Original Article

Hypoglycemic Action of Seed Kernel of Caesalpinia bonducella Fleming In Normal and Alloxan- Induced Diabetic Albino Rats

G Sarma, S Das

Keywords

alloxan, diabetes mellitus, ethanolic extract, hypoglycemic effect

Citation

G Sarma, S Das. Hypoglycemic Action of Seed Kernel of Caesalpinia bonducella Fleming In Normal and Alloxan- Induced Diabetic Albino Rats. The Internet Journal of Pharmacology. 2008 Volume 6 Number 2.

Abstract

The aim of the present study is to evaluate the hypoglycemic action of ethanolic extract of seed kernel of Caesalpinia bonducella Fleming on normal and alloxan-induced diabetic albino rats. The ethanolic extract (200mg/kg/d) was administered orally for two weeks to alloxan-induced diabetic rats. Blood glucose was estimated every week for two consecutive weeks along with body weight monitoring. For evaluation of mechanism of action of test drug, glycogen estimation was done in liver, heart and skeletal muscle and effect on adrenaline-induced hyperglycemia was seen. The test drug significantly (p<0.05) reduced the rise in blood glucose induced by alloxan. The test drug produced significant (p<0.05) increase in liver glycogen and also significantly (p<0.05) reduced adrenaline-induced hyperglycaemia. Significant (p<0.05) lowering of normal blood glucose was also found. Thus, the seed kernel of Caesalpinia bonducella has significant antidiabetic and hypoglycemic activity.

 

Sources and Support

Animals: Central Animal House, A.M.C.H., Dibrugarh, Assam.
Drugs & Equipment: Department of Pharmacology, A.M.C.H, Dibrugarh.

Introduction

Diabetes mellitus is a major endocrine disorder affecting nearly 10% of population all over the world 1 . According to the world ethnobotanical information reports, almost 800 plants may possess antidiabetic potential. In the past decade, research has been focused on scientific evaluation of traditional drugs of plant origin and screening of more effective and safe hypoglycemic agents has continued to be an important area 2 .

Caesalpinia bonducella (L.) Fleming (Syn. Caesalpinia bonduc (L.) Roxb. ; Syn. Caesalpinia crista Linn.), belonging to the family Fabaceae, is a shrub widely distributed all over the world especially, in India, Sri Lanka and Andaman and Nicobar Islands 3 . All parts of the plant have medicinal properties 4 . The plant has been reported to possess anxiolytic 5 , antinociceptive, antidiarrhoeal 6 and antifilarial activities 7 . Phytochemical analysis of seeds of Caesalpinia bonducella has revealed the presence of alkaloids, flavonoids, glycosides, saponins, tannins and triterpenoids 78 . The powdered seed kernel of Caesalpinia bonducella is used by the local people of Assam in the treatment of diabetes. Keeping this in view, the present study was aimed at evaluating the hypoglycemic activity of ethanolic extract of the seed kernel of Caesalpinia bonducella on normal and alloxan-induced diabetic albino rats with stress on evaluation of probable mechanism of antidiabetic action.

Materials And Methods

Plant material and extraction

The seeds of Caesalpinia bonducella Fleming were collected from the local market in Dibrugarh in the months of June to August. The plant material was authenticated by Dr. L.R. Saikia, Reader, Department of Life Sciences, Dibrugarh University, Dibrugarh. A voucher specimen (No. DU/LS/212) was deposited at the Department of Life Sciences, Dibrugarh University.

The seed kernels of Caesalpinia bonducella Fleming were manually separated from the outer seed shell, air dried, powdered (1200 g) and ethanolic extracts were prepared using 90% ethanol by percolation method 9 followed by steam evaporation. A final yield of 133.5 g of the extract (11.1% w/w) was obtained.

Animals

Healthy adult Wistar albino rats (Rattus norvegicus) weighing 200—250 grams each were used for the study. All the animals were taken care of under ethical consideration as per the guidelines of the CPCSEA with due approval from the Institutional Animal Ethical Committee (Registration no: 634/02/a/CPCSEA; dated 19/5/2002).

Acute toxicity study

Acute oral toxicity test for the ethanolic extract of seed kernel of Caesalpinia bonducella Fleming (EESKCB) was carried out as per OECD Guidelines 425 10 . When administered orally, seed extract of Caesalpinia bonducella was found to be relatively non-toxic 5 . As such, the limit test at 2000 mg/kg was performed.

