An Evaluation of the Hypoglycemic, Antioxidant and Hepatoprotective Potentials of Onion (Allium cepa L.) on Alloxan-induced Diabetic Rabbits
Diabetes mellitus is a chronic disorder of carbohydrate metabolism whose prevalence is raising globally, especially the resource -starved countries such as Nigeria. Since antiquity, diabetes has been treated with plant medicines. Several investigations have confirmed the efficacy of many of these traditional preparations, some of which have proven efficacy. In the present study, the hypoglycemic, antioxidant and hepatoprotective effects of Allium cepa (A.cepa) aqueous extracts on alloxan-induced diabetic rabbits was investigated. Diabetes mellitus was induced in 15 adult male rabbits, using 200 mg kg-1 of alloxan monohydrate as a single intraperitoneal injection. These alloxan -diabetic rabbits were then divided into three groups; one group was administered aqueous extract of A. cepa 100 mg Kg-1 b.wt. orally daily for 30 days, another group received A. Cepa 300 mg kg-1 b.wt. orally daily for 30 days and the last group of diabetic rabbits received peanut oil (the vehicle) instead of A. cepa to serve as the diabetic control. There were also five rabbits which received neither alloxan nor A. cepa (the negative control group). All the liver histological derangements caused by diabetes were attenuated in the A. cepa-treated group. Increasing dosages of A. cepa aqueous extract produced a dose-dependent significant reduction in the blood glucose levels. Additionally, A. cepa remarkably improved the reduction of antioxidant parameters-Superoxide dismutase, catalase (SOD), catalase (CAT) Glutathione Peroxidase (GPx) , Reduced Glutathione (GSH) and increased malondialdehyde (MDA), a product of lipid peroxidation. It is concluded based on these findings that A. cepa may be effective in ameliorating diabetics related hepatotoxicity and alterations of biochemical parameters.
to cite this article:
O.S. Ogunmodede, L.C. Saalu, B. Ogunlade, G.G. Akunna and A.O. Oyewopo, 2012. An Evaluation of the Hypoglycemic, Antioxidant and Hepatoprotective Potentials of Onion (Allium cepa L.) on Alloxan-induced Diabetic Rabbits. International Journal of Pharmacology, 8: 21-29.
Received: November 04, 2011;
Accepted: January 21, 2012;
Published: February 15, 2012
Diabetes Mellitus (DM) is an endocrine disorder which is characterized by chronic
hyperglycemia (high blood sugar) due to disturbances of carbohydrate, fat and
protein metabolism resulting from defects in insulin secretion, insulin action
or both (WHO, 1999). Diabetes mellitus is the most common
metabolic condition that affects more than 100 million people worldwide which
represents about 6% of the world population (WHO/Acadia,
1992; ADA, 2005). More worrisome is the fact incidence
the disorder is increasing rapidly and it is estimated that by the year 2030,
this number will double (ADA, 2005). Erasto
et al. (2005) asserted that DM is a common and very prevalent disease
affecting the citizens of both developed and developing countries. Several factors
are incriminated in the rising incidence of DM worldwide. Some of these factors
are the increasing proportion of the aging population, consumption of calorie
rich diet, obesity and sedentary life style (Vats et
The chronic hyperglycemia of DM is associated with long term complications
and poses huge social and financial burdens on countries ill-equipped to meet
them. These complications include renal failure, blindness or diabetic cataract,
poor metabolic control and increased risk of cardiovascular disease including
atherosclerosis and advance-glycation end (AGE) products (Zimmet
et al., 2001). The secondary complications in DM are due mainly to
sustained hyperglycemia and increased oxidative stress resulting from excessive
productive or reduced scavenging of free radicals (Baynes,
1991; Bayraktutan, 2002).
