
2 wks
5 wks
7 wks
a
aa
a
b
b
b
Figure 3: Serum cholesterol levels in STZ-induced diabetic rats treated with aqueous extract of garlic. Cholesterol levels
were measured in serum of normal rats, STZ-induced diabetic rats (control diabetic) and garlic-treated STZ-induced diabetic
rats (garlic treated diabetic). Normal cholesterol levels were averaged over the experimental period and are depicted as a
broken line. Analysis was done after STZ injection (post STZ), and after 2, 5 and 7 weeks of treatment.
a Significantly increased compared to normal (p <0.05), b Significantly decreased compared to diabetic control (p <0.05).
0
10
20
30
40
50
60
70
80
90
100
blood triglycerides (mg/dl)
control diabetic garlic treated diabetic normal
post-STZ 2 wks 5 wks 7 wks
a
a
a
a
b
b
b
Figure 4: Serum triglyceride levels in STZ-induced diabetic rats treated with aqueous extract of garlic. Triglyceride levels
were measured in serum of normal rats, STZ-induced diabetic rats (control diabetic) and garlic-treated STZ-induced diabetic
rats (garlic treated diabetic). Normal triglyceride levels were averaged over the experimental period and are depicted as a
broken line. Analysis was done after STZ injection (post STZ), and after 2, 5 and 7 weeks of treatment. a: Significantly
increased compared to normal (p< 0.05), b: Significantly decreased compared to diabetic control (p< 0.05).
In Figure 3, one week after STZ-injection (post-STZ), the
serum cholesterol levels of the diabetic rats were
significantly higher than the normal levels. After treatment,
the serum cholesterol levels of garlic-treated diabetic rats
were significantly lower in comparison with the control
diabetic rats. The serum cholesterol reduction elicited by
garlic was sustained throughout the course of treatment with
serum cholesterol levels below the normal level after 5 and
7 weeks of garlic treatment. Figure 4 shows a reduction in
serum triglyceride levels to normal levels in garlic-treated
diabetic rats through the 7 weeks of treatment. In contrast,
both cholesterol and triglyceride levels remained elevated in
the control diabetic animals throughout the experimental
period.
Anti-diabetic effects of garlic
112
0
2
4
6
8
10
12
14
16
18
20
urine protein (mg/24 hrs)
control diabetic garlic treated diabetic normal
post-STZ 2 wks 5 wks
7 wks
a
a
a
a
b
b
b
Figure 5: Urinary protein levels in STZ-induced diabetic rats treated with aqueous extract of garlic. Protein levels were
measured in urine of normal rats, STZ-induced diabetic rats (control diabetic) and garlic-treated STZ-induced diabetic rats
(garlic treated diabetic). Normal urinary protein levels were averaged over the experimental period and are depicted as a
broken line. Analysis was done after STZ injection (post STZ), and after 2, 5 and 7 weeks of treatment.
a Significantly increased compared to normal (p<0.05). b Significantly decreased compared to control diabetic (p<0.05).
Figure 6: Urine output in STZ-induced diabetic rats treated with aqueous extract of garlic. Urine output was measured in rats
after STZ-injection (post STZ) and after 2, 5 and 7 weeks of garlic treatment of STZ-induced diabetic rats. Normal urine
output levels were averaged over the experimental period and are depicted as a broken line. Urine output levels in control
diabetic rats were averaged over the experimental period and are presented as an open bar.
a Significantly increased compared to normal (p<0.05).
The urinary protein levels of garlic-treated diabetic rats
were significantly lower than urinary protein levels in the
control diabetic rats (Figure 5). One week after STZ-
injection (post-STZ), the urinary protein level of the control
diabetic rats was double that of the normal rats and
remained elevated throughout the experimental period. In
contrast, at weeks 2, 5 and 7 of garlic treatment, urinary
protein levels in garlic-treated diabetic rats were lowered by
28%, 53% and 49%, respectively, with the urinary protein
levels at 5 and 7 weeks of garlic treatment reaching the
normal level. In the analysis of the data collected on urine
output, it was found that the effect of garlic treatment was
insignificant (Figure 6).
In fact, the urine output of the garlic-treated diabetic rats
remained elevated during the 7 weeks of treatment. In
contrast, the garlic-treated diabetic rats had decreased water
intake after 2 weeks of treatment, after which
0
50
100
150
200
250
300
urine output (ml/day)
control diabetic garlic treated diabetic normal
control diabetic post- 2 wks 5 wks 7 wks
a
a
a
a
a
Thomson et al
113
0
50
100
150
200
250
300
water intake (ml/day)
control diabetic garlic treated diabetic normal
control diabetic post-STZ 2 wks 5 wks 7 wks
a
a
a
a
a
b
Figure 7: Water intake in STZ-induced diabetic rats treated with aqueous extract of garlic. Water intake was measured in
rats after STZ-injection (post STZ) and after 2, 5 and 7 weeks of garlic treatment of STZ-induced diabetic rats. Normal
water intake levels were averaged over the experimental period and are depicted as a broken line. Water intake levels in
control diabetic rats were averaged over the experimental period and are presented as an open bar. a Significantly increased
compared to normal (p<0.05).b Significantly decreased compared to control diabetic (p<0.05).
there was no significant reduction in water intake in the
garlic-treated diabetic animals compared to the control
diabetic rats (Figure 7).
