INTRODUCTION:

Diabetes mellitus regarded scientifically a clinical syndrome characterized by inappropriate or improper hyperglycemia caused by a relative or absolute deficiency of insulin or by a resistance to the action of insulin at the cellular or molecular level and is the most common endocrine disorder, affecting around 200 million worldwide¹. The presence of sugar in the urine of diabetics was demonstrated by Dobson in 1755². Diabetes mellitus is now recognized as a serious global health problem³. Westernized fashion, cultures and populations experiencing rapid acculturation are showing a sharp rise in non-insulin-dependent diabetes mellitus⁴.

The prevalence of NIDDM is increasing exponentially^{5, 6,7,8,9}. According to recent study Type 2 diabetes (Non-insulin-dependent diabetes), accounts for more than 85% of cases worldwide. It is a heterogeneous type ranging from insulin resistance to insulin deficiency as well as a multi factorial disease with both a genetic component and an important non-genetic component(s)^10,11,12.

Some of the plants recently reported to possess antidiabetic activity are Phragmites australis, Chloroxylon swietenia, Stevia rebaudiana, Bougainvillea spectabilis, Abelmoschus esculentus, Albizzia lebbeck, Dolichandrone atrovirens, Coccinia grandis and Acacia nilotica^13-21.

Tectona grandis Linn commonly known as Teak in English, Sagwan in Hindi and Saguan in Odia belonging to Verbenaceae family is a large to very large deciduous tree distributed in South and South-East Asia; indigenous to India, Burma and western parts of Thailand. The bark is astringent, acrid, cooling, anthelmintic, and depurative and traditionally it is used for the treatment of bronchitis, hyperacidity, dysentery, diabetes, leprosy and skin diseases^22,23.

Taking into consideration the traditional claims, the present study was planned to evaluate the effect of methanol fractions of defatted hydro-alcoholic extract of Tectona grandis Linn. Bark (MFTG) on normal and Streptozotocin induced diabetes mellitus in rats.

MATERIAL AND METHODS:

Plant Material:

The fresh bark were collected from Sadeipur village of Jagatsinghpur district (Odisha), India and authenticated at Department of Botany, Utkal University, Odisha. A voucher specimen number IPT/PC/HM-29/11 was deposited in the institute museum for future reference. The samples were carefully observed for presence of foreign materials, washed with distilled water and dried under shed for a period of 30 days. The dried bark were made to coarse powder by a mechanical grinder and then passed through number 40 sieve mesh.

Preparation of barks extract and fractions:

The dried bark powder (2Kg) was defatted with petroleum ether (60-80°C) and then extracted with hydro-alcoholic (water: ethanol, 50: 50) solution for 72 hour using a soxhlet apparatus. The liquid extract was concentrated under vacuum to yield dry extract. The dried extract fractionated successively with n-butanol, chloroform, ethyl acetate and methanol. All the fractions were concentrated to dryness under reduced pressure and controlled temperature (48°C–50°C) using a rotary evaporator. The fractions were stored in a closed bottle and kept in refrigerator until tested.

Preparation of the test samples:

The measured quantities of fractions obtained from hydro-alcoholic extract of Tectona grandis Linn. bark and Glibenclamide (2.5mg/kg) was suspended in 2% Tween 20 in distilled water and used as test drug for oral administration.

Acute toxicity study and dose selection:

An experiment was conducted to find whether the fractions produce any toxic sign and dose selection on normal rats. Three normal healthy rats starved for 12 hour were administered orally with MFTG starting at the dose of 2000mg/kg body weight. Animals were dosed individually and observed continuously for 8h on the first day and thereafter for 14 days their behavioural and neurological parameters were observed for a sign of acute toxicity; a dose of 2000mg/kg (body weight) was assessed according to the Organization for Economic Cooperation and Development (OECD) guidelines 423. On the basis of acute toxicity study, selection of 3 doses of the drug (1/10^th, 1/20^thand 1/40^th) was carried out. All rats were allowed to a standard pellet diet and tap water ad libitum, and the mortality caused by the fractions within this period of time was also observed.

