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Makara J. Health Res., 2017, 21(2): 54-60
doi: 10.7454/msk.v21i2.7393
54 August 2017 Vol. 21 No. 2
The Antidiabetic Activity of Curry Leaves “Murraya Koenigii” on the Glucose
Levels, Kidneys, and Islets of Langerhans of Rats with Streptozotocin Induced
Diabetes
Imad M Al-Ani
1*
, Rahajoe I Santosa
1
, Muhammad H Yankuzo
1
, Anil K Saxena
1
,
Khalid S Alazzawi
2
1. Department of Basic Medical Science, Kulliyyah of Medicine, International Islamic University Malaysia,
25200 Kuantan, Pahang Malaysia
2. Department of Environmental Biotechnology, Biotechnology Research Centre, Al-Nahrain University, Baghdad, Iraq
*
E-mail: imad_alani@yahoo.com
Abstract
Background: The aims of this study were to explore the antihyperglycemic effect of curry leaves, Murraya koenigii
“MK” aqueous extract, and to examine its possible protective effects on the islets of Langerhans and kidneys of
streptozotocin (STZ) diabetic rats. Methods: Thirty healthy adult male Sprague Dawley rats were randomized into five
groups (n=6); normal control, normal treated with “MK” control, diabetic control (non-treated with “MK”), diabetic
treated with 200 mg/kg MK aqueous leaf extract and diabetic treated with 400 mg/kg MK aqueous leaf extract. Blood
glucose levels and body weight were monitored gravimetrically. The animals were sacrificed on the 30th day; the
kidney and pancreatic tissues were processed for histological studies. Results: The diabetic group showed considerable
loss of body weight and increase in blood glucose levels and degeneration of the glomeruli and renal convoluted tubules
and atrophied islets with disintegration of β-cells. Treatment of diabetic rats with MK extract showed significant (p <
0.001) improvement in blood glucose levels and body weight gain. The MK extract also caused an improvement in
tissue injury induced by STZ injection in the kidney and islets of Langerhans. Conclusions: These findings highlighted
the beneficial effects of MK aqueous extract against cellular oxidative damage in STZ-induced diabetic rats.
Keywords: blood glucose, body weight, islet of langerhans, kidney
Introduction
Diabetes mellitus (DM), is the commonest metabolic
disease, involves metabolic disorder of carbohydrates,
proteins and lipids is often characterized by “chronic
hyperglycemia”, and is currently considered as one of
the five leading causes of death worldwide; it has become
a serious problem threatening the global public health in
view of its associated fatal vascular complications and
the lack of effective long term treatment.
1
The prevalence
of diabetes is rising globally both in developed and
developing countries and it has become an important
health concern and the leading cause of chronic renal
failure in Brazil, The South Asian region, and The United
Kingdom.
2-4
Diabetic nephropathy is a spectrum of progressive renal
lesions secondary to DM ranging from renal hyperfiltration
to end stage kidney disease; it is associated with a state
of decreased total protein concentration and increased
urea level.
5
Glomerular lesions mimic to those found in
human diabetes have been observed in experi-mental
animals treated with streptozotocin (STZ).
6
STZ has a high specific cytotoxic action on the β cells
of the pancreatic islets and has been shown to induce a
chronic diabetic state in animal’s model.
7,8
Induced DM
by STZ in many animal species has been reported to
resemble human hyperglycemic DM as it develops many
features as seen in human patients.
9
Long-term effects
of STZ induced diabetes in experimental animals demon-
strated glomerular nephropathy along with tubular
degeneration, and massive inflammatory infiltrates in
the interstitial tissue.
6,10
Currently many medicinal plants have been recommended
for the treatment of diabetes.
11,12
Curry leaves, Murraya
koenigii (MK), are natural flavouring agents with a
number of important health benefits that makes food
healthy and enhances both taste and aroma. They are
rich in medicinal nutraceutical properties and even have
cosmetic uses.
