INTRODUCTION:

Diabetes mellitus (DM) is a major heterogeneous metabolic disorder, characterized by altered metabolisms of carbohydrate, lipid and protein, which not only lead to hyperglycaemia but also cause malfunction of different organs, particularly the eyes, kidneys, nerves, heart, and blood vessels^1,2,3 due to a relative or absolute deficiency of insulin or by a resistance to the action of insulin at the cellular or molecular level⁴.

It is the most common endocrine disorder, affecting around 463million worldwide in 2019 and is estimated to be rising to 578million by 2030 and 700million by 2045 in which India ranked 2^nd having 77million among top 10 countries or territories for number of people with diabetes (20–79 years)^5. However among all forms, the prevalence of NIDDM (Non-insulin-dependent diabetes) or Type 2 diabetes is increasing exponentially and accounts for more than 85% of cases worldwide^6,7,8.

As the currently-available allopathic treatments have their own drawbacks and limitations either in terms of efficacy and/or safety, there is a clear need for development of indigenous, inexpensive botanical sources for management Type 2 diabetes more efficiently^9,10.

Some of the medicinal plants such as Phragmites australis, Albizzia lebbeck, Acacia nilotica, Chloroxylon swietenia, Stevia rebaudiana, Bougainvillea spectabilis, Abelmoschus esculentus, Dolichandro neatrovirens, Coccinia grandis are recently reported to possess antidiabetic activity^11-19.

Solanum torvum Swartz (Family: Solanaceae) is known as Devil’s fig in English, Bhurat in Hindi and Denga-vegi in Odia, is a spiny herb or shrub, found throughout the tropical part of Indian subcontinent, West Indies, Bermuda, Indonesia, Malaya, China, Philippines and tropical America. Traditionally the plant is useful for the treatment of liver and spleen enlargement, cough and haematopoietic, antimicrobial, sedative, diuretic and digestive^20,21. In diabetes decoction of its fruits is very useful^22,23. The plant fruits also reported to possess antibacterial, antifungal and anti-yeast activity^24,25.

In order to prove the traditional claims, the present study was planned to evaluate the effect of methanol fractions of defatted hydro-alcoholic extract of solanum torvum Swartz. fruits (MFST) on normal and Streptozotocin induced diabetes mellitus in rats.

MATERIAL AND METHODS:

Plant Material:

The fresh fruits were collected in the month of March from Sadeipur village of Jagatsinghpur District (Odisha), India and authenticated at Department of Botany, Utkal University, Odisha. A voucher specimen number IPT/PC/HM-11/11was deposited in the herbal museum of our institute for future reference. The fruits samples were carefully observed for presence of any foreign materials, washed thoroughly with distilled water and dried under shed for a period of one month. The air dried fruits 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 Solanum torvum fruits powder (2kg.) was defatted with petroleum ether (60-80°C) and thereafter extracted with water and ethanol (50:50) mixture for 72 hours adopting a hot continuous soxhlet procedure. The Solanum torvum fruits hydro-alcoholic extract was concentrated under vacuum to yield dry extract. The dried hydro alcoholic extract was 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 methanol fractions obtained from hydro-alcoholic extract of Solanum torvum Swartz fruits 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 fraction produces any toxic sign on normal rats and to select the oral dose. Three (3) numbers of normal healthy rats starved for 12hr were administered orally with MFST at a dose of 2000mg/kg body weight (b.w.). Animals were dosed individually and observed continuously for a period of 8hr on the first day, and thereafter for 14days their gross behavioural and neurological parameters were observed for a sign of acute toxicity; a dose of 2000mg/kg (b.w.) was assessed according to the Organization for Economic Cooperation and Development (OECD) guidelines number 423. On the basis of acute toxicity study, selection of three (3) doses of the drug (1/10^th, 1/20^th and 1/40^th) was carried out. All rats were allowed to a standard pellet diet and normal tap water ad libitum, and the mortality caused by the fraction within this period of time was also noticed.

