KR100988510B1 - Composition for Prevention of Type 2 Diabetes and its Complications and Health Supplement Foods containing The same - Google Patents

Abstract

The present invention relates to a composition for the prevention and treatment of type 2 diabetes and diabetes complications, comprising a dibenzo-p-dioxine derivative as an active ingredient, patients with type 2 diabetes and diabetes complications It has an excellent effect in preventing and treating liver and kidney damage caused by their oxidative stress and inhibits the expression of NFkB, a transcription factor closely related to the development of insulin resistance and type 2 diabetes. Provided is a composition for preventing and treating type 2 diabetes and diabetic complications having a characteristic, and a dietary supplement comprising the same.

The composition of the present invention is not toxic at all and can be ingested in the form of food for a long time, and can naturally treat type 2 diabetes and diabetic complications through diet and lifestyle of daily life in the long term.

Type 2 diabetes, diabetic complications, dibenzo-p-dioxin, NFkB, insulin resistance

Description

Composition for Prevention of Type 2 Diabetes and its Complications and Health Supplement Foods containing The same}

1 is a graph showing the inhibitory effect of NFkB activity in liver and kidney tissue of diabetic rats of the composition according to the present invention, and

Figure 2 is a graph showing the effect of reducing the number of NFkB active cells in diabetic rat adipose tissue of the composition according to the present invention.

The present invention relates to a composition for the prevention and treatment of type 2 diabetes and diabetic complications, and more particularly, by containing a dibenzo-p-dioxin derivative, damage to the liver or kidney due to oxidative stress accompanying diabetes. The present invention relates to a composition and a dietary supplement comprising the same, which are effective in preventing and treating type 2 diabetes and diabetic complications by protecting against the expression of NFkB which is closely related to insulin resistance and type 2 diabetes.

Diabetes is a disease in which glucose in the blood is excreted through urine and is one of the chronic degenerative diseases that does not cure fundamentally. In modern times, due to changes in diet and lack of exercise, a great change occurred in the body's own energy metabolism process, and thus chronic degenerative diseases such as diabetes are increasing. In Korea, the prevalence of diabetes is known to reach 5-10% and shows a continuous increase. In the United States, diabetes has increased six-fold over the past 40 years, and this growth rate is expected to reach 26 million by 2050.

Diabetes is a metabolic syndrome characterized by hyperglycemia resulting from insulin action, insulin secretion, or both. The causes of diabetes vary from insulin deficiency due to autoimmune mechanism to insulin resistance, and in most cases, insulin secretion disorder and insulin resistance exist simultaneously. Diabetes mellitus can lead to fatal problems in patients with pain and lifespan by causing complications such as retina, kidney, nerve, and cardiovascular system due to chronic chronic hyperglycemia. have.

 Diabetes is the most representative disease caused by metabolic disorders of the endocrine system. Recently, oxidative stress has been considered as the cause of insulin resistance, type 1 and type 2 diabetes (Ceriello et al. Metabolism 2000; 49:27). Hyperglycemia causes oxidative stress in the body, which leads to superoxide ions, glycosylation of proteins, and automatic oxidation of glucose (Brownlee. Nature 2001; 414: 813, Baynes.Clin Chem Lab Med 2003; 41: 813 , Wollff et al. Biochem J 1987; 245: 243, Wolff Free Radic Biol Med 1991; 10: 339). It is also known that free radicals are produced by free fatty acids (Wojtczak et al. Biochim Biophys Acta 1993; 1183: 41). Moreover, free radicals induced by hyperglycemia or FFA produce toxic substances such as NFkB in the body (King et al. Cell Biol 2004; 122: 333, Evans et al.Endocr Rev 2002; 23: 599).