Allium cepa (onion), also known as the bulb onion, common onion and
garden onion, is the most widely cultivated species of the genus Allium
(Fritsch and Freisen, 2002). It has a globose bulb
that is an underground part of the stem, it is biennial and perennial and it
is widely distributed in the temperate regions. Allium cepa (A. cepa)
is used commonly in foodstuff and as a traditional remedy in the treatment of
a variety of disorders. The pharmacological evidence for the use of A. cepa
as an anti-asthmatic, anti-hypertensive, anti-hyperglycemic, anti-hyperlipidemic
and anti-tumor agent has been reported (Augusti, 1996;
Stajner and Varga, 2003).
Active ingredients in A. cepa include phenolic compounds (flavonoids,
antocyanins, phenolic acids and flavonols), organosulphur compounds, vitamins
and some minerals (Teyssier et al., 2001; Kamal
and Daoud, 2002; Campos et al., 2003; Gabler
et al., 2003; Ismail et al., 2003;
Wang et al., 2005; Elhassaneen
and Sanad, 2009). These compounds may mediate the pharmacological effects
of A. cepa. Thus, phenolic acids, such as caffeic, chlorogenic, ferulic,
sinapic, p-coumaric acids, vanillic, syringic and p-hydroxybenzoic appear to
be active antioxidants (Larson, 1988; Ibrahim
et al., 2004). Its vitamins, especially vitamin C have a protective
function against oxidative damage and a powerful quencher of singlet oxygen
(O2), hydroxyl (OH.) and peroxyl (RO2) radicals
(Niki, 1991; Saalu et al.,
Herbal products are commonly utilized in the management of disease in nearly
every culture and society on earth. Resort to folkloric medication is particularly
prominent in Africa where traditional beliefs induce people to use medicinal
plants whenever they have health problems. Further, the cost of administrating
modern treatment including antidiabetic drugs is beyond the reach of most people
in the low income group and those living in the rural areas, hence the use of
plants for the treatment of common diseases such as diabetes are very common.
It is in realization of these facts that the WHO (1980),
expert committee on diabetes recommended that traditional methods of management
of diabetes should be further investigated.
It is partly in response to the above charge that investigate in the present
study the potentials of Allium cepa as a hypoglycemic, antioxidant and
hepatoprotective agent in alloxan-induced diabetic rabbits.
MATERIALS AND METHOD
Animals: A total of twenty adult Rabbits (10 females and 10 males) were obtained from a breeding stock maintained in the animal house of the college of health sciences, Ladoke Akintola University of Technology (LAUTECH), Ogbomosho, Nigeria and housed at animal facility of the department of Anatomy, Ladoke Akintola University of Technology (LAUTECH), Ogbomosho, Nigeria. The rabbits were maintained under standard natural photoperiodic condition.
Experimental procedures involving the animals and their care were conducted
in conformity with international national and institutional guidelines for the
care of laboratory animals in biomedical research (National
Research Council, 1996).
Allium cepa: Twenty fresh mature A. cepa fruits weighing
200 g were bought from Sabo market Ogbomosho, Oyo state Nigeria on 12th December,
2010. The botanical identification and authentication of the plant sample was
done at the Herbarium Section, Department of Pure and Applied Biology, Ladoke
Akintola University of Technology, Nigeria (Voucher No. 20).
Aqueous extract of AC fruit was obtained using the method described by Azu
et al. (2007).
Acute oral toxicity study of Allium cepa extract: The acute oral
toxicity study for Allium cepa extract was conducted using the Organization
for Economic Cooperation and Development (OECD, 2000)
Guidance Document on Humane End points that should reduce the overall suffering
of animals used in this type of toxicity test. The test used was the limit dose
test of the up and down procedure.
Chemicals: Alloxan® (Sigma, St. Louis, MO, USA) was obtained
from a chemical shop in Lagos Nigeria and was dissolved in 0.1 M cold citrate
buffer, pH 4.5 (Lenzen, 2008).
