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Effect of curcumin on metabolism of lipids in streptozotocin induced diabetic and normal rats.

INTRODUCTION

Diabetes mellitus is one of the most challenging health problems in the 21st century. It is estimated that the diabetes affect nearly 10% of the population in the world [1-3].Hyperglycemia, hypercholesterolemia and hypertriglyceridemia are the most common disorders of diabetes, resulting from defects in insulin secretion or reduced sensitivity of the tissue to insulin (insulin resistance) and/or combination of both[4-6].Patients with type1diabetes also present with lipid disorders. Dyslipidemia plays an important role in the initiation and acceleration of the atherosclerotic process in individuals with diabetes. Hence, a prudent strategy for preventing cardiovascular complications in patients with diabetes would be treating dyslipidemia with lipid-lowering agents [7-9].There is a growing interest in herbal remedies because of their effectiveness and minimal side effects in clinical experience. Herbal drugs or their extracts are prescribed widely, even when their biological active compounds are unknown. The World Health Organization (WHO) also approves the use of plant drugs for different diseases, including diabetes mellitus. The potential role of the medicinal plants as anti-diabetic agents has been reviewed by several authors, supported by the ethnobotanical surveys and traditional medicines of different cultures [10-12]. Polyphenolic compounds are widely distributed in plants and fruits and are present in normal diets. These compounds have been shown to possess beneficial effects in diabetes, cardiovascular diseases, atherosclerosis, allergy, inflammation, cancer, asthma andosteoporosis [13-16]. Curcumin[1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione]a yellow colourpolyphenolic pigment ,was first isolated from the plant Curcuma longa around two centuries ago, and its structure as diferuloylmethane was determined in 1910. Curcumin has two isomers, the planar enolform(fig-1) and nonplanarketo form. The planar enol form is more stable than the nonplanardiketo form[17-19].

[FIGURE 1 OMITTED]

Turmeric (Curcuma longa) is extensively used as a spice, food preservative and colouring material. It has been used in traditional medicine as a household remedy for various diseases. It has been shown that curcumin has a wide spectrum of biological actions. These include its antiinflammatory, antioxidant, anticarcinogenic, antimutagenic, anticoagulant, antifertility, ant diabetes, antibacterial, antifungal, antiprotozoal, antiviral, antifibrotic, antivenom, antiulcer, hypotensive and hypocholesteremic activities [20-22]. Based on this information, present study was designed to investigate the association between diabetes and lipid levels and the effect of curcumin on lipids metabolism.

MATERIAL AND METHODS

Chemicals:

Curcumin[1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] provided from Sigma Chemicals Company (St Louis, MO, USA) and Streptozotoc in provided from Pharmacia & Upjohn (Kalamazoo, MI, USA).

Animals:

Male adult Wistar rats (2.5 months) weighting 190 [+ or -] 10g were used in these experiments. The animals were housed as six rats per cage at room temperature (22-24[degrees]C) with lights on from 08:00 to 20:00 h. They were fed with standard rodent diet. Food and water were ad libitum.

Diabetes induction:

Streptozotocin-induced hyperglycemia has been described as a useful experimental model to study the activity of antidiabetic agents. Streptozotocin selectively destroys the pancreatic insulin secreting [beta] cells [12].The animals were allowed to acclimatize 2 days before experiment in new environment. For two days prior to the experiment, diabetic state was induced by a single dose intraperitoneal injection of streptozotocin (STZ) (70 mg/kg body weight, dissolved in a citrate buffer 0.1 M, pH 4.5) [23]. The blood glucose levels were then measured after 2 days.

Treatment with curcumin:

Rats were divided into two classes of Normal rats (N) and diabetic rats(D) and each class divided into five groups (n = 6), as below: (I) Normal control group (NO): rats in this group received grape seed oil(solvent of curcumin) (O) orally for 30 days through a gastric cannula in a single dose (0.5 ml) at 8:30 pm. (II) Diabetic control group(DO): rats in this group received grape seed oil (O) as group I. (III) Normal groups receiving curcumin(NC): rats in these groups received curcumin at 10, 20, 40 and 80 mg/kg body weight (respectively, NC10, NC20, NC40, NC80) dissolved in grape seed oil, orally for 30 days through a gastric cannula in a single dose (0.5 ml) at 8:30 pm. (IV) Diabetic groups receiving curcumin (DC): rats in these groups received curcumin at 10, 20, 40, 80 mg/kg body weight (DC10, DC20, DC40, and DC80 respectively) as above.