Nuclear Factor kappa B (NFkB) is known to be the most important transcription factor in the development or progression of various diseases (verma. Ann Rheum Dis Suppl. 2 2004; 63: ii57, Baldwin. J Clin Invest 2001; 107: 241). In recent years, many papers have been shown to be closely related to the progression of neurological diseases, cancer, immune deficiency, rheumatoid arthritis, arteriosclerosis, asthma, and lipid arteriosclerosis, including type 2 diabetes and insulin resistance. Chen et al. Demers Clin Chem 1999; 45: 7, Yuan et al. Science 2001; 293: 1673, Cai et al. Nat Med 2005; 11: 183, Arkan et al. Nat Med 2005; 11: 191). In other words, NFkB is present in cells, but when activated by free radicals, stimuli that cause inflammation, carcinogens, toxins, ultraviolet rays, etc., NFkB is transferred into the nucleus and inhibits cell death, cell transformation, proliferation, invasion, metastasis, or chemical reaction. It induces the expression of over 200 genes that cause resistance and inflammation. Therefore, it is directly related to cancer, arteriosclerosis, diabetes, allergy, asthma, arthritis, Alzheimer's disease, and obesity. Therefore, by suppressing the expression of NFkB, it is possible to prevent the onset, progression and onset of various chronic diseases including diabetes and diabetic complications (Chen. Biochem Biophy Res Comm 2005; 332: 1, Jove et al. Endocrinology 2005; 146: 3087, Dandona et al. Circulation 2005; 111: 1448, Aggarwal et al. Ann NY Acad Sci 2004; 1030: 434).

On the other hand, type 2 diabetes and its complications should be treated naturally through the diet and lifestyle of daily life in the long term, the drug with toxicity is limited. Therefore, it is very important to be able to take in the long term in the form of food. Therefore, in the prevention and treatment of type 2 diabetes and diabetic complications, it is necessary to prevent oxidative stress, inhibit the activity of NFkB, and develop a substance that is not toxic.

Therefore, an object of the present invention has an excellent effect in preventing and treating liver and kidney damage caused by oxidative stress in patients with type 2 diabetes and diabetic complications, and is closely related to insulin resistance and development of type 2 diabetes. It is to provide a composition for preventing and treating type 2 diabetes and diabetic complications having a property of inhibiting the expression of factor NFkB.

Another object of the present invention to provide a dietary supplement that is effective in preventing and treating type 2 diabetes and diabetic complications comprising the composition.

According to an aspect of the present invention, at least one dibenzo-p-dioxine derivative is included as an active ingredient, and liver and kidney due to oxidative stress in patients with type 2 diabetes and diabetic complications For preventing and treating complications of type 2 diabetes and diabetic complications, which have an excellent effect in preventing and treating injuries and which inhibit the activity of NFkB, a transcription factor closely related to insulin resistance and development of type 2 diabetes. A composition is provided.

According to another aspect of the present invention, there is provided a dietary supplement effective in preventing and treating type 2 diabetes and diabetic complications comprising the composition.

Hereinafter, the present invention will be described in detail.

The present inventors found that dibenzo-p-dioxine derivatives are strong antioxidants that prevent damage caused by oxidative stress in the liver or kidney caused by the destruction of antioxidant system in diabetic patients, and induce inflammation or various cytotoxicity. Dibenzo-p-dioxine derivatives were found to inhibit the activity of NFkB, which promotes the expression of substances, and to reduce blood sugar, thereby improving and treating type 2 diabetes and diabetic complications, and thus dibenzo-p-dioxine derivatives. The present invention was completed by confirming that it can be used for the prevention and treatment of type 2 diabetes and diabetic complications.

The dibenzo-p-dioxin derivative included in the composition of the present invention is a compound first known in edible large brown algae, and is known to have antioxidant activity, antiplasmin inhibitory activity, antibacterial activity and the like. In the present invention, such a dibenzo-p-dioxin derivative exhibits NFkB inhibitory activity closely related to insulin resistance and the like, reduces blood sugar in diabetic mice, and prevents damage to liver and kidney accompanying diabetes. Experimental results have shown that they are excellent for preventing and treating complications.

The dibenzo-p-dioxin derivatives of the present invention may be any suitable dibenzo-p-dioxin. In one embodiment, the dibenzo-p-dioxin derivative has one of the following formulas.

[Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

Wherein each R is H, alkyl, alkenyl, phenyl, phenylalkyl, alkanoyl, hydroxyphenyl, dihydroxyphenyl or acyl. Preferably each R is H.

Such dibenzo-p-dioxin derivatives may be used in the composition of the present invention as a single compound or in combination or two combinations of such compounds, for example, 3 or more, 4 or more, 5 or more, 6 or more, 7 Or more, 8 or more, 9 or more, or 10 compounds, such as two or more combinations of these compounds. For example, in one embodiment, the compositions of the present invention may comprise two or more of Formulas 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

In one embodiment, the composition of the present invention comprises 0.1-6% by weight of the dibenzo-p-dioxin derivative of formula 1, 5-60% by weight of the dibenzo-p-dioxin derivative of formula 2, dibenzo- of formula 3 1-30% by weight of p-dioxin derivative, 0.5-80% by weight of dibenzo-p-dioxin derivative of formula 4, 0.1-10% by weight of dibenzo-p-dioxin derivative of formula 5, dibenzo of formula 6 0.5-15% by weight of p-dioxin derivative, 0.1-5% by weight of dibenzo-p-dioxin derivative of formula 7, 0.1-5% by weight of dibenzo-p-dioxin derivative of formula 8, 0.1 of formula 9 -10% by weight and 0.1-12% by weight of the dibenzo-p-dioxin derivative of the formula (10).

Suitable dibenzo-p-dioxin derivatives are, for example, Eisenia bicyclis ), Eisenia arborea), kids Senia des Mares Tio Rhodes (Eisenia desmarestioides), kids Senia Gala par Janice (Eisenia galapagensis ), Eisenia masonii , Ecklonia kurome ), Ecklonia cava ), Eclonia stolonifera stolonifera), Eccles Catalonia maxima (Ecklonia maxima), Eccles Catalonia radiah other (Ecklonia radiata ), Ecklonia bicyclis ), Ecklonia biruncinate), Eccles Catalonia Bush the day the lease (Ecklonia buccinalis), par S. Tips for (Ecklonia in Catalonia Eccles South caepaestipes), Eccles Catalonia exciter SARS peota (Ecklonia exasperta), Eccles Catalonia Paz Tee Hunger other (Ecklonia fastigiata), Eccles Catalonia breather bipseu (Ecklonia brevipes), Eccles Catalonia Ara beam LEA (Ecklonia arborea ), Ecklonia latifolia , and Eclonia mutifolia muratii ), Ecklonia radicosa ), Ecklonia richardiana ), Ecklonia wrightii ). Preferably, the dibenzo-p-dioxin derivative is Eisenia bicyclis ), Ecklonia cava , Eclonia kurome kurome ) or from brown algae, such as Ecklonia stolonifera .

The composition of the present invention may contain any suitable amount of dibenzo-p-dioxin derivatives. In one embodiment, the composition comprises about 0.01-100% by weight of one or more dibenzo-p-dioxin derivatives. In one embodiment, the composition is a food comprising about 0.01-10% by weight of one or more dibenzo-p-dioxin derivatives.

The compositions of the present invention can be prepared in any suitable dosage form. Suitable dosage forms include, but are not limited to, those suitable for administration of the oral, rectal, buccal (eg sublingual), parenteral (eg intravenous), topical, ocular, pulmonary or subcutaneous routes. Examples of suitable dosage forms include, for example, tablets, powders, capsules, suspensions, syrups, beverages, foods (eg bars or bread) or any other suitable dosage form. In one embodiment, the composition comprises, for example, an alcoholic beverage, a soda, water, tea or a beverage such as a capsule, a tablet, or a bar (such as sneakers or free time), bread, snacks, cereals, Candies, gums, chocolates, soups, hamburger patties, meatballs, ham, sausages, pepperoni, salad dressings, sauces, ice cream, popsicles, yogurt, cookies, cakes, or any other food suitable for digestion.