13
The major phytoconstituents identified in
MK are carbazole alkaloids, glycosides, and flavonoids.
14
The antihyperglycaemic effects of MK in different
animal models have been reported in many literatures
with variable results. Significant blood glucose lowering
effects of dose dependent MK aqueous extract has been
The Antidiabetic Activity of Curry Leaves “Murraya Koenigii” 55
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reported in both diabetic rabbits and rats.
15-17
The
objectives of this study were to investigate the effects of
the aqueous crude extract of MK on serum glucose
levels and histopathological changes in the kidney and
the islets of Langerhans in STZ induced diabetes
mellitus in rats.
Methods
Plant Material. Fresh plant material was obtained from
the local wet market in Kuantan, Pahang, Malaysia.
Specimen sample was authenticated by a Taxonomist
and deposited in the Faculty’s Herbarium. Isolated fresh
leaves were dried and pulverized to powdered using the
Fritsch universal cutting mill (AZM-160-23) and stored in
a desiccator at 20 ºC for subsequent use in the experiment.
Preparation of aqueous extract. The powdered leaves
(600 g) were subjected to cold maceration in 2 L of
distilled water on three occasions, with intermittent
stirring at 48 hour intervals. The extract was filtered and
the yield was 550 mL. The extract was concentrated
using a rotary vacuum evaporator (BUCHI R-205) to a
final adjusted volume of 500 mL. The concentrated water
soluble extract (500 mL) was frozen at – 70 ºC and were
immediately freeze dried for a continuous two week
period until the extract was completely dried, with the
final extract weighing 78 g. The extract was then preserved
in the laboratory chiller at 2 ºC for subsequent use. The
final concentration of the aqueous extract was adjusted
to 100 mg/mL.
Animals and experimental design. Thirty healthy adult
male Sprague Dawley rats (12 normal; 18 diabetic) of
10-12 weeks old and body weight 150-250 g were housed
(in triplets) in polypropylene cages under standard
laboratory conditions (temperature: 24 ± 4
ο
C; relative
humidity: 46-79%; 12:12 hrs light: dark cycle, adequate
cross ventilation) and were allowed one week period to
acclimatize prior to the test. The rats were divided into
five groups of six animals each, they were fasted
overnight and their fasting blood sugar (mmol/L) was
measured. The first group (NC1/normal control rats).
The second group (NC2/normal treated control rats) was
given MK 400 mg/kg; the third group (DC/diabetic
control rats) was given 70 mg/kg STZ; the fourth group
(MK-200/diabetic rats treated with curry leaf 200 mg/kg
MK) was given 70 mg/kg STZ and 200 mg/kg MK, the
fifth group (MK-400/diabetic rats treated with curry leaf
400 mg/kg MK) was given 70 mg/kg STZ and 400 mg/kg
MK. All groups were maintained on standard commercial
dry pellet diet containing 22% crude protein, 46% fat,
4% fibre, 7.6% ash, 12.0% moisture, 1.2% calcium, and
0.73% phosphorus (Gold Coin Feed Mills Sdn. Bhd. Kuala
Lumpur, Malaysia), and water ad libitum (Table 1).
Diabetes was induced under light ether anesthesia by a
single intraperitoneal injection of 70 mg/kg of STZ. The
Table 1. Distribution of Rats into Groups According to the
Treatment
Group Definition Treatment
NC 1 Normal control rats Rat pellets and water
only
NC 2 Normal treated con-
trol rats Rat pellets, water &
MK 400 mg/kg
DC Diabetic control rats STZ 70 mg/kg, +
pellets and water
MK-200
mg/kg/day Diabetic rats treated
with curry leaf (MK)
200 mg/kg
STZ 70 mg/kg, MK -
200 mg/kg + pellets
and water
MK-400
mg/kg/day Diabetic rats treated
with curry leaf (MK)
400 mg/kg
STZ 70 mg/kg, MK -
400 mg/kg + pellets
and water
injected volume was prepared to contain 1.0 mL/kg.