Discussion
Diabetes mellitus is the most common endocrine disorder
that affects more than 194 million people worldwide. If
nothing is done to control this disease, the number will
exceed 333 million by 2025 (6.3% of population). In 2003,
Kuwait was among the five countries of the world with the
highest diabetes prevalence in the adult population
(12.8%).
32
In addition to the primary effects of diabetes, diabetes is
accompanied by increased risk factors such as
hyperglycaemia, dyslipidaemia, hypertension, decreased
fibrinolytic activity, increased platelet aggregation, and
severe atherosclerosis.
33-34
Many synthetic drugs have been
developed for the treatment of diabetes. However, these
drugs have limits in terms of efficacy and side effects.
35
Therefore, there is much interest in discovering natural
treatments without negative side effects that can reduce
these risk factors in diabetic patients.
Garlic has been reported to possess a variety of medicinal
properties including hypoglycaemic, hypocholesterolaemic
and hypolipidaemic activities.
36
However, previous studies
on the hypoglycaemic activity of garlic preparations have
produced variable results.
7,17-24
Since we are interested in
the beneficial effects of consumption of whole garlic, we
chose to study the complete aqueous extract. In addition, in
our previous studies, we have obtained consistent results
using an aqueous extract of garlic in both rats and
rabbits.
4,5,6,7,8,9,10,11,12, 26, 27,28
In these experiments, the aqueous extract of garlic was
given IP since, in previous experiments,
both oral and IP
administrations were found to be beneficial and IP
administration required less handling of the animals.
6
The
dosage was chosen to be 500 mg/kg since it is a safe amount
of garlic to be given daily and does not cause toxicity.
14, 36
In addition, we have previously administered this dose (500
mg/kg) via the IP route with no detrimental effects in terms
of toxicity and mode of administration.
26, 28
The effects of the extracts of raw garlic were observed over
a period of seven weeks. STZ-induced diabetic rats showed
significant elevation of serum glucose, cholesterol and
triglyceride levels. Our results confirmed that raw garlic has
significant hypoglycaemic, hypocholesterolaemic and
hypolipidaemic effects. Therefore, the present study
reinforces the findings of previous papers that garlic had a
significant effect in reducing blood glucose,
17,18,19,20,21, 37, 38
cholesterol
12
and triglyceride levels
8
in diabetic animal
models.
We also observed that the weight loss that occurred in STZ-
induced diabetic rats was attenuated by garlic treatment. In
addition, at 7 weeks, the garlic-treated diabetic group had a
lower mortality (one out of eight) compared to the control
diabetic group (three out of eight). These changes may be a
reflection of the improved health of the garlic-treated
diabetic animals.
Proteinuria is a major predictor of glomerular injury and
elevated rates of protein excretion are selective markers of
progressive nephropathy.
39
STZ-induced diabetic rats are
characterized by the development of proteinuria.
40
Furthermore, it has been shown that STZ has no long-term
Anti-diabetic effects of garlic
114
direct effects on the kidney, but STZ has secondary effects
on the kidney as a result of the development of diabetes
mellitus.
41
Our results showed that raw garlic may alleviate
renal damage caused by STZ-induced diabetes, which was
manifested by the significant lowering of urinary protein
levels in the raw garlic-treated rats. Similar results were
observed in alloxan-induced diabetic rats by El-Demerdash
et al. who emphasized the alleviating effect of garlic on
renal damage.
42
However, garlic treatment did not alleviate
the characteristic polydypsia or polyuria observed in the
STZ-induced diabetic rats. This is in agreement with the
results of Liu et al. who also observed no change in water
intake or urine output in STZ-induced diabetic rats treated
with garlic oil or diallyl trisulphide.
20
It is not clear how garlic actually works in alleviating
hyperglycaemia. The hypoglycaemic action of garlic could
possibly be due to an increase in pancreatic secretion of
insulin from β-cells, release of bound insulin or
enhancement of insulin sensitivity. It has been previously
suggested that garlic (allicin) can enhance serum insulin by
effectively combining with compounds like cysteine, which
would spare insulin from SH group reactions which are a
common cause of insulin inactivation.
21
Another mechanism
proposed by Augusti and Sheela states that the antioxidant
effect of S-allyl cysteine sulfoxide, an isolated product from
garlic, may contribute to its beneficial effect in diabetes.
7
Jain and Vyas postulated that garlic may act as an anti-
diabetic agent by increasing either the pancreatic secretion
of insulin from the β-cells or release of bound insulin.
43
This
explanation is supported by the results of Liu and coworkers
who reported that treatment of STZ-induced diabetic rats
with garlic oil or diallyl sulphide resulted in increased
serum insulin levels.
20
The results of this study strongly suggest that garlic may be
very useful in the alleviation of diabetic complications as
well as in the prevention of the development of
atherosclerosis and nephropathy generally observed in
diabetic patients. In the future, further work is needed to
investigate the active ingredients in garlic. In addition, more
parameters should be studied such as insulin enhancement,
HbA
1c
level, free radical production, etc., to elucidate the
mechanism of action of the active constituents of garlic.
Acknowledgments
This work was supported by Kuwait University grant
number SB01/99 and the College of Graduate Studies,
Kuwait University for which the authors are grateful.
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