Thus, the compositions of the present invention can be administered systemically, for example by oral administration. They can be stacked into hard or soft shell gelatin capsules, compressed into tablets, or directly included in foods or drinks. For oral therapeutic administration, the active compound may be mixed with one or more excipients and used in the form of ingestible tablets, pincer tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. In one embodiment, the composition is administered in the form of a pharmaceutical composition and, for example, with a pharmaceutically acceptable medium such as an inert diluent or an absorbable edible carrier. Of course, any material used to make any unit dosage form should be non-toxic in use. In one embodiment, such active compounds may be incorporated into delayed-release preparations and devices.

The composition of the present invention may comprise any additive or additive mixture. The additives may be for example seasonings such as sweeteners or other flavors, dietary fibers, pigments, for example nutritional supplements such as vitamins, minerals, herbs or herbal extracts, or any other, for example food or nutritional agents. It may be any suitable additive including a functional ingredient. The composition may be mixed with one or more additives in any suitable combination. In one embodiment, the composition is for example apples, bananas, barley, beans, strawberries, broccoli, cactus, carrots, cherries, chocolate, citrus fruits, cocoa, cola, corn, berries, fruit punch, garlic, ginger, grapes Grapefruit, Jujube, Kiwi, Lemon, Lime, Melon, Peanut, Peanut Extract, Oat, Onion, Orange, Pear, Pineapple, Pine Leaf, Raspberry, Rice, Seaweed, Raspberry, Tangerine, Tomato, Vanilla, Vegetable, Vegetable Extract Seasonings such as vegetable fermentation, walnuts, watermelon, wheat or any other suitable seasoning. In one embodiment, the seasoning is, for example, such as sucralose, fructose, sucrose, stevia, honey, aspartame, crystalline fructose, dextrose, saccharin, acesulfame K or any other suitable sweetener. It is a sweetener. In one embodiment, the composition comprises a sweetener mixture comprising at least one sweetener. In one embodiment, the composition comprises a pigment such as, for example, crosine, crocetin, catamas yellow, anthocyanin or any other suitable pigment.

In one embodiment, the composition comprises at least one such as, for example, polydextrose, dextrin, undigestable dextrin, galactomannan, alginate, pectin, fucoidan, oligosaccharide, laminarin or any other suitable diet fiber. Contains diet fiber. In one embodiment, the additive is a nutritional supplement such as, for example, vitamins, herbs or any other suitable nutritional supplement. In one embodiment, the composition comprises at least one of, for example, omega-3 oils such as carnitine, DHA and EPA, stanol and stanol esters, lycopene, lutein, xylitol, coenzyme Q10, beta-carotene or flavonoids. It includes a functional ingredient of. In one embodiment, the composition comprises at least one vitamin such as, for example, vitamin C, E, B-complex, folic acid. The composition may also comprise at least one amino acid, for example comprising L-arginine or L-tryptophan, and / or at least one mineral such as, for example, selenium, calcium or zinc. In one embodiment, the composition comprises one or more herbal extracts such as ginseng, ginkgo biloba, saw palmetto, tea, aloe, echinacea or any other suitable herbal extract. In one embodiment, the composition is a general food or nutrient such as, for example, peanuts, vegetable oils, fish oils, vinegar, starch, proteins (eg, meat, soy protein, whey protein, gelatin or protein hydrolysates) or fats. It includes.

The dibenzo-p-dioxin derivatives of the invention may be combined in a single dosage form or in multiple independent dosage forms. The desired dosage form may conveniently be in a single dosage form or may be administered in divided doses at appropriate intervals, such as, for example, two, three, four or more subadministrations per day. The subadministration itself may also be divided into multiple administrations, for example. Dosage forms can be the same or different.

The composition of the present invention may be administered to an animal, preferably a mammal. In one embodiment, the composition may be administered daily at a dosage of about 0.1-100 mg / Kg, preferably about 1-100 mg / Kg, based on the net intake of the dibenzo-dioxin compound.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited thereto.