Measured parameters:

The body weight of rats was measured in the first day of experiment. Ingestion of food and water and urine volume for 24h was measured every morning at 9:00 am with metabolic cage. Blood glucose levels were measured in blood samples extracted from the tail of the animal with aglucometer (One Touch Profile, Life Scan) two days after injection of STZ. Body weight of the rats was measured after day30, and the animals were then sacrificed underlight ether anesthesia. Blood samples were collected from rats hearts and were placed on ice, then' centrifuged at 3000g for five minutes. Serum was stored at -20[degrees]C for less than 1 week before subsequent analyses. Blood glucose, cholesterol, triacylglycerol, high-density lipoproteins(HDL) and low-density lipoproteins (LDL)concentrations were measured with standard biochemical kits. Estimates of Very Low Density Lipoprotein(VLDL) were calculated from the formula(VLDL-C = Triacylglycerol /5)[8].

Statistical analysis:

The data were analyzed by one-sample Kolmogrov-Smirnov test and then by the Levene's test. One way analysis of variance (ANOVA) followed by Tukey's post hoc test for multiple comparisons were used to compare difference between experimental groups. The criterion for statistical significant was P<0.0

Results:

Blood glucose:

To make sure that diabetes state is happened, the blood glucose levels were measured 2 days after administration of STZ. Administration of STZ resulted in high levels (408.4 [+ or -] 39.8mg/dl) of blood glucose in the treated groups in compare to the normal control group in which blood glucose levels were in the range of106.4 [+ or -] 11.2mg/dl.In the end of experimental period, the blood glucose levels were measured and the results are shown in fig. 2. In diabetic control group (DO) as compared to normal control group (NO) the blood glucose level significantly increased. In diabetic and normal groups treated with curcumin, the blood gluse levels reduced. For example this reduction in dose 40 mg/kg-B.W, in diabetic and normal rats were 34.3% and 35.1% respectively.

[FIGURE 2 OMITTED]

Lipids:

Cholesterol:

In diabetic control group(DO)as compared to normal control group(NO) the blood cholesterol level significantly increased(40.4%). In diabetic and normal groups treated with curcumin, the blood cholesterol levels reduced. For example this reduction in dose 40mg/kg-B.W, in diabetic and normal rats were 35.4% and 22.1% respectively (As shown in fig-3).

[FIGURE 3 OMITTED]

LDL:

The levels of LDL in rats with diabetes were found to be elevated (As shown in fig-4). In diabetic control group(DO) as compared to normal control group(NO), the LDL level was significantly increased (65.4%). In diabetic and normal groups with treated curcumin, the blood LDL levels were reduced. For example this reduction in dose 40 mg/kg-B.W, in diabetic and normal rats were 45.1% and 26.2% respectively.

[FIGURE 4 OMITTED]

HDL:

In diabetes state, the level of HDL is less than normal state [23, 24]. In diabetic control group (DO) in comparison with normal control group(NO), HDL was significantly decreased (29.4 [+ or -] 3.6 v 45.4 [+ or -] 4.8(P<0.05). In diabetic groups that treated with curcumin, HDL were found to be elevated. For example this enlargment in dose 40 mg/kg-B.W was49.8%. However changes were not significant in normal groups (fig-5).

[FIGURE 5 OMITTED]

Triglycerides:

In diabetic control group(DO) as compared to normal control group(NO), the blood triglycerides level was significantly increased (133.3 [+ or -] 13.9 v 82.3 [+ or -] 8.2) (P<0.05). In diabetic and normal groups treated with curcumin, the blood triglycerides levels were reduced. For example this reduction in dose 40 mg/kg-B.W, in diabetic and normal rats were 78.3 [+ or -] 8.5 v 133.3 [+ or -] 13.9(P<0.05) and 62.3 [+ or -] 6.9v 82.3 [+ or -] 8.2(P<0.05) respectively (fig-6).