One–tenth of the upper bound dose of the extract from the limit test was decided to be considered for the experiments 11 .

Chemicals used

Crude powder of glibenclamide was obtained from Aventis Pharma Ltd., Goa while alloxan monohydrate was purchased from Sigma Aldrich India, Bangalore. The glucose kit for blood glucose estimation was obtained from Sigma Diagnostic (India) Pvt. Ltd., Baroda.

Study of hypoglycemic effect in normal rats

Three groups of animals (six in each) were divided as follows: Group–A : Normal Control. Received normal saline, 10 ml/kg/d orally. Group–B : Test Drug. Received EESKCB, 200 mg/kg/d orally. Group–C : Standard Drug. Received glibenclamide, 0.5 mg/kg/d orally 13 .

All the rats were kept fasting for 18 hours with free access to water before the experiment. Blood samples were collected from the orbital sinus of rats 14 for glucose estimation at ‘0’ min before drug administration and also at ‘120’ min after the above treatment. Blood glucose estimation was done by glucose oxidase method 15 using a glucose kit.

Experimental design for antidiabetic study

A total of thirty animals were equally divided into four groups with six animals in each group:

Group–A : Normal Control. Received normal saline, 10 ml/kg/d.
Group–B : Diabetic Control. Received normal saline, 10 ml/kg/d.
Group–C : Diabetic Test. Received EESKCB, 200 mg/kg/d.
Group–D : Diabetic Standard. Received glibenclamide, 0.5 mg/kg/d.

The above drugs were administered orally, once daily, for two weeks.

Induction of diabetes

Leaving aside six rats for Normal Control Group, 24 rats were induced diabetes by a single intraperitoneal injection of alloxan monohydrate in the dose of 150 mg/kg body weight. The fasting blood glucose was determined after 72 hours. Only 18 rats showing blood glucose level greater than 200 mg/100 ml were taken for the study 17 .

Blood glucose was estimated every week for two consecutive weeks. Blood glucose estimation was done by glucose oxidase method. During the experimental period, the rats were weighed on day ‘0’ and day ‘15’ of the experiment and the change in body weights was compared 18 .

Probable mechanism of antidiabetic action

Glycogen estimation of liver, skeletal muscle and cardiac muscle 19 : Out of 30 rats, 24 rats were induced diabetes by alloxan monohydrate (150 mg/kg body weight) intraperitoneally and 18 rats with blood glucose level greater than 200 mg/100ml were taken after 72 hours of diabetes induction. All the rats were kept fasting for 18 hours before the experiment. The rats were divided into four groups with six animals in each, as before.

Group–A : Normal Control. Received normal saline, 10 ml/kg/d.
|Group–B : Diabetic Control. Received normal saline,10 ml/kg/d and alloxan.
Group–C : Diabetic Test. Received EESKCB, 200 mg/kg/d and alloxan.
Group–D : Diabetic Standard.Received glibenclamide, 0.5 mg/kg/d and alloxan.

After two hours of administration of above drugs. The animals were killed by decapitation. The liver, leg muscle and heart tissues were taken out with care and their glycogen content was estimated by use of Anthrone reagent.

Effect on adrenaline-induced hyperglycemia

The rats were divided into three groups with six animals in each as before.

Group–A : Normal Control. Received normal saline, 10 ml/kg/d.
Group–B : Test Drug. Received EESKCB, 200 mg/kg/d.
Group–C : Standard Drug. Received glibenclamide, 0.5 mg/kg/d.

The above drugs were administered orally after drawing fasting blood samples. Adrenaline hydrochloride 100 g was administered intraperitoneally to all the rats one hour after drug administration. Blood samples were again collected half an hour later.

Statistical analysis

The data was statistically analysed using One-way ANOVA 21 followed by Dunnett’s multiple comparison test 22 . The body weights of the rats before (on ‘0’ day) and after (on 15 th day) drug administration were compared using Student’s ‘t’ test (Paired) 23 . The statistical analysis was done using computerised GraphPad Prism software version 5.00. Values of p < 0.05 were considered significant.

Results

Acute Toxicity Test

There was no mortality recorded among the rats upto the maximum dose of 2000 mg/kg (three consecutive animals survived at 2000 mg/kg). Hence, the LD50 can be said to be above 2000 mg/kg.

Effect on fasting blood glucose level

The data was statistically analysed using One-way ANOVA followed by Dunnett’s multiple comparison test.