Example  1. Preparation of Extracts from Seaweeds and the Preparation of Each Extract NFkB  Inhibitory effect measurement

Seaweeds ( Ecklonia ) and rhubarb ( Eisenia s), collected from offshore, are first washed with distilled water to remove debris and then dried in the shade and then crushed. 500 g of the algae (350 g of Ecklonia cava and 150 g of rhubarb) are extracted under reflux for 2 hours to elute the active substance using 20 times the amount of 10% alcoholic solvent. This process was repeated twice. Then, the residue was filtered off and the solvent extract was concentrated under reduced pressure using a rotary evaporator. The concentrate is suspended in 20 times distilled water, extracted using the same amount of ethyl acetate solvent and the ethyl acetate fractions are concentrated under reduced pressure. The concentrate was loaded on 15 times the amount of silica gel, and then concentrated by distilling the dibenzo-p-dioxin derivative using a mixed solvent of ethyl acetate / acetone (volume ratio 9/1) to prepare a crude extract.

The crude protein-1 inhibitory activity of the crude extract was carried out according to the method in the literature (Dongad 91: 609). Mouse macrophage line 264.7 was incubated for 24 hours at 37 ° C. in a 96-well plate using Dulbecco's modified Eagle's medium (DMEM) medium containing 10% FCS and antibiotics. Dispense the cells into a 96-well plate at a concentration of 5x10 ⁵ and confirm that the cells adhere well to the bottom of the plate after 24 hours, and then treated with the extract at a concentration of 50ug / ml or 100ug / ml, LPS (5ug / ml) and IFN-r. (3ng / ml) is treated to cause irritation. After 12 hours of incubation, the culture solution was treated with a lysis buffer, and then TNF-α concentration, which is a toxic substance that induced NFkB activity in the culture medium, was measured using Enzyme immunoassay. Obtained by measuring absorbance at 492 nm (Mukhopadhyay et al. J Immunol 2002; 168: 2914). The results were obtained by calculating the concentration of TNF-a in the culture from each absorbance (ng / ml) and converting it to a relative value by comparing with the result of the control group. In addition, the inhibition rate was calculated by the following equation from the relative concentration (A) when the extract was added, and the relative concentration (A0) when the sample was not added. The results are shown in Table 1 below.

Inhibition Rate = A / A0 × 100

As shown in Table 1, the inhibitory activity of crude extracts was relatively high at 40% and 49% at 50 and 100ug / ml, respectively.

TABLE 1 Relative NFkB activity and inhibition rate of crude extract

Example  2 to 11

The crude extract prepared in Example 1 was filtered through a 0.2 μm membrane filter and loaded on high performance liquid chromatography. In high-performance liquid chromatography, the column was HP ODS Hypersil column, distilled water and methanol as solvent, and the solvent supply was linear gradient over 15 minutes from 15% to 70% methanol at 1.0 ml / min flow rate. ) To separate into single water. The activity of NFkB was measured for each single water. The results are shown in Table 2.

Example  12 to 16

The activity of NFkB was measured using a mixture of the samples of Examples 2 to 11 at a concentration of 10 ug / ml. The results are shown in Table 2.

Example  17 to 19

The activity of NFkB was measured using the compounds of Examples 2 to 11 having hydrogen and other functional groups at a concentration of 10 ug / ml. The results are shown in Table 2.

Comparative example  1 to 6

Catechin, resveratrol, green tea extract, grape seed extract, quercetin, and isoflavone, known as polyphenolic substances, were used as a control at a concentration of 10 ug / ml to measure the activity of NFkB. The results are shown in Table 2.

TABLE 2 Relative NFkB Activity of Singles or Mixtures

It can be seen that the ability of the composition of the present invention to inhibit the expression of NF-KB is relatively superior to the comparative examples.

Example  20 Dibenzo -p- Dioxin derivatives  Prevention of diabetes complications according to the diabetic inhibitory and liver and kidney function protection of the composition

Streptozotocin (STZ), widely used as a diabetic animal experimental model for measuring the diabetic inhibitory effect and the protective effect of liver function and renal function for the prevention of diabetic complications of dibenzo-p-dioxin derivatives The diabetic induction model was used, and the extracts of Examples 7 and 14 (hereinafter referred to as Extract 7 and Extract 14) having excellent NFkB inhibitory effects were used as samples, and green tea extract and rasveratrol were used as a comparison group. .