[FIGURE 6 OMITTED]

VLDL:

Following increasing triglycerids in rats with diabetes, VLDL were also increased. Level of VLDL was significantly increased(61.81%) in diabetic control group (DO) as compared to normal control group (NO). In diabetic groups and normal groups treated with curcumin VLDL levels were reduced. For example this reduction in dose 40 mg/kg-B.W, in diabetic and normal rats were 43.1% and 24.2% respectively(fig-7).

[FIGURE 7 OMITTED]

Food intake:

As shown in table 1, food intake was significantly increased in the diabetic control group (DO) compared with the normal control group (NO) (34.1 [+ or -] 2.8gv22.2 [+ or -] 2.3g, P<0.01). Upon administration of curcumin, food intake was reduced in all groups receiving the treatment. However the three doses of C20, C40 and C80had almost the same effect in diabetic and normal groups.

Bodyweight:

Results of body weight measured at day 30 are shown in table 1. As a known consequence of type 1 diabetes, the body weight in the diabetic control group was significantly reduced in comparison with the normal control group (201.2 [+ or -] 14.1g v249.2 [+ or -] 16.8g, P<0.01). In diabetic and normal groups treated with curcumin, body weight were reduced, However the three doses of C20, C40 and C80 had almost the same effect in diabetic and normal groups.

Water intake:

Water intake was observed to significantly increase in the diabetic control group (DO) compared with normal control group(NO)(110.3 [+ or -] 9.4ml v 37.8 [+ or -] 3.9ml, P<0.001) (fig-8). Curcumin administration nearly in a dose-dependent manner decreased the amount of water intake in diabetic groups. However curcumin had no significant effect on the water intake in the normal groups.

Urine volume:

In diabetes state, following increasing in water intake, the urine volume increase. In diabetic control group(DO), urine volume was significantly increased compare to the normal control group(NO) (92.7 [+ or -] 9.8ml v18.2 [+ or -] 1.7ml, P<0.001) (fig-8).Administration of curcuminin diabetic reduced urine volume nearly in a dose-dependent manner. However there was no significant difference between DC40 and DC80.Crcumin had no significant effect on the urine volume in the normal groups.

[FIGURE 8 OMITTED]

Discussion:

Diabetes mellitus is one of the most widespread diseases of world. According to the International Diabetes Federation(IDF), the global prevalence of diabetes is predicted to grow from 6.6% in 2010 to 7.8% in 2030 and it is fourth or fifth leading cause of death in the world [23].Diabetes is one of the most common endocrine disorders and is characterized by hyperglycemia, hypercholesterolemia, and hypertriglyceridemia [4-6]. Dyslipidemia is observed as a consequence of both type 1and type 2 diabetes, and could contribute to an increased incidence of cardiovascular diseases if untreated [7, 9]. Atherosclerosis is also a major cause of cardiovascular disease caused by high cholesterol. The World Health Organization (WHO) reported that Cardiovascular disease (CVD) is one of the main causes of mortality globally [25, 26]. Hyperlipidemia is induced by secondary effect of diabetes, therefore, the agent having some antioxidant and anti-diabetes effect also showed favorable effect to hyperlipidemia. Plants and phytochemicals have been shown to exert CVD protective effects. These effects could be due to plant polyphenolic compounds such as curcumin. It is yellow pigment of curcuma, exhibits anticarcinogenic, antioxidative and hypocholesterolemic activities [27-29].The aim of this research was to study the effect of curcumin on lipids metabolism diabetic and normal rats. Results of this study showed that curcumin cause reduction of cholesterol and LDL level in diabetic and normal rats. These effects may be based on this fact that curcumin cause increase excretion bile acid via increasing the amount mRNA of cholesterol 7[alpha]-hydroxylase, a liver-specific enzyme that catalyzes the rate limiting step in the biosynthesis of bile acid from cholesterol[25,30]. Curcumin reduced the level mRNA of HMG-CoA reductase, a liver-specific enzyme that catalyzes the rate limiting step in the biosynthesis of cholesterol[27]. Curcumin cause reduce the level of triglycerides and VLDL in diabetic and normal rats. These effects of curcumin maybe based on this actuality that curcumin cause increase the activity of fatty acid [beta]-oxidation, hepatic lipase and lipoprotein lipase but decrease fatty acid synthase activity [27, 31,]. Curcumin as an antiatherosclerosis agent in rats with diabetes cause increase the level of HDL via increasing the serum level of apolipoprotein A and the level of plasma lecithin cholesterol acyltransferase(LCAT) activity [27, 32]. Weight loss and decrease of food intake were also observed in diabetic and normal rats. It may be due to curcumin as a polyphenolic compound which could cause the reduction of calorie intake by inhibition of alpha amylase and decrease of carbohydrates digestion [23]. It seems that curcumin is an effective agent for the treatment and even the prevention of obesity. Water intake and urine volume in diabetic rats is also showing a remarkable decrease nearly in a dose-dependent manner. It is in accordance with its effect on blood glucose, and interesting in terms of the therapeutically benefits that it could have on these discomforting consequences of diabetes in patients. Curcumin had no significantly effect on the water intake and urine volume in the normal groups. Between four doses, 40mg/kg body weight of curcumin had the best results of improving the lipids metabolism in diabetic and normal rats. It may be concluded that curcumin as a lipid-lowering agents has beneficial effects in the treatment of diabetes and related disorders such as dyslipidemia.