Induction of diabetes: Alloxan monohydrate was used to induce diabetes
mellitus in normoglycemic rabbits. Animals were allowed to fast for 12 h and
were injected intraperitonially with freshly prepared alloxan monohydrate in
normal saline in a dose of 200 mg kg-1 b. wt. (Federiuk
et al., 2004). Blood glucose levels of these rabbits were estimated
24 h after alloxan administration using One Touch Ultra Mini Glucometer (Life
Scan Inc. Milpitas, CA, USA). Animals with blood glucose equal or more than
200 mg dL-1 were declared diabetic and were used in the experimental
groups (Lenzen, 2008). Twenty five hour after induction
of experimental diabetes, the experimental protocol was started.
Animals grouping and treatment: Twenty rabbits weighing between 1,500 and 1,800 g were randomly allocated into four groups:
Normal control animals received 5.0 mL kg-1 b.wt. sterile water intraperitonially (i.p.).
Diabetic control group of rabbits received 200 mg kg-1 b.wt. of
alloxan monohydrate i.p. as a single dose. This dosage is known to induce diabetes
in rabbits (Federiuk et al., 2004). The animals
were started on peanut oil (the vehicle) 5 mL kg-1 b.wt. orally daily
after 24 h for 30 days.
Diabetic with low dose A. cepa group of animals were administered alloxan monohydrate 200 mg kg-1 b.wt., i.p. as a single dose; the animals were started after 24 h on aqueous extract of A.cepa 100 mg kg-1 b.wt. per oral daily for 30 days.
Diabetic with high dose A. cepa group of rabbits received alloxan monohydrate 200 mg kg-1 b.wt., i.p. as a single dose. Then animals were started after 24 h on aqueous extract of A. cepa 300 mg kg-1 b.wt. per oral daily for 30 days.
Prior to injection of sterile water or alloxan, blood was taken from the auricular vein of the rabbit to determine the basal blood glucose level. Blood of the animals was similarly sampled for glucose concentration at the end of the experimental period.
Animal sacrifice and sample collection: After blood sampling for glucose concentration the animals were sacrificed. Each rabbit was at the time of sacrifice was first weighed and then anaesthesized by placing it in a closed jar containing cotton wool sucked with chloroform anaesthesia. The abdominal cavity was opened up through a midline abdominal incision to expose the liver. Then the liver was excised and trimmed all of fat. The liver weight of each animal was evaluated with an electronic analytical and precision balance (BA 210S, d = 0.0001- Sartoriusen GA, Goettingen, Germany). The liver volume was measured by water displacement method.
A portion of the median lobe of the liver was dissected and fixed in fixed in 10% formol-saline for histological examination. The remaining parts of the liver were frozen quickly in dry ice and stored at -25°C for biochemical analysis.
Histological procedures and analysis: This was done as described in
our earlier studies (Saalu et al., 2007; Saalu
et al., 2008). Photomicrographs were taken with a JVC colour video
digital camera (JVC, China) mounted on an Olympus light microscope (Olympus
UK Ltd, Essex,UK).
Assay of liver enzymatic antioxidants
Assay of catalase (CAT) activity: Catalse activity was measured according
to the method of Aebi (1983) as modified by Akunna
et al. (2011). Activity of enzyme was expressed as units mg-1
Assay of superoxide dismutase (SOD) activity: Superoxide dismutase activity
was measured according to the method of Winterbourn et
al. (1975) as described by Rukmini et al.
(2004). It was expressed as u mg-1 protein.
Assay of glutathione peroxidase (GPx) activity: Glutathione peroxidase
activity was measured by the method described by Rotruck
et al. (1973). The absorbance of the product was read at 430 nm and
expressed as nmol mg-1 protein.
Assay of liver non-enzymatic antioxidants
Assay of liver reduced glutathione (GSH) concentration: GSH was determined
by the method of Ellman (1959). The absorbance was read
at 412 nm, expressed as nmol mg-1 protein.
