JP2008019198A - Insulin resistance-improving composition obtained from plant belonging to genus silybum - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition for preventing or improving the type 2 diabetes, obesity or insulin resistance by ingesting crushed products or extracts derived from a plant that has abundant dietary experiences and exhibits adiponectin production-promoting actions. <P>SOLUTION: The composition exhibiting adiponectin production-promoting activities comprises crushed products or extracts of seeds, leaves, flowers, stems or the like of a plant belonging to the genus Silybum, preferably milk thistle, or extracts obtained therefrom using a solvent. The insulin resistance-improving agent comprises the composition. Foods and drinks and fodder exhibiting insulin resistance-improving actions comprise the composition. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a composition having adiponectin production promoting activity, a method for producing the same, an insulin resistance improving agent, a food and drink having an insulin resistance improving action, and a feed, and more specifically for improving insulin resistance and the like. The present invention relates to a highly safe composition having adiponectin production promoting activity and a drug, food, drink or feed containing the composition.

  Modern people are likely to become obese due to satiety, changes in dietary habits (high-fat diet), decreased physical labor associated with changes in social life, decreased exercise habits, overeating and overdrinking caused by stress As a result, it is easy to cause type 2 diabetes and more serious metabolic syndrome (hyperlipidemia, hypertension, arteriosclerotic disease, hyperinsulinemia, hypertriglyceridemia, hyper-LDL, abnormal glucose tolerance, etc.) It has become.

  Adipocytes produce and secrete adipocytokines (adiponectin, leptin, PAI-1, TNF-α, angiotensinogen, etc.), which are various endocrine factors, and are important for sugar and lipid metabolism and maintenance of arterial wall homeostasis It has become clear that it plays a role. Among them, adiponectin is a “good adipocytokine” produced specifically for adipose tissue identified from human adipocyte tissue, and its blood concentration is high if adipocytes are in a precursor state, but obesity and type 2 diabetes, In an ischemic disease, adipocytes differentiate and enlarge and decrease. At this time, the concentration of “bad adipocytokine” that causes insulin resistance increases, and the risk of insulin resistance increases. Experiments using humans and animals have confirmed that a low adiponectin state caused by high calorie intake and fat accumulation increases insulin resistance and causes arteriosclerosis. On the other hand, experiments have shown that administration of adiponectin by injection and increasing blood concentration can reduce blood glucose levels in diabetic model mice and suppress the formation of vascular lesions that lead to arteriosclerosis. (Refer nonpatent literature 1-3.).

  Although a method of directly administering adiponectin is useful, it is considered to be very important for the prevention and treatment of long-term lifestyle-related diseases to improve or promote the production failure of adiponectin in the body. In an oral administration test using a diabetic model mouse, isobutylmethylxanthine (non-patent document 4), which is a cAMP degrading enzyme inhibitor, and thiazolidine derivative (see patent document 1, non-patent document 5), which is a therapeutic agent for type 2 diabetes, It has been confirmed that the concentration of adiponectin in the blood is increased.

In addition, it has recently been found that ingredients that can be taken orally as foods also have an adiponectin production promoting action from preadipocytes. For example, rose or grape plant fruit extract (Patent Document 2), citrus fruit flavanones (Patent Document 3), soy isoflavones (Non-Patent Document 6), rice bran, arahan fruit, shimeji, chrysanthemum, rye, birch , Sterols derived from moon peach (patent document 4), curcumin of ginger family turmeric (patent document 5), gingerol (patent document 6) contained in ginger and the like, and adiponectin production promotion in plants of thistle genus It has not been known at all that there is an activity or an insulin resistance improving action.
Ichiro Shimomura et al., Experimental Medicine, Vol. 20, No. 12, 1762-1767 (2002) A. H. Berg et al., Nature Medicine, 7, 947-953 (2001) Y. Okamoto, Circulation, 106, 2767-2770 (2002) A. K. G. Loeffler, Horm. Metab. Res. , 32, 548-554 (2000) N. Maeda et al. , Diabetes, 50, 2094-2099 (2001) Nagasawa A, Fukui K et al., Horm Metab Res., 34, 635-9 (2002) US Pat. No. 6,153,432 JP 2000-186043 A JP-A-11-171766 JP 2005-68132 A JP 2005-60308 A JP 2006-45210 A