20-1) Diet and  Experiment method

Male Winstar rats were used as experimental animals, and after approximately two weeks of adaptation, extracts 7 and 14 containing dibenzo-p-dioxin derivatives were tested, normal control group, diabetes-induced control group, and green tea extract and las as control groups. The experiment was divided into six groups such as the veratrol group, and in the test group except the normal control group and the diabetic induction group, each sample was dissolved in water at a concentration of 0.02% so that it could be freely drunk like water. Ten animals were used in each group, and the animal laboratory controlled light at a 12 hour period while maintaining 20 ± 2 ° C. and a humidity of 50 ± 10%. Diabetes-induced controls and test groups of rats except the normal control group were induced by intraperitoneal injection of STZ dissolved in 10 mM sodium citrate buffer (sodium citrate, pH 4.5) at a concentration of 70 mg / kg body weight. Five days after administration of STZ, the concentration of glucose in plasma was measured by collecting blood from the tail vein. Diabetes was considered to be a plasma glucose concentration of 14mmole / L or more. Glucose was taken from a rat tail vein and measured using a blood glucose detector. The experiment was continued for 8 weeks, and fasted for 18 hours before sacrifice of the animals after 8 weeks of diabetes-induced diabetes by STZ, and then fasting blood glucose and body weight were checked immediately before anesthesia. After anesthesia with ethyl ether, the abdomen was opened, blood was collected through the abdominal aorta, kidneys and livers were extracted, pretreated, and stored frozen at -80 ° C until chemical analysis. Blood was immediately centrifuged at 1800 × g, 4 ° C. for 15 minutes to separate serum and stored frozen at −80 ° C.

20-2) liver and kidneys Within the organization  Determination of Antioxidant Enzymes Activity

Frozen liver and kidney tissue was added to phosphate buffer solution (phosphate buffer, KCl 140mmole / L, phosphate 20mmole / L, pH7.4) at 0 ° C, homogenized, and centrifuged at 14,000 X g for 10 minutes. The activity of each enzyme is measured by the following method. Each value is shown in Tables 3 and 4.

20-2-1) GPx  ( Glutathion peroxidase Activity measurement

The activity of glutathion peroxidase was measured using the method of Flohe (Methods Enzymol 1974; 105: 15). When the cumene-hydroperoxidem was added to the substrate, the rate at which the oxidized glutathione produced by glutathione peroxidase action was reduced again in the presence of excess glutathione reductase and a certain amount of NADPH was measured. 1.55 ml of mother liquor (0.25mM reduced glutathione, 0.12mM NADPH, glutathione reductase 1 unit / ml) was added to 0.1 ml of the sample and expressed as nmol number of NADPH oxidized at 37 ° C. for 1 minute.

20-2-2) TBARS  ( thiobarbituric  acid reactive substances) measurement

The amount of material produced by lipid oxidation was measured using the method of Gonzales-Flecha (Free Radic Biol Med 1991; 10:41). After diluting with 10 mM potassium phosphate buffer (pH7.4) so that the protein concentration of each sample was about 2mg / ml, 1ml in a screw-cap tube and shaken warmed for 60 minutes in a 37 ℃ constant temperature water bath. 1 ml of 10% (w / v) trichloroacetic acid and 1 ml of 0.67% TBA (thiobarbituric acid) were added thereto, followed by vigorous mixing for 30 seconds, closing the stopper with boiling water and bathing for 15 minutes. After the bath was rapidly cooled in iced water and centrifuged at 1,000 g for 10 minutes, the absorbance was measured at 535 nm as the supernatant. At this time, TEP (tetraet hoxypropane) was dissolved in methanol as a standard solution.