Maintenance of Animals and approval of protocol:

Adult healthy male Wistar strain of albino rats aged about 3-4 months, weighing 150–200gm bodyweight were collected from the Institutional animal house and were used for the study. Before the commencement of experiment, the selected animals were housed in acrylic cages in standard environmental conditions (temperature: 20–25⁰C; relative humidity: 45-55% under 12 hour light/dark cycle), fed with standard commercial 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 which was duly approved by the Institutional Animal Ethics Committee (1053/PO/Re/S/07/CPCSEA) with approval number-16/IAEC-IPT/13.

Induction of Diabetes Mellitus:

Experimental Diabetes Mellitus was induced in overnight fasted rats by a single intraperitoneal injection of streptozotocin (45mg/kg b.w.) dissolved in freshly prepared 0.1M of ice-cold citrate buffer (pH 4.5) solution. Since, STZ is capable of inducing fatal hypoglycemia due to massive pancreatic insulin release, the rats were provided with 10% glucose solution after 6 hr of STZ administration and for the next 24 hr to overcome marked hypoglycemia. Neither death nor any noticeable adverse effect was observed during this period. After one week time, for the development and aggravation of diabetes, rats showing moderate diabetes (i.e. fasting blood glucose concentration,>250mg/dl) that exhibited hyperglycemia were selected for the study^26.

Determination of blood glucose levels:

Blood samples were collected from the tip of tail at the defined time patterns and fasting blood glucose concentration was measured, using a Glucomonitor (Optium make), based on the glucose oxidase method²⁷.

Experimental design:

Study on normoglycemic rats (Single dose and Multi dose treatment):

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

This experimental design is as follows:

Group I – Normal Control (Tween + Water)

Group II – Reference Control (Glibenclamide)

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

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

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

Blood glucose level of each rats are measured at 0, 1, 2, 4 and 8 hr 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 respectively.

Study on diabetic rats (Single dose and Multi dose treatment):

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

This experimental design is as follows:

Group I –Diabetic Control (Tween + Water)

Group II – Reference Control (Glibenclamide)

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

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

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

Blood glucose level of each rats are calculated at 0, 1, 2, 4 and 8 hr 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 respectively.

Study on glucose loaded hyperglycemic rats:

All the groups were fed with glucose (2g/kg/p.o) 30 minutes after treatment with all fractions and standard drug as per the above manner and blood glucose level was obtained just prior to drug administration (0 hour) and at 0.5, 1, 2, and 3hours interval after glucose loading.

Statistical analysis:

All the results obtained after experiment were analysed statistically using one-way analysis of variance (ANOVA) followed by Dunnet’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 (n=6) in each group.

RESULT:

Acute oral toxicity studies (OECD guideline no. 423) revealed the non‒toxic nature of the methanol fraction of Solanum torvum fruits Hydro-alcoholic extract as no lethality or toxic signs found at the dose level of 2000 mg/kg body weight during the observation period (14 days) as well as no behavioural changes appeared except slight sedation which occurs after 1.5 hour of administration through oral route.

Table no-1: Effect of methanol fractions of the Solanum torvum fruits on the blood glucose level on single dose treatment in normoglycemic rats.

Group	Treatment	Dose (mg/kg)	Fasting 0hr	Blood glucose concentration (mg / dl)
				Time (hr) after treatment				% decrease at 8hr
				1	2	4	8	% decrease at 8hr
I	Control	2 ml/kg	97.63±2.48	96.38±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	101.16±2.63	96.5±4.58	92.83±3.68	88.33±5.43	84.66±4.23	16.31
IV		100	99.5±2.52	95±3.42	91.66±4.09	82.16±3.14	74.33±3.26*	25.29
V		200	98.33±3.09	94.16±3.23	89.66±3.43	74.16±3.96*	60.83±4.72**	38.13

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

Table no-2: Effect of methanol fractions of the Solanum torvum fruits on the blood glucose level on single dose treatment in STZ induced diabetic rats.