Rats were supplied with 5% glucose solution for 48hrs
immediately after STZ injection to counteract severe
acute hypoglycemic effect. Control rats received an
equivalent volume of phosphate buffered saline. Diabetes
induction was confirmed by determination of high fasting
blood glucose (FBG) level, on the fifth day after STZ
administration. Rats with FBG level ≥ 14 mmol/L were
selected for subsequent experiment. Following the
confirmation of diabetes, oral treatment with MK aqueous
extract using oral gavage was started on the sixth day
after STZ administration and it was considered as the
first day of treatment. Oral gavage was performed with
the aid of special designed metal ball-ended needle and
syringe. FBG levels and body weight (g) measurements
for all rats were recorded on day 3, 10, 20, and 30 of the
experiment. Blood samples from the overnight fasted
normal and STZ-induced diabetic rats were obtained
from the rat tail vein after a mild prick for repeated
measurement of FBG by glucometer (Life Scan One-
touch Ultra Glucose Meter, USA) on day 0, 5, 10, and
20 of the experiment. On the 30th day animals were
sacrificed using high dose Nembutal anesthesia. Pancreatic
and renal samples from each group of rats were fixed in
10% formal saline for 72 h, dehydrated by ethanol, cleared
in xylene and embedded in paraffin wax. Sections of 5
µm thickness were stained with Hematoxylin and Eosin
(H & E). Images that showed considerable histological
differences from control group were captured and studied
by two experienced pathologists who were blind to
study groups. The animals were treated according to the
standards and regulations for the Care and Use of
Laboratory Animals of the National Institutes of the
Health and to the guidelines of IIUM animal ethical
committee number (IIUM/519/14/ 4/IACUC).
Statistical Analysis. Results were expressed as mean ±
SD. Comparison of the mean values between the res-
pective groups at various time intervals was done using
one-way repeated measure analysis of variance (ANOVA),
followed by Tukey’s honestly significant difference (HSD)
test. p < 0.05 were considered statistically significant.
56 Al-Ani, et al.
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Figure 1. Effect of MK Aqueous’ Extract on Body Weight
(g) at Various Time Intervals in Normal and
STZ-induced Diabetic Rats
Figure 2. Effect of MK Aqueous’ Extract on Fasting Blood
Glucose Levels (mmol/L) at Various Time Inter-
vals in Normal and STZ-Induced Diabetic Rats
Results
Effect of MK aqueous extract on body weight. The
mean basal body weight values for all the animal groups
ranged from 166 to 172 grams with no significant inter-
group variation. Five days after STZ administration the
diabetic rat (DC) groups showed insignificant marginal
loss of body weight in comparison to the normal control
(NC 1) and showed continuous decrease throughout the
experimental period with maximal reduction of 42% (p
< 0.001) achieved on 30
th
day in comparison to the
basal level. In contrast, the normal control rats (NC 1),
achieved 55% increase in body weight at the end of the
experiment.
Regaining of body weight among the treated groups
(MK 200 and MK 400) started marginally from the 10
th
day, stabilized around the 20
th
day and equilibrates basal
levels by the 30
th
day of the experiment (Figure 1).
However, these groups still maintain statistically
significant difference (p < 0.001) in comparison to the
normal rats weight gain at the same corresponding time
intervals. The overall result as depicted in Figure 1,
shows statistically significant difference for day in all
the five groups (Wilk’s Lambda = 0.018, F (5, 26) =
275.9; p < 0.001, eta squared = 0.982 and observed
power = 1.00).
Antihyperglycemic effect of MK aqueous extract.