Maintenance of Animals and approval of protocol:

Adult healthy male Wistar strain of albino rats aged 3-4 months, weighing 150–200g bodyweight were collected from the Institutional animal house and were used for the study. The selected animals were housed in acrylic cages in standard environmental conditions (temperature: 20–25⁰C; relative humidity: 45-55% under 12hour light/dark cycle), fed with standard rodent diet for one week in order to adapt to the laboratory conditions and water ad libitum. The experiments on animals were conducted in accordance with the internationally accepted principles for laboratory animal use and as per the experimental protocols duly approved by the Institutional Animal Ethics Committee (1053/PO/Re/S/07/CPCSEA) having approval number-16/IAEC-IPT/13.

Induction of Diabetes Mellitus:

Experimental diabetes was induced in overnight fasted rats by single intra-peritoneal injection of streptozotocin (45mg/kg body weight) dissolved in freshly prepared 0.1M of cold citrate buffer (pH 4.5). Since, STZ is capable of inducing fatal hypoglycemia due to massive pancreatic insulin release, the rats were provided with 10% glucose solution after 6 hour of STZ administration for the next 24 hour to overcome drug induced hypoglycemia. Neither death nor any other adverse effect was observed. After a week time, for the development and aggravation of diabetes, rats with moderate diabetes (i.e. fasting blood glucose concentration, >250 mg/dl) that exhibited hyperglycemia were selected for further experimentation.^24,25,26

Determination of blood glucose levels:

Fasting blood glucose concentration was measured, using a glucomonitor (Optium make), based on the glucose oxidase method. Blood samples were collected from the tip of tail at the defined time patterns²⁷.

Experimental design:

1. Study of Hypoglycemic effect of methanol fractions of Tectona grandis bark hydro-alcoholic extract on single dose treated and multi dose treated normoglycemic rats.

2. Study of anti-diabetic effect of methanol fraction of Tectona grandis bark Hydro-alcoholic extract on single dose and multi dose treated diabetic rats.

3. Study of glucose lowering effect of methanol fraction of Tectona grandis bark hydro-alcoholic extract on Single dose treated glucose loaded hyperglycemic rats.

Experimental design no 1:

The animals were fasted for 12 hour, but were allowed to avow free access to water before and throughout the duration of experiment. At the end of the fasting period, taken as zero time (0 hour/ 0^th day), the rats were then divided into five groups of six rats per group. Normal Control group are administered only vehicle at a dose 2ml/kg body weight. Standard drug Glibenclamide was administered orally at a dose of 2.5mg/kg body weight which served as Reference Control. Test groups are administered methanol fractions at a dose of 50, 100 and 200mg/kg body weight by oral route.

The experimental design is as follows:

Group I – Normal Control (Tween + Water)

Group II – Reference Control (Glibenclamide)

Group III – Test Fraction (50mg/kg body weight)

Group IV – Test Fraction (100mg/kg body weight)

Group V – Test Fraction (200mg/kg body weight)

Blood glucose levels are estimated at 1, 2, 4 and 8 hour after treatment for single dose study and at 0^th, 5^th, 10^th, 15^th, 20^th, 25^th and 30^th day for multi dose study.

Experimental design no 2:

The streptozotocin induced hyperglycemic rats were kept fasted for 12 hour, with water ad libitum before and throughout the duration of experiment. At the end of the fasting period, taken as zero time (0 hour/ 0^th day), the rats were then divided into five groups of each having six rats. Diabetic Control group are administered only vehicle at a dose 2ml/kg body weight. Reference Control group were administered the standard drug Glibenclamide orally at a dose of 2.5mg/kg body weight. The Test groups were administered methanol fractions at a dose of 50, 100 and 200mg/kg body weight by oral route.

The experimental design is as follows:

Group I –Diabetic Control (Tween + Water)

Group II – Reference Control (Glibenclamide)

Group III – Test (methanol fraction 50mg/kg body weight)

Group IV – Test (methanol fraction 100mg/kg body weight)

Group V – Test (methanol fraction 200mg/kg body weight)

Blood glucose levels are estimated at 1, 2, 4 and 8 hour after treatment for single dose study and at 0^th, 5^th, 10^th, 15^th, 20^th, 25^th and 30^th day for multi dose study.

Experimental design no 3:

All the groups were loaded with glucose (2g/kg/p.o) 30 minutes after treatment with fractions and standard drug as per the above manner and blood glucose level was measured just prior to drug administration and at 0.5, 1, 2, and 3 hour interval after glucose loading.

Statistical analysis:

All the results were analysed statistically using one-way analysis of variance (ANOVA) followed by Dunnett’s t-test. A p-value less than 0.05 are considered significant. All the results are expressed as Mean±S.E.M for six animals in each group.