20-2-3) Determination of Catalase (EC 1.11.1.6) Activity

The activity of catalase was determined by the method of Chance (Methods Enzymol 1995; 2: 764). The absorbance of H ₂ O ₂ in each sample was measured at 240 nm and the results were expressed in U / g protein.

TABLE 3 Plasma glucose content and effect of extract administration in liver tissue

[Table 4] Effect of extract administration in renal tissue

20-3) Determination of NFkB activity in liver and kidney tissue

Nucleic extracts were prepared from the stored tissue samples according to the method of Essani (J Immunol 1996; 156: 2956), and the amount of activated transition factor NFkB was determined from the electrophoretic mobility shift assay (EMSA) method (Zandi et al. Cell 1997; 91: 243, Romics et al. Hepatology 2004; 40: 376) and the results are shown in FIG.

The improvement effect on the diabetic and diabetic complications of the extract can be summarized as follows from Table 1, 2, and the results of FIG.

(1) In the results of STZ-induced diabetic animal experiments, the amounts of plasma glucose were reduced by 47% and 40%, respectively, by the extracts 7 and 14, compared with those of the diabetic control group.

(2) In the lipid production by oxidative stress in liver or kidney tissue, the extract showed inhibitory effects of 26-30% and 28-39%, respectively, compared to the diabetic control group.

(3) The activity of catalase, an antioxidant enzyme in liver or kidney tissue, was increased by 35-41% and 36-45%, respectively, by the extract compared to the diabetic control group.

(4) The activity of glutathione peroxidase, an antioxidant enzyme in liver or kidney tissue, was increased by 20-23% and 24-26%, respectively, compared to the diabetic control group.

(5) It showed a higher effect than the green tea extract or rasveratrol used in the comparison group.

(6) From the results of Figure 1 it can be seen that the extract significantly inhibits the activity of NFkB in liver tissue and kidney tissue compared to the diabetes-induced control.

As a result, it can be seen that the extract containing the dioxy-p-dibenzo derivative is excellent in preventing diabetes and diabetic complications.

Example  21 Dibenzo -p- Dioxin  Of the composition comprising derivatives Diabetic rats  Transcription Factor Using Model NFkB  Inhibitory effect

In order to measure antidiabetic activity, ie, NFkB inhibitory activity associated with insulin resistance or various inflammatory responses, using a diabetic rat model of the composition comprising a dibenzo-p-dioxin derivative, Animal experiments using C57BL / 6JL Lep ob mice (ob / ob mice) exhibiting high blood glucose levels were reviewed. NFkB is a transcription factor that is activated by various factors such as oxidative stress or toxic substances and is known to play a major role in causing chronic diseases such as diabetes. Diabetic rat model was used to verify the antidiabetic effect by inhibiting the activity of the transcription factor NFkB of the extract. In order to verify the antidiabetic effect, the extract of Example 14 was used as a sample.

21-1) Diet and  Experimental method and NFkB  Measure

Nine-week-old male ob / ob mice were divided into three groups: group 1 (normal control, water), group 2 (0.02% sugar water), and group 3 (0.02% extract 14). The sample was allowed to drink freely. Each stock solution was stored in a dark place at 5 ° C. at 0.1%, and supplied diluted at 0.02% twice a week, and the weight of each was recorded. The experiment was conducted for 10 weeks. After 10 weeks, liver, kidney, pancreas, and cardiac tissues were extracted and stored at -80 ℃ for analysis. The expression of NKkB was measured by immunohistochemistry in the heart, liver, kidney, and pancreatic tissues of the cells containing p65 protein, an element of NFkB. Figure 2 shows the effect of reducing the number of NFkB active cells in the tissue by the extract.

Example  22: Rat  4-week repeated dose toxicity test

In order to investigate the toxicity by repeated oral administration of dibenzo-p-dioxin derivatives, 10 SD male and female male and female media control and test substance (Example 14) were administered at doses of 1000, 333 and 111 mg / kg, respectively. The test results of 4 weeks repeated oral administration to rats were as follows.

(1) No dead animals associated with administration of the test substance were observed.

(2) No change of general symptoms related to administration of test substance was observed.