  As described above, pharmaceuticals that increase the concentration of adiponectin in the blood are already known, but all have problems in terms of safety and side effects. That is, isobutylmethylxanthine is not approved as a pharmaceutical product, and thiazolidine derivatives are highly hepatotoxic. Therefore, their use must be under the strict control of doctors and cannot be taken easily.

  On the other hand, as described above, some foods or their components are known to have adiponectin production-promoting activity, but their actions are not sufficient and are not satisfactory.

  Under such circumstances, there is abundant dietary experience, and expecting to prevent or improve type 2 diabetes, obesity or insulin resistance by ingesting plant-derived crushed or extract having an adiponectin production promoting action It had been.

  The present invention has been made in view of the above circumstances, and promotes adiponectin production from preadipocytes to differentiate into adipocytes, thereby increasing blood sugar levels by allowing blood sugar to be taken up. A composition having an adiponectin production-promoting activity excellent in the effect of suppressing insulin, further improving insulin-resistant diabetes, and further preventing or improving the occurrence of obesity and insulin resistance, and improvement of insulin resistance containing the composition It is intended to provide drugs, food and drink, and feed.

  The present inventors have intensively studied a plant-derived composition having an adiponectin production promoting action, and found that the activity of the extract of the genus Milk thistle is high, and have completed the present invention.

  That is, the first aspect of the present invention is a composition having adiponectin production promoting activity characterized in that it is obtained from a plant of the genus Milkiax. Preferably, the plant of the genus Milkweed is a milk thistle. The second aspect of the present invention is a gist of the above-described method for producing a composition having adiponectin production promoting activity, characterized in that an extract is obtained from a plant of the genus Milk thistle using a solvent. Is a solvent selected from the group consisting of methanol, ethanol, hexane and carbon dioxide, or a mixture of two or more.

  The third aspect of the present invention is to provide an insulin resistance improving agent characterized by comprising the above-mentioned composition having adiponectin production promoting activity as an active ingredient.

  A fourth aspect of the present invention is a food or drink having an insulin resistance improving action containing the composition, and a fifth aspect of the invention is a feed containing the composition.

  According to the present invention, it is possible to expect the progression of diabetes and related diseases, or the improvement of these diseases, by using a dietary experienced milk genus plant as a pharmaceutical composition or food composition.

  Hereinafter, the present invention will be described in detail.

  The asteraceae plant in the present invention is a biennial plant distributed from the Mediterranean to Africa and Asia. A typical plant of thistle genus is the milk thistle (Sylumum marianum), which is also known as Maria thistle or milk thistle.

  In Europe, it is also used for dishes such as salads, and in the Greek herbal book Dioscorides it appears under the name “Sylbon”, and the young leaves are described as being edible with oil and salt. In the first century C.E., the Roman naturalist Plinius recommended it as a liver medicine, and it has long been regarded as a liver medicine. Species include flavonolignans such as silybin, silydianin, and silyristine, which are collectively called silymarin. Silymarin increases the amount of glutathione in the liver, strengthens the detoxification function, protects hepatocytes, promotes regeneration of hepatocytes, has high antioxidant activity and lipoxygenase inhibitory effect, activates epidermal basal cells The skin aging prevention effect by elastin production promotion etc. is known. Seeds and leaves are mainly used. In Germany, a purified seed extract was approved in 1968 as an anti-hepatotoxic drug, and subsequently approved in France, Italy, China, South Korea, and the like.

  As described above, for the milk thistle plant, the liver function improving effect and the