RESULT:

Acute oral toxicity studies (OECD guideline 423) revealed the non‒toxic nature of the methanol fraction of Tectona grandis bark Hydro-alcoholic extract. No lethality or toxic reaction found at the dose level of 2000 mg/kg body weight selected for the observation duration (14 days) as well as no behavioural changes appeared except slight sedation occurs after 60 minutes.

The experimental results of methanol fractions of the Tectona grandis bark on the blood glucose level on single dose treated normoglycemic rats, single dose treated diabetic rats, single dose treated glucose loaded hyperglycemic rats, multi dose treated normoglycemic rats and multi dose treated diabetic rats are given in Table No. 1, 2, 3, 4 and 5 respectively.

Table No.-1: Effect of methanol fractions of the Tectona grandis bark on the blood glucose level on single dose treated normoglycemic rats.

Group	Treatment	Dose (mg/kg)	Fasting 0 hour	Blood glucose concentration (mg / dl)
				Time (hour) after treatment				% Decrease at 8 hour
				1	2	4	8	% Decrease at 8 hour
I	Normal Control (Tween + Water)	2 ml/kg	97.66±2.48	96.33±2.1	98.16±2.25	98.83±2.12	99.66±2.49	-
II	Glibenclamide	2.5 mg/kg	97.5±2.95	93.83±2.40	88.5±2.12	72.5±4.62^**	59.16±4.85^**	39.32
III	Methanol fraction	50	99±2.92	95.66±5.28	93±2.91	91.66±5.73	86.83±3.68	12.29
IV		100	98±2.04	96.5±3.02	92.83±4.93	85.33±2.84	77.33±3.63*	21.09
V		200	98.66±2.21	94.5±3.35	90.5±2.46	75.66±3.45*	62.16±4.4**	36.99

Values are expressed as Mean ± SEM; (n = 6); One Way ANOVA followed by Dunnett’s t-test; *p<0.05, **p<0.01vs. Control Group/Group I

Table No. -2: Effect of methanol fractions of the Tectona grandis bark on the blood glucose level on single dose treated diabetic rats.

Group	Treatment	Dose (mg/kg)	Fasting 0 hour	Blood glucose concentration (mg / dl)
				Time (hour) after treatment				% decrease at 8 hour
				1	2	4	8	% decrease at 8 hour
I	Diabetic Control (Tween + Water)	2 (ml/kg)	275.33±9.2	277.16±5.81	276.5±7.71	282.66±8.91	279.83±12.12	-
II	Glibenclamide	2.5	282.16±10.2	231±10.11*	175±14.88**	122.66±9.23**	98.33±9.93**	65.15
III	Methanol fraction	50	283.83±14.82	269.16±14.27	261.16±10.63	250.33±9.75	235.66±11.23*	16.97
IV		100	277.33±10.81	232.16±9.03*	196±14.91**	165.66±7.44**	133.66±9.8**	51.8
V		200	272.16±14.41	226.66±10.68*	182.5±13.42**	140.83±8.8**	101.5±11.26**	62.71

Values are expressed as Mean ± SEM; (n = 6); One Way ANOVA followed by Dunnett’s t-test; *p<0.05, **p<0.01vs. Control Group/Group I

Table No. -3: Effect of methanol fractions of the Tectona grandis bark on the blood glucose level on single dose treated glucose loaded hyperglycemic rats.

Group	Treatment	Dose (mg/kg)	Fasting	Blood glucose concentration (mg / dl)
				Post treatment				% decrease at 3 hour
				0.5 hour	1 hour	2 hour	3 hour	% decrease at 3 hour
I	Normal Control (Tween + Water)	2 ml/kg	93.66±2.69	128.5±10.14	148.66±12.64	159.83±13.26	153.33±13.63	-
II	Glibenclamide	2.5	96.83±2.84	128.16±7.32	105.16±9.38^*	91±10.8^**	77.66±10.02^**	39.4
III	Methanol fraction	50	90.16±9.63	126.33±11.36	123.33±10.02	120.83±11.8	112.16±11.27^*	11.21
IV		100	94.5±3.75	130.66±12.9	127.33±13.1	108.5±13.01^*	103.83±10.41^*	20.53
V		200	98.83±10.01	131.5±12.02	106.83±8.13^*	98.83±7.09^**	82.16±6.63^**	37.52

Values are expressed as Mean ± SEM; (n = 6); One Way ANOVA followed by Dunnett’s t-test; *p<0.05, **p<0.01 vs. Control Group/Group I

Table No. -4: Effect of methanol fractions of the Tectona grandis bark on the blood glucose level on multi dose treated normoglycemic rats.