(3) No change in body weight was found in both male and female.

(4) No abnormalities related to the administration of the test substance were recognized in all the male and female groups in the feed and water intake.

(6) In the ophthalmologic examination, no abnormalities were observed in all groups of male and female.

(7) In urinalysis, no toxicological abnormalities were observed in all male and female groups.

(8) In the hematological examination, no toxicological changes were observed by administration of test substance in all groups of male and female.

(9) No toxicological changes related to the administration of test substance were observed in blood biochemical tests.

(10) In autopsy findings, no abnormal findings were observed in all male and female treatment groups.

(11) No significant change in organ weight was observed in all groups of male and female.

(12) Histopathological examination showed no toxicological changes due to the administration of the test substance.

In view of the above results, no toxicological changes were observed in the study by 4 weeks of repeated oral administration in rats. Therefore, NOAEL of this test substance was judged to be more than 1000 mg / kg / day.

The composition for preventing and treating type 2 diabetes and diabetic complications of the present invention is not only excellent in the prevention and treatment of diabetes-induced and diabetic complications, but also has no toxicity and can be consumed in the form of food for a long time. And lifestyle can prevent diabetes and diabetes complications.

Claims (10)

A dibenzo-p-dioxine derivative selected from the group consisting of the following Chemical Formulas 1 to 10 as an active ingredient, the agent having the property of inhibiting the activity of NFkB (Nuclear Factor Kappa B) Composition for the prevention of type 2 diabetes. [Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

(Wherein each R is H) delete delete The method of claim 1, wherein the composition (a) 0.1-6% by weight of the dibenzo-p-dioxin derivative of Formula 1; (b) 5-60% by weight of a dibenzo-p-dioxin derivative of formula 2; (c) 1-30% by weight of the dibenzo-p-dioxin derivative of Formula 3; (d) 0.5-80% by weight of a dibenzo-p-dioxin derivative of formula 4; (e) 0.1-10% by weight of the dibenzo-p-dioxin derivative of formula 5; (f) 0.5-15% by weight of the dibenzo-p-dioxin derivative of formula 6; (g) 0.1-5% by weight of the dibenzo-p-dioxin derivative of formula 7; (h) 0.1-5% by weight of the dibenzo-p-dioxin derivative of formula 8; (i) 0.1-10% by weight of the dibenzo-p-dioxin derivative of formula 9; And (j) 0.1-12% by weight of a dibenzo-p-dioxin derivative of formula 10 A composition comprising one or more of. The composition of claim 1, wherein the dibenzo-p-dioxin derivative is extracted from brown algae. The method of claim 5, wherein the brown alga is Eisenia bicyclis ), Eisenia arborea , Esenia des Maresiodes desmarestioides ), Eisenia galapagensis ), Eisenia masonii ), Ecklonia kurome ), Ecklonia cava ), Eclonia stolonifera , Eclonia maxima , Eclonia radiata , Eclonia bicyclis bicyclis), Eccles Catalonia Byron Nate (Ecklonia biruncinate), Eccles Catalonia Bush the day the lease (Ecklonia in buccinalis), Eccles S. Tips for Catalonia car wave (Ecklonia caepaestipes), Eccles Catalonia exciter SARS peota (Ecklonia exasperta ), Ecklonia fastigiata ), Eclonia Brebbi ( Ecklonia brevipes ), Ecklonia arborea ), Ecklonia latifolia), Eccles Village Tea Catalonia (Ecklonia muratii), Eccles Catalonia radio Xhosa (Ecklonia radicosa ), Ecklonia richardiana and Ecklonia wrightii . The composition of claim 1, wherein the composition is orally administered at a daily dosage of 0.1-100 mg / Kg. The composition of claim 1, wherein the composition is in the form of a capsule or tablet. A dietary supplement effective for preventing type 2 diabetes, comprising 0.1-100% by weight of the composition of claim 1. 10. The dietary supplement of claim 9, wherein the dietary supplement is in the form of a beverage, bread, capsule or tablet.

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