The basal mean FBG levels for all groups of rats were
not statistically different from each other (M= 5.0. SD=
0.7, p > 0.05). However, on the fifth day after STZ
administration the values advanced three to five folds
higher (p < 0.001) in all other groups (DC, MK 200 and
MK400) when compared to normal controls (NC1)
group. Blood glucose levels in all the treated groups
(MK 200 and MK 400) at various time intervals
decreased marginally towards normal value, unlike in
the diabetic control (DC) group where it remained
persistently high. However, the percentage of blood
glucose reduction was not dose dependent among the
MK treated groups (MK 200 and MK 400); for
example, maximal reduction achieved by MK 200
mg/kg (85%) on 30
th
day was slightly above than that of
MK 400 mg/kg (83%) on same day. The mean fasting
blood sugar level for diabetic control (DC) group (M =
34.01, SD = 3.33) remained statistically significant (p <
0.001) in comparison to the treatment groups throughout
the experimental period. On the other hand, the normal
control groups (ideal “NC1” and “NC2” treated)
showed persistent normoglycaemic values throughout
the course of the study. The overall result (Figure 2)
shows statistically significant difference in all the five
groups (Wilk’s Lambda = 0.018, F (5, 26) = 275.9; p <
0.001, eta squared = 0.982 and observed power = 1.00).
Histological observation. The kidneys of rats of both
control groups (NC1 and NC2) showed normal histo-
logical structure; the renal cortex consisted of numerous
renal corpuscles, which were formed of tuft of capillaries
“glomerulus”, enclosed by Bowman’s capsule. Both
proximal and distal convoluted tubules were normal
(Figure 3A).
The kidneys of the STZ hyperglycaemic rats showed
variable pathological changes in glomeruli and renal
convoluted tubules; there was a moderate enlargement
of glomeruli, dilatation and congestion of glomerular
capillaries in comparison to the control group (Figure
3B). The proximal convoluted tubules were filled with a
heterogeneous eosinophilic material, and haemorrhage
was also seen in the Bowman’s space that was related to
the glomerular damage (Figure 3C). Some sections
168 180 205
228 250
170
183 215 240
270
166 153 129 117 97
168 149 150 162 170
Day 0 Day 5 Day 10 Day 20 Day 30
NC 1 NC 2
DC MK - 200 MK - 400
5.6 5
5.1
5.3
20.1
33.4 33.4 33.4
5
25.2
11.4
4.3 3.8
23.5
12
5.3 4.3
Day 0 Day 5 Day 10 Day 20 Day 30
NC 1 NC 2 DC MK - 200 MK - 400
The Antidiabetic Activity of Curry Leaves “Murraya Koenigii” 57
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exhibited degeneration of the glomeruli as end stage
associated with mesangial cells hyperplasia, hydropic
tubular epithelium, vacuolations and dilatation (Figure
3D). Some sections in few rats showed the presence of
interstitial fibrosis associated with destroyed glomeruli
and mononuclear inflammatory cells infiltration (Figure
3E). The incidence and intensity of glomerular degene-
ration and tubular vacuolations were much lower in
STZ-diabetic rats treated with MK extract (MK -200
and MK -400 groups) compared to diabetic control
kidneys (Figure 3 F).