Group	Treatment	Dose (mg/kg)	Fasting 0hr	Blood glucose concentration (mg / dl)
				Time (hr) after treatment				% decrease at 8hr
				1	2	4	8	% decrease at 8hr
I	Control	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	278.5±13.52	273.16±12.08	258.83±11.03	244.33±9.35	224.66±10.53*	19.33
IV		100	282.66±11.26	233.33±9.13*	195.83±13.61**	159.16±8.19**	129.83±8.73**	54.06
V		200	285.16±12.46	231.66±11.73*	182.33±10.39**	136.5±9.81**	102.33±7.18**	64.11

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

Table no-3: Effect of methanol fractions of the Solanum torvum fruits on the blood glucose level on single dose treatment in glucose loaded hyperglycemic rats.

Group	Treatment	Dose (mg/kg)	Fasting	Blood glucose concentration (mg / dl)
				Time (hr)Post treatment				% decrease at 3hr
				0.5	1	2	3	% decrease at 3hr
I	Control	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	92.33±8.32	127.16±9.51	124.16±8.62	118.83±10.22	110.5±9.14^*	13.1
IV		100	95.16±7.65	130.5±11.06	124.66±12.18	106.16±12.01^*	100.33±11.26^*	23.11
V		200	97.66±9.03	129.83±9.09	106.16±9.01^*	95.5±7.78^**	79.16±7.29^**	39.02

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

Table no-4: Effect of methanol fractions of the Solanum torvum fruits on the blood glucose level on multi dose treatment in 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	Solvent 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	98.16 ± 3.25	94.66 ± 3.42	88.66 ± 3.37	84.83 ± 3.74	80.33 ± 4.24	75.83 ± 3.51*	74.16 ± 3.22**	24.44
IV		100	97.5 ± 4.43	93.16 ± 4.39	87.66 ± 5.68	83.16 ± 4.77*	76.33 ± 4.36*	72.16 ± 4.76*	68.16 ± 4.53**	30.09
V		200	99.83 ± 5.76	95.66 ± 5.48	87.16 ± 5.49	79.16 ± 4.51*	71.33 ± 5.33**	67.5 ± 5.57**	62.83 ± 4.74**	37.06

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

Table no-5: Effect of methanol fractions of the Solanum torvum fruits on the blood glucose level on multi dose treatment in STZ induced 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	Solvent 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	288.83 ±4.82	265.16 ± 3.42	254.33 ± 3.37	231.66 ± 3.74	189. 5 ± 4.24	181.16 ± 3.51*	162.33 ± 3.22*	43.79
IV		100	286.33 ±5.81	268.83 ± 4.39	246.5 ± 5.68	219.33 ± 4.77*	182.16 ± 4.36*	165.33 ± 4.76*	150.16 ± 4.53**	47.55
V		200	286.16 ±4.41	256.33 ± 5.48	219.16 ± 5.49	198.5 ± 5.49*	156.66 ± 5.33**	125.83 ± 5.57**	98.66 ± 5.74**	65.52

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

DISCUSSION:

The preliminary phytochemical investigation reported that the methanol fractions of the Solanum torvum fruits found to have are alkaloids, carbohydrates, proteins, tannin and phenolic compounds, saponins, flavonoids and glycosides with the absence volatile oil, fixed oil and mucilage.²⁸

The effect of methanol fractions of the Solanum torvum fruits in single dose treatment on normoglycemic rats (Table 1) exhibited that blood glucose levels decline significantly with effect from 4hr (p<0.05 and p<0.01) onwards till the end of 8hr in case of standard and test fraction (200mg/kg) treatment group, while the % reduction of glucose levels calculated as 39.32in case of standard drug and 16.31, 25.29, 38.13in case of test fractions respectively. The data obtained from the normoglycemic model manifest that the test fractions produce dose dependent hypoglycemic effect which is comparable with the standard drug and accordingly the further studies have been carried out.