Estimation of lipid peroxidation (Malondialdehyde): Lipid peroxidation
in the liver tissue was estimated colorimetrically by thiobarbituric acid reactive
substances TBARS method of Buege and Aust (1978). Concentration
was calculated using the molar absorptive of malondialdehyde which is 1.56x105
M-1 cm-1 and expressed as nmol mg-1 protein.
Statistical analysis: All data were expressed as Mean±SD of number
of experiments (n = 5). The level of homogeneity among the groups was tested
using Analysis of Variance (ANOVA) as done by Snedecor and
Cochran (1980). Where heterogeneity occurred, the groups were separated
using Duncan Multiple Range Test (DMRT). A value of p<0.05 was considered
to indicate a significant difference between groups (Duncan,
Acute oral toxicity studies: There were no deaths of rabbits dosed 3000 mg kg-1 b.wt. of the plants extract both within the short and long outcome of the limit dose test of Up and Down method (Table 1). The LD50 was calculated to be greater than 3000 mg kg-1 b.wt. /orally.
Blood glucose levels: The increasing dosage (100 and 300 mg kg-1) of A. cepa aqueous extracts produced dose-dependent significant (p<0.05) reductions in the blood glucose levels of diabetic rabbits after 30 days of treatment when compared with that of the control rabbits (Fig. 1). A. cepa at 100 mg kg-1 reduced fasting blood glucose levels by 53.3% (300.2±11.2 to 140.1±3.4) and 300 mg kg-1 it reduced fasting blood glucose levels by 73.3% (300.2±11.2 to 80.4±1.2). Peanut oil 5 mg kg-1 which was used as a vehicle for A. cepa had no effect on the fasting blood glucose.
||Effect of A. cepa on the levels of SOD in the liver
|| Results of acute toxicity test for Allium cepa (AC)
extract (up and down procedure) in rabbits
|S = Survival; REP = Right ear pierced; LEP = Left ear pierced;
TC = Tail cut; RDC = Right leg tagged; I = Intact rabbit
Changes in the liver oxidative status
Activities of liver enzymes-superoxide dismutase (SOD), catalase (CAT) and glutathione
peroxidase (Gpx): Figure 2 to 4 show
changes in the activities of SOD, CAT and Gpx in liver of normal and treated
rabbits. The activities of SOD, CAT and Gpx levels in liver decreased in diabetic
control rabbits when compared the control values (15.2±0.5 vs. 42.1±0.3
u mg-1 protein; 3.9±0.1 vs. 18.5±1.2 u mg-1
protein; 0.25±0.01 vs. 0.7±0.03 nmol mg-1 protein,
|| Effect of A. cepa on levels of CAT in liver of rabbits
|| Effect of A. cepa on levels of liver GPX in rabbits
After treatment with the two dosage regimes of A. cepa, the levels
came back to near normal values. It was further observed that the higher dose
of A. cepa provided showed a better ability in reducing the liver oxidative
stress as compared to the lower dose.
Liver content of glutathione (GSH) and malondialdehyde (MDA): There was a notable reduction in GSH content in diabetic control group of animals. Administration of both doses of A. cepa significantly elevated the liver content of GSH compared to animals that were given alloxan without a follow up plant extract treatment (Fig. 5). Co-administration of alloxan and A. cepa exhibited a remarkable reduction in the liver MDA level compared to alloxan-alone treated rabbits.
As shown in Fig. 6, diabetic control rabbits showed significantly elevated liver content of lipid peroxides (products of lipid peroxidation) expressed as MDA when compared to control animals.
Like was the case with liver antioxidative enzymes, the beneficial changes in GSH and MDA were dose-dependent, the higher dose showing better potentials.