The islets of Langerhans of both control groups were
normal in histological appearance; they were unevenly
scattered in the pancreatic tissue and they were of
varying sizes in the same lobule of the pancreas, the
islet cells were closely situated close to capillaries
(Figure 4 A). The pancreas of STZ diabetic rats showed
atrophied islets with moderate degranulation and disin-
Figure 3. Microphotographs of Kidney Sections. A; Control
Showing Normal Architectures, B; STZ Diabetic
Rat Showing Moderate Enlargement of Glomeruli,
Dilatation and Congestion of Glomerular Capilla
Ries (arrow), C; STZ Diabetic Rat Showing Atrop
Hied Glomeruli (arrow) and Tubular Damage with
Eosinophilic Materials (S) and Hemorrhage (H) in
Blood Vessel, D; STZ Diabetic Rat Showing Dege-
neration of the Glomeruli (arrow) Associated with
Mesangial Cells Hyperplasia and Hydropic Tubu-
lar Epithelium, Vacuolations and Tubular Dilata-
tion (V), E; STZ Diabetic Rat Showing Interstitial
Fibrosis (F) Associated with Destroyed Glomerulus
(arrow) and Mononuclear Inflame Matory Cells
Infiltration (M), F; STZ Diabetic Rat Treated with
Curry Leaf Showing Normal Looking Glomeruli
(arrow) and Tubules. H & E. “A & B 200 x; C, D
&F 100x; E 40x”
Figure 4. Microphotographs of Pancreas. A; Control Show-
ing Normal Islets of Langerhans, B; STZ Diabetic
Rat Showing Shrunken Islet with Degranulated
β-cells, Hyaline Deposition and Congested Capil-
laries (arrow), C; STZ Diabetic Rat Showing Two
Shrunken Islets with Degranulated β-cells, Hyaline
Deposition, and Congested Capillaries (arrow),
D; Pancreas of STZ Diabetic Rat Treated with
Curry Leaf Extract Showing Normal Looking
Appearance of the Islet Structure. H & E. “200x”
tegration of β-cells, the endocrine cells were separated
by empty spaces and hyaline masses and congested
blood capillaries (Figure 4 B & C), fibrotic changes
were observed at the periphery of the pancreatic islets
(Figure 4 C). Treatment with MK extract to STZ diabetic
rats stimulated significant improvement in degenerative
changes induced by STZ injection in endocrine pancreas
(Figure 4 D).
Discussion
In the present study hyperglycemia was confirmed five
days after STZ administration and immediately followed
by daily treatment with graded dose (200 & 400 mg/kg) of
MK aqueous extract for 30 days. There was a significant
blood glucose lowering effect in diabetic treated rats as
compared to normal controls; the maximum fall of 85%
for the rats treated with MK-200 mg/kg on the 30th day
was slightly above that of MK-400 mg/kg treated rats
(83%). This phenomenon of dose independent response
is common with indigenous plants as it has been observed
with Vinca rosea;
18
the blood glucose lowering effect in
normal rats was almost negligible (4%).
The present study has revealed a significant (p < 0.001)
loss of body weight in diabetic group when compared to
the normal rats throughout the experiment. However,
daily administration of MK aqueous extract for 30 days
reversed the body weight to normal level. The normal
58 Al-Ani, et al.
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controls on the other hand, had a significant (55%)
increase in body weight on 30
th
day in comparison to the
experimental groups (16.3%, 17.3%. and 19%). Thus,
the result of our finding is in support of other literature
reports; advocating the effectiveness of MK aqueous extract
in partially attenuating the catabolic effects of STZ in
diabetic rats, through reversal of the body weight loss.
19
The present investigation revealed structural damage
in the pancreatic islets and the kidney of the STZ
treated rats. The pancreatic islets appeared atrophied
with degenerated β-cells associated with hyaline
deposition and congested blood vessels; these
observations agree with previous investigations in
rabbits,
20
rats,
21,22
and mice.
7
Hyper-trophy of the
glomeruli and thickening of glomerular basement
membrane associated with mesangial cells together
with tubular damage and interstitial fibrosis was
observed in the diabetic kidneys of the present study.
These pathological changes are consistent with those
observed in STZ diabetic rabbits,
mice, hamsters,
rats,
and alloxan diabetic rabbits.
6,12,20,23-25
In the present study, histopathological assessment of
the diabetic islets treated with either dose (200 and
400 mg/kg) of MK for30 day showed improvement in
islet morphology; this was associated with the
improved glucose levels and increased body weight
observed in these animals. Our results are in
agreement with previous studies using MK aqueous
extract in STZ,
26
and alloxan induced diabetic rats.
27
Akinola et al.
28
observed improve-ment in islet’s
histological structure of STZ diabetic Wistar rats
treated on (500mg/kg) ethanolic extract of the
Azadirachta indica Leaves for 50 days. Diabetic rats
treated daily with oral dose of 12.5 mg of Anastatica
hierochuntica for two weeks showed significant
impro-vement in the islet injury induced by STZ.