The study on single dose treated antidiabetic activity in STZ induced diabetic rats (Table 2), revealed that the test fractions in the dose level 100 and 200mg/kg body weight significantly reduces the blood glucose level starting from 1hr (p<0.05) of the experiment to the end of 8hr (p<0.01) in a dose proportionate manner, while the standard drug, glibenclamide produced similar effect during the period of the experiment. The decrease in the blood sugar level at the end of 8hr calculated as 19.33, 54.06, and 64.11% for test fractions, whereas 65.15% for the standard drug. The antidiabetic effect of the plant methanol fractions may be due to the pancreatic and/or extra pancreatic action.

The Table No. 3 represents oral glucose loaded hyperglycemic model which showed that the test fractions can able to decline the blood glucose level considerably (p<0.01) in dose level of 200mg/kg (39.02%), while standard drug registered 39.4% reduction till the end of 3hr with statistical significant. The methanol fractions of the Solanum torvum fruits improved the condition probably by escalating glucose uptake or inhibiting intestinal absorption of glucose.

Further the studies on hypoglycemic and antidiabetic effect of fractions were evaluated by administering multi dose treatment.

The results of methanol fractions of the Solanum torvum fruits on blood sugar level of multi dose treated normoglycemic rats (Table 4) indicates that, there is a significant reduction (p<0.05 to p<0.01) in blood glucose level starting from 15^th day onwards, and registered 24.44, 30.09 and 37.06% decrease at the end of 30^thday, in animals treated with 50, 100 and 200 mg/kg body weight of the test fractions, whereas the standard drug glibenclamide reduces the blood glucose 37.03% with p<0.01, when compared with solvent control group at the same day. The study result indicates that, the test fractions exhibit a dose dependent and marked hypoglycemic action on long term use.

The antidiabetic activity result of methanol fractions on multi dose treatment in STZ induced diabetic rats are illustrated in Table no.5 revealed that, the test fractions at the dose 50, 100 and 200mg/kg body weight reduces the blood glucose level to an extent of 43.79%, 47.55% and 65.52% respectively at the end of the 30^th day of the study, with a statistical significance ranges between p<0.05 to p<0.01, which is comparable to the standard drug glibenclamide (66.74%) at the same day of the study.

The above results from multi dose study suggests that with recurrent administration, the efficacy of the test fractions enhanced and exhibits dose proportionality with increasing doses which is comparable with that of the standard drug and which may be due to increased absorption.

The diabetogenic agent Streptozotocin is specifically cytotoxic to the β-cells of pancreas and as a consequence of this, destruction of β-cells occurs by necrosis which generate conspicuous increase in the concentrations of blood glucose and lessen glucose utilization by various tissues. The glucose concentration in blood is sustained mainly by insulin that modulates the uptake, utilization and storage of glucose. The tabulated data clearly represents that, elevated blood glucose level observed in diabetic rats was almost normalized upon treatment with fractions which may be due to amplification of pancreatic insulin secretion from existing residual β-cell of islets, decreasing hepatic glucose production, decreasing intestinal absorption of glucose and/or augmenting insulin sensitivity by increasing peripheral glucose uptake and utilization.

CONCLUSION:

From the above experimental analysis, it is concluded that the methanol fractions of defatted hydro-alcoholic extract of Solanum torvum Swartz fruits possess noticeable hypoglycemic and anti-hyperglycemic activity in normal and STZ induced diabetic rats as well as when the animals are exhibited to glucose feed hyperglycaemia which may be due to the occurrence of various biologically active secondary metabolites as reported from the preliminary phytochemical screening such as flavonoids, tannins and phenolic compounds. Further study is required to evaluate the underlying cellular or molecular mechanism of action, also its long term effect on other vital organs to understand the safety profile and to isolate the active constituent(s) responsible for the cause of improving the diabetic condition.

CONFLICT OF INTEREST:

Nil.

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Received on 14.04.2020 Modified on 21.11.2020

Research J. Pharm.and Tech 2022; 15(4):1443-1448.

DOI: 10.52711/0974-360X.2022.00239