Normal Rats: A significant (p < 0.05) lowering of normal blood glucose was found in Test Drug and Standard Drug groups when compared to Normal Control Group after 120 min of drug administration (Table–1).

Legend for Table-1:

Values are expressed as Mean ± SEM; n=6 rats in each group. One-way ANOVA followed by Dunnett’s multiple comparison test was done. * p<0.05 when compared to Normal Control Group.

Figure 1
Table 1: Effect of EESKCB on blood glucose level of normal rats

Diabetic Rats: On repeated administration of the extract and glibenclamide for two weeks, a significant (p < 0.05) decrease in blood glucose was found in Diabetic Test Group and Diabetic Standard Group respectively as compared to Diabetic Control Group which showed a significant (p < 0.05) rise in blood glucose as compared to Normal Control Group. However, both the drugs failed to restore the blood glucose level to that of the Normal Control Group (Table–2).

Legend for Table-2:

Values are expressed as Mean ± SEM; n=6 rats in each group. One-way ANOVA followed by Dunnett’s multiple comparison test was done. * p<0.05 when compared to Normal Control Group. † p<0.05 when compared to Diabetic Control Group.

Figure 2
Table 2:Effect of EESKCB on blood glucose level of alloxan-induced diabetic rats

Effect on changes in body weight

The body weights of the rats before (on ‘0’ day) and after (on 15 th day) drug administration were compared using Student’s ‘t’ test (Paired).

The final body weight showed significant (p<0.05) increase from the initial body weight in all the groups except in Diabetic Control Group, in which there was significant (p<0.05) decrease in body weight compared to the initial body weight (Table–3).

Legend for Table-3:

Values are expressed as Mean ± SEM; n=6 rats in each group. One-way ANOVA followed by Student’s t-test (Paired) test is done. * p <0.05 when compared to the Initial body weight.

Figure 3
Table 3: Effect on body weight in alloxan-induced diabetic rats

Effect on glycogen estimation

The data was statistically analysed using One-way ANOVA followed by Dunnett’s multiple comparison test.

There was a significant (p < 0.05) increase in the glycogen content of liver, skeletal muscle and cardiac muscle in Diabetic Test Group and Diabetic Standard Group as compared to Diabetic Control Group which showed a significant (p < 0.05) reduction in glycogen content in the above tissues as compared to Normal Control Group (Table–4).

Legend for Table-4:

Values are expressed as Mean ± SEM; n=6 rats in each group. One-way ANOVA followed by Dunnett’s multiple comparison test was done. * p<0.05 when compared to Normal Control Group. † p<0.05 when compared to Diabetic Control Group.

Figure 4
Table 4:Effect of EESKCB on glycogen concentration in liver, skeletal muscle and cardiac muscle

Effect on adrenaline-induced hyperglycemia

The test drug and the standard drug significantly (p < 0.05) reduced hyperglycemia induced by adrenaline.The percentage reduction of blood glucose by EESKCB was 31.50 % and that caused by glibenclamide was 50.01 % (Table–5).

Legend for Table-5:

Values are expressed as Mean ± SEM; n=6 rats in each group. One-way ANOVA followed by Dunnett’s multiple comparison test was done. * p<0.05 when compared to the Normal Control Group.

Figure 5
Table 5: Effect of EESKCB on adrenaline-induced hyperglycemia in albino rats

Discussion

From the study, it was seen that EESKCB significantly (p < 0.05) lowered the blood glucose level in diabetic rats. EESKCB also significantly (p < 0.05) lowered the normal blood glucose level at 120 minutes after drug administration. The hypoglycemic action of EESKCB may be attributed to the insulin-like effects of the constituents of the seed kernel of Caesalpinia bonducella. Raised blood glucose level is the principal stimulus for insulin secretion 24 . The fact that the ethanolic extract of seed kernel of Caesalpinia bonducella has lowered normal blood glucose level, asserts the presence in it of some constituents with insulin-like action, which might have directly lowered the blood glucose level independent of insulin secretion. However, the probability of an insulin releasing action of the constituents of Caesalpinia bonducella cannot be ruled out.

Alloxan, a β-cytotoxic agent, rapidly and selectively accumulates in pancreatic β-cells and causes β-cell death and apoptosis by generation of reactive oxygen species (ROS), superoxide radicals and hydrogen peroxide 2526 . β cell death causes hyperglycemia due to insulin deficiency which further aggravates the oxidative stress induced by alloxan 27 .