29
Restoration of the normal architecture of the
pancreatic islet structure was observed in STZ
diabetic treated with 200mg/kg of cinnamon aqueous
extract for 30 days.
30
Terminalia arjuna extract at the dose of 500 mg/kg
body weight for 30 days was found to effectively
improve the liver, kidney and pancreas function and
reduced the lesions associated with diabetic state in
alloxan diabetic rats.
31
Treatment of diabetic rats with
200 mg/kg Triumfetta pilosa Roth for 21 days
prevented the histopathological alteration in kidney
and caused a return to their normal structure.
32
Pronounced improvement in the renal function and
reduced kidney lesions was detected in STZ diabetic
rats treated with 300 mg/kg of Anacardium
occidentale for 5 weeks.
33
In vivo studies
demonstrated that curcumin (7.5 mg/kg/day)
protected pancreatic islets from C57/BL6J mice
against STZ-induced death or dysfunction.
34
These
variations may be related to species differences and/or
the type and dose of the used medicinal plant, the
duration of treatment and to the examined organ.
The precise mechanisms by which the medicinal plants
induce improvement in the function and structure of the
kidney and the pancreatic islets are inconclusive and
insufficient data are available to make any generalized
conclusion. The hypoglycemic action of the of herbal
plants extract in STZ diabetic rats may be related to the
insulinomimictic action or by inhibiting glucose absorption
from intestine, stimulation of glucose uptake by peripheral
tissue, or inhibition of endogenous glucose production
from hepatocytes.
35
Two possible explana-tions for the
protective effect of Aloe vera in STZ diabetic rats have
been suggested by preventing the death of the cells and/
or second, it may permit recovery of partially destroyed
cells.
36
The efficacy of oral fed MK aqueous extract in improv-
ing the parameters of renal function (serum urea and
creatinine) was estimated in STZ diabetic rats.
16
These
changes in diabetic animals were presumably suggested
to be as a result of increased oxidative stress. Curry leaf
extract helps reduce oxidative stress on pancreatic cells
by restricting the action of pancreatic alpha-amylase
enzymes. The aqueous slurry of dried leave powder of
this herb is useful in combating diabetes and serving as
a potential hypoglycaemic agent without preparing any
organic solvent extract.
26
The mode of action Murraya
koenigii has been suggested to be either due to in-
creased glycogenesis or decreased glycogen-nolysis
or gluconeo-genesis and/or due to insulin secre-
togogue effect of MK, which causes an increased
glucose uptake and its con-sumption by cells.
17
The
characterization of the active principle responsible
for the antihyperglycemic activity of MK has not yet
been elucidated. However, “carbazole alkaloid”
which has anti-hyperglycaemic and antihyper-
lipidaemic activity, has been found in the leaves of
MK.
16
The present study also corroborates with
several literature reports that claim an anti-
hyperglycaemic effect of MK in different animal
models.
15,37
It is possible that MK may have direct or
indirect effect on insulin release. Radioimmunoassay
studies are needed to elucidate the effect of MK
treatment on insulin and other hormones “related to
glucose metabolism” secretion. Further electron
microscopic investigations on the kidney and the pan-
creatic islets of STZ diabetic rats treated with MK are
in progress.
Conclusions
It is concluded from the present study that MK
extract shows hypoglycaemic activity and renal and
endocrine protective effects in STZ diabetic rats.
The Antidiabetic Activity of Curry Leaves “Murraya Koenigii” 59
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Acknowledgements
We are thankful to Professor Dr. Salim R. Al-Ubeidie,
Department of Pathology, College of Medicine, Baghdad
University, for his scientific comments on the present
histopathological observation. This study was supported
by the grant program from RMC, International Islamic
University Malaysia; Research Endowment Fund Grant
No. EDW B 100800419.
Conflicts of Interest Statement
The authors have no conflicts of interest to declare.
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