ARTICLE INFO

Article history:

Received 2 April 2014

Received in revised form 13 May 2014

Accepted 28 June 2014

Available online 23 July 2014

ACKNOWLEDGMENTS

The authors are grateful to research deputy dean of the Islamic Azad University, Jahrom Branch, Razy laboratory center of university of science and research of Tehran, laboratory of gland and metabolism center of Tehran University and Shariaaty hospital of Tehran.

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Mahmood Najafian

Department of Biology, Jahrom Branch, Islamic Azad University, Jahrom, Iran.

Corresponding Author: Mahmood Najafian, Department of Biology, Jahrom Branch, Islamic Azad University, Jahrom, Iran.

Tel: 00989171901742 E-mail: d.najafian@jia.ac.ir
Table 1: Effect of curcumin treatment on food intake and body
weightinin diabetic and normal ra.

                            Food intake(g/day)

Groups          Diabetic rats              Normal rats

Control      34.1 [+ or -] 2.8          22.2 [+ or -] 2.3
Dose 10      26.9 [+ or -] 2.9 (a)      17.8 [+ or -] 1.9
Dose 20      21.5 [+ or -] 2.4 (a,b)    14.8 [+ or -] 1.8 (a)
Dose 40      21.8 [+ or -] 2.6 (a,b)    15.1 [+ or -] 1.9 (a)
Dose 80      21.6 [+ or -] 2.5 (a,b)    14.6 [+ or -] 1.7 (a)

                             Body weight (g)

Groups         Diabetic rats              Normal rats

Control     201.2 [+ or -] 14.1       249.2 [+ or -] 16.8
Dose 10     183.8 [+ or -] 13.6       220.4 [+ or -] 18.5
Dose 20     172.4 [+ or -] 14.4 (a)   195.5 [+ or -] 13.2 (a)
Dose 40     168.5 [+ or -] 15.3 (a)   192.4 [+ or -] 13.8 (a)
Dose 80     163.2 [+ or -] 15.8 (a)   189.6 [+ or -] 15.2 (a)

Data are expressed as mean [+ or -] SD for six rats.
In each case (a) is significantly different from control groups
and (b) is significantly different from Dose 10 mg/kg-b.w, using
one way ANOVA with Tukey's post hoc test for multiple comparisons
were used to compare difference between experimental groups.
The criterion for statistical significant was P<0.05 .
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Author:Najafian, Mahmood
Publication:Advances in Environmental Biology
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Date:Jul 1, 2014
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