Liver histopathological results: The histopathological examination of diabetic rabbits showed marked distortion and degeneration of the liver parenchyma. The liver also, showed dilated and congested portal vessels (Fig. 7).
||Effect of A. cepa on the levels pf liver GSH in rabbits
There was a more organized cytoarchitecture of the liver in the group that receive alloxan with low dose of A. cepa as compared with untreated diabetic group (Fig. 8). Furthermore, in the group where the diabetes rabbits were treated with high dose of A. cepa extract, the cyto-architecture appeared well restored with visible central veins surrounded by hepatocytes and well arranged hepatic ducts (Fig. 9).
||Effect of A. cepa on the liver contents of MDA in rabbits
||Selection showed diabetic control. (H and E x40). CV: Central
vein, ILBD: Interlobular bile duct, SD: Sinusoids and BD: Bile duct
||Section showed slightly improved histology with low dose.
(H and E x40). CV: Central vein, SD: Sinusoids, ISBD: Interlobular septum
and bile duct
||Section showed improved histology with high dose of onion.
(H and E x40). CV: Central vein, BPV: Branches of portal vein, SD: Sinusoids
Recent studies have shown that many chronic diseases initiated and propagated
at least in part by oxidative stress mediated through reactive oxygen species
(Halliwell, 2001; Klaunig and Kamendulis,
2004; Stocker and Keaney, 2004; Dalle-Donne
et al., 2006; Saalu, 2010; Saalu
et al., 2010). Diabetes mellitus, the most common metabolic disorder
is multifactorial in causation. Of particular interest in the pathogenesis of
diabetes mellitus is the correlation between oxidative stress and development
of diabetes (Baynes, 1991; Bayraktutan,
2002; Abdel-Hamid et al., 2008). It has indeed
been asserted that the major concern in diabetes is oxidative stress (Khaki
et al., 2010).
Herbal products are commonly utilized in the management of diseases in nearly every culture and society on earth. However, only a few of these plant products have been scientifically evaluated. Allium cepa (onion) known to contain antioxidative bioflavonoids is evaluated in this study for its capacity to reduce blood sugar, moderate liver oxidative stress and attenuate the alterations in liver cytoarchitecture usually associated with diabetes. We are encouraged to carry out this study because few previous reports investigating the potentials of A. cepa assess all these three broad but complementary parameters.
This study demonstrated a raised blood sugar in diabetic alloxinized diabetic
rabbits models which was reduced by A. cepa in a dose dependent
manner, with the higher percentage reduction at the higher dose. The elevated
blood glucose in diabetes was also the finding in several previous reports (Mathew
and Augusti, 1975; Hamme et al., 1991; Sharpe
et al., 1998; Tukuncu et al., 1998;
Zhou and Sato, 2008). Studies have found that Allium
cepa (onions) has blood sugar lowering effects (Sharma
et al., 1977; Sheela and Augusti, 1992). The
molecular mechanism by which A. cepa mediate its antihyperglycocemic
and antioxidative effects has not been properly elucidated. Andallu
et al. (2001) reported the active compounds of onion are mainly,
sulfur-containing compounds-allyl propyl disulfide (APDS). It has been postulated
that these active ingredients lower glucose levels by competing with insulin
(which is also a disulfide) for insulin-inactivating sites in the liver (Kumari
et al., 1995) resulting in an increase of free insulin. There are
also reports that A. cepa could lower blood sugar by facilitating better
glycogen storage (Guo et al., 2002) and improve
oxidative status by increasing glutathione peroxidase (Helen
et al., 1999).
Klanns-Dieter (1983), earlier explained that onion contains
sulfur-containing compounds such as dialkyl disulfides and their oxidized thiols
which can trap electrons from other systems. Onion oil containing these compounds
has been reported to have an antioxidative effect against the oxidative damage
caused by nicotine in experimental animals (Helen et
al., 2000). It is there plausible to infer that these antioxidative
constituents of A. cepa may have provided the protection against oxidative
stress and hepatotoxicity in alloxan-induced diabetic rabbits evidenced in the
In conclusion, the present investigation shows that aqueous extract of A. cepa possess antihypergylcemic effect, antioxidant activity and ultimately hepatoprotective potentials. It is therefore recommended that further studies be carried out to determine the probable place of this nutraceutical in diabetes management.
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