Group	Treatment	Dose (mg/kg)	Blood Glucose Levels (mg/dl)
Group	Treatment	Dose (mg/kg)	0^thday	5^th day	10^th day	15^th day	20^th day	25^th day	30^th day	% decrease at 30^th day
I	Normal Control (Tween + Water)	2(ml/kg)	98.5 ± 4.70	97.66 ± 4.66	95.5 ± 4.67	101.5 ± 4.35	97.83 ± 4.65	98.83 ± 5.50	103.16 ± 4.80	_
II	Glibenclamide	2.5	94.5 ± 2.57	87.83 ± 2.57	78.33 ± 2.55^*	71.5 ± 2.67^**	65.33 ± 2.43^**	61.33 ± 3.86^**	59.5 ± 2.29^**	37.03
III	Methanol fraction	50	99.16 ± 3.35	97.33 ± 3.12	94.66 ± 3.57	89.83 ± 3.31	84.83 ± 4.33	79.33 ± 3.31^*	76.16 ± 3.17^*	23.19
IV		100	95.33 ± 4.63	92.83 ± 4.62	88.83 ± 4.68	84.16 ± 4.27	77.16 ± 4.56^*	72.66 ± 4.34^*	68.16 ± 4.14^**	28.5
V		200	97.66 ± 2.67	93.66 ± 5.78	85.66 ± 5.39	78.33 ± 5.26^*	73.33 ± 5.52^*	68.16 ± 5.38^**	64.83 ± 2.44^**	33.61

Values are expressed as Mean ± SEM; (n = 6); One Way ANOVA followed by Dunnett’s t-test; *p<0.05, **p<0.01 vs. Control Group/Group I

Table No. -5: Effect of methanol fractions of the Tectona grandis bark on the blood glucose level on multi dose treated diabetic rats

Group	Treatment	Dose (mg/kg)	Blood Glucose Levels (mg/dl)
Group	Treatment	Dose (mg/kg)	0^thday	5^th day	10^th day	15^th day	20^th day	25^th day	30^th day	% decrease at 30^th day
I	Diabetic Control (Tween + Water)	2(ml/kg)	282.33±3.2	285.16 ± 3.66	288.5 ± 4.75	291.5 ± 4.35	295.66 ± 4.15	297.33 ± 4.50	298.83 ± 4.70	_
II	Glibenclamide	2.5	280.16 ± 2.2	247.33 ± 2.45	213.16 ± 2.35^*	188.33 ± 2.77^**	149.16 ± 2.34^**	118.5 ± 3.66^**	93.16 ± 2.92^**	66.74
III	Methanol fraction	50	282.83 ±3.42	260.16 ± 3.22	251.66 ± 3.27	233.33 ± 3.44	191.66 ± 3.24	183.16 ± 3.31^*	165.33 ± 3.12^*	41.54
IV		100	283.66 ±3.18	257.66 ± 4.19	247.33± 4.38	219.33 ± 4.75^*	181.5 ± 4.16^*	169.16 ± 4.66^*	159.66 ± 4.73^**	43.71
V		200	280.33 ±4.31	252.83 ± 4.68	216.16 ± 4.39	196.16 ± 4.79^*	154.5 ± 4.43^**	126.83 ± 4.77^**	98.5 ± 4.43^**	64.86

Values are expressed as Mean ± SEM; (n = 6); One Way ANOVA followed by Dunnett’s t-test; *p<0.05, **p<0.01 vs. Control Group/Group I

DISCUSSION:

The preliminary phytochemical investigation report indicates that the methanol fractions of the Tectona grandis bark found to have alkaloids, glycoside, proteins and amino acid, carbohydrates, flavonoids, terpenoid, tannins, saponin and sterols whereas the volatile oil, fixed oil and mucilage were found to be absent²⁸.