The antidiabetic activity of the seed kernel of Caesalpinia bonducella might be attributed to the presence in it of flavonoids, known to be natural antioxidants 28 , which protect the existing β-cells (which escaped alloxanization) from dying by their free radical scavenzing action 29 . Further, previous studies have reported the protective action of flavonoids against oxidative stress induced cellular damage 30 and also the ability of flavonoids to regenerate β-cells 31 . Triterpenoids (lupeol), present in the seed kernel of Caesalpinia bonducella , have the ability to protect cells and tissues from oxidative stress by increasing the transcriptional activity of NRF2, which induces the formation of cytoprotective enzymes like catalase, superoxide dismutase, etc. 32 . Saponines from Gymnema sylvestre have been reported to inhibit glucose transport across the intestine by inhibiting sodium glucose co-transporter-1 (S-GLUT-1) 33 . The saponines present in the seed kernel of Caesalpinia bonducella might contribute to its antihyperglycemic action in a similar manner.

The effect of EESKCB on body weight reduction in alloxan-induced diabetic rats is statistically significant (p<0.05) in this study. Loss of body weight is one of the symptoms of diabetes 34 . This loss of body weight in diabetes is due to increased lipolysis and increased muscle wasting and loss of tissue proteins caused by insulin deficiency 35 . EESKCB, due to the insulin-like and insulin releasing action of its ingredients, probably prevented this lipolysis and proteolysis by ameliorating the extent of insulin deficiency and thereby caused an increase in body weight.

Insulin is a potent activator of the enzyme glycogen synthase while inhibiting the enzyme glycogen phosphorylase responsible for glycogenolysis in liver and muscle 36 . Insulin deficiency in diabetes, as such, results in reduced concentrations of glycogen in liver and muscle. EESKCB caused an increase in glycogen concentration of the liver probably by stimulating the enzymes glycogen synthase and hexokinase, both of which contribute to increase glycogen synthesis 37 . The increase in liver glycogen may also have been brought about by inhibition of the enzyme glucose-6-phosphatase leading to accumulation of glucose-6-phosphate, which allosterically inhibited the enzyme glycogen phosphorylase 38 . Diminished phosphatidylinositol 3-kinase (PI-3K) activation in diabetes as a result of insulin deficiency has been reported to be associated with impaired skeletal muscle glycogen synthase enzyme 39 . EESKCB due to the insulin-like action of its ingredients probably increased PI-3K activation leading to stimulation of muscle glycogen synthase. The increase concentration of glycogen in skeletal and cardiac muscle also might be due to increased expression and translocation of GLUT-4 glucose transporters as a result of increased PI-3K activation, leading to increased peripheral uptake of glucose 24 .

Adrenaline produces hyperglycemia by inhibiting insulin release, stimulating glycogenolysis in muscle and thus providing substrate in the form of lactate for hepatic gluconeogenesis, stimulating glucagon secretion and stimulating ACTH secretion which, in turn, stimulates glucocorticoid secretion from the adrenal cortex 40 . It has also been reported that adrenaline produces hyperglycemia by increasing glucose uptake from both the large and small intestine 41 . The test drug significantly (p<0.05) reduced the adrenaline induced hyperglycemia probably by inhibiting adrenaline induced stimulation of α2 receptors in β-cells of pancreas and thus promoting further insulin release 42 .

Conclusion

Thus, the hypoglycemic and antidiabetic effect of EESKCB may be partly due to its positive effect on glycogen synthesis in liver, skeletal muscle and heart muscle due to the insulin-like action of its constituents, and partly due to the stimulatory action on insulin release by blocking the α2 receptors in β-cells of pancreas. However, further studies to isolate the active principle of Caesalpinia bonducella responsible for hypoglycemia, together with studies on serum insulin assay to confirm it’s insulin releasing action have to be undertaken.

Correspondence to

Gayatri Sarma, Department of Pharmacology, Assam Medical College & Hospital, Dibrugarh-786002. Phone: +919435043164. E-mail: dr.gayatrisarma@yahoo.co.in

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Author Information

Gayatri Sarma, MBBS
Final Year Post graduate student, Pharmacology, Department of Pharmacology, Assam Medical College & Hospital

Swarnamoni Das, MD
Professor and Head, Pharmacology, Department of Pharmacology, Assam Medical College & Hospital

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