The experimental results of the effect of methanol fractions of the Tectona grandis bark in single dose treated normoglycemic rats (Table 1) showed that blood glucose levels decrease significantly with effect from 4^th hour (p<0.05 and p<0.01) onwards till the end of 8^th hour in case of standard and test fractions (100 and 200mg/kg) treated group, while the percentage reduction of glucose levels calculated as 39.32% in case of standard drug and 12.29, 21.09, 36.99% in case of test fractions respectively. The results of the normoglycemic model showed that the test fractions have dose dependent hypoglycemic effect which is comparable with standard drug. So, accordingly the further studies have been undertaken.

The Table No. 2 represents single dose treated anti-diabetic activity in Streptozotocin induced diabetic rats, which showed that the test fractions in the dose level 100mg/kg and 200mg/kg, reduces the blood glucose significantly starting from 1hour (p<0.05), of the study in a dose dependent manner, while the standard drug, Glibenclamide showed similar effect during the course of the experiment. The test fractions in the dose level 50mg/kg only manage to reduce the blood glucose level significantly (p<0.05) at the end of 8^th hour. The percent decrease of blood sugar at the end of 8^th hour calculated as 16.97, 51.8, 62.71% for the test fractions, while standard drug showed 65.15% at the same time. The anti-diabetic activity of the plant may be due to the pancreatic and/or extra pancreatic effect of the methanol fraction.

The study of oral glucose loaded hyperglycemic model revealed that the fractions significantly reduces the blood glucose level (p<0.01) in dose level of 200mg/kg (37.52%), while standard drug registered 39.4% with statistical significant reduction till the end of 3^rd hour (Table 3).

In case of the study of oral glucose loaded hyperglycaemic model, the methanol fractions of the Tectona grandis bark improved the condition probably by enhancing glucose uptake or inhibiting intestinal absorption of glucose.

Further the animals have been exhibited to study the hypoglycemic and/or anti-diabetic effect of fractions in multi dose treatment.

The results of methanol fractions of the Tectona grandis bark on blood sugar level of multi dose treated normoglycemic rats are depicted in Table no.4. The test result indicates that, there is a significant reduction (p<0.05) in blood glucose level from15^thday onwards, and registered 23.19, 28.5 and 33.61% reduction at the end of 30 days, in animals treated with 50, 100 and 200 mg/kg of the test fractions. However the standard drug Glibenclamide at the same day reduces the blood glucose 37.03% with p<0.01, when compared with normal control group. The study result suggests that, the fractions exhibit a dose proportionate hypoglycemic effect on long term use.

The results of methanol fractions on blood sugar level of multi dose treated diabetic rats are illustrated in Table no.5 reveals that, the fractions reduces the blood glucose level to an extent of 41.54%, 43.71% and 64.86% at 50mg/kg, 100mg/kg and 200mg/kg body weight respectively at the end of the 30^thday of the study, with a statistical significance ranges between p<0.05 to p<0.01which is comparable to the standard drug Glibenclamide (66.74%) at the same day of the study.

These results from multi dose study reveal that with repeated administration, the efficacy of the fractions increases and shows dose proportionality with increasing doses which is comparable with that of the standard drug and may be due to increased absorption.

Streptozotocin is specifically cytotoxic to β-cells of the pancreas and as a result destruction of β-cells occurs by necrosis which induces pronounced increase in the concentrations of blood glucose and reduced glucose utilization by various tissues. Blood glucose levels are maintained mainly by insulin that regulates the uptake, utilization and storage of glucose. The elevated blood glucose level observed in diabetic rats was almost normalized upon treatment with fractions which may be due to potentiating of pancreatic secretion of insulin from existing residual β-cell of islets, decreasing hepatic glucose production, decreasing intestinal absorption of glucose and/or improving insulin sensitivity by increasing peripheral glucose uptake and utilization.

CONCLUSION:

From the above experiment, it is concluded that the methanol fractions of defatted hydro-alcoholic extract of Tectona grandis Linn bark possess hypoglycaemic and anti-diabetic activity in normal and STZ induced diabetic rats as well as when the animals are challenged to glucose feed hyperglycemia which may be due to the presence of various biologically active secondary metabolites as revealed from the preliminary phytochemical investigation such as flavonoids, terpenoid, tannins and sterols.

Further study is required to investigate the underlying molecular mechanism of action, also its long term effect on other organs and to isolate the active constituent responsible for improving the diabetic condition.

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Received on 12.02.2020 Modified on 15.06.2020

Research J. Pharm. and Tech. 2021; 14(8):4247-4252.

DOI: 10.52711/0974-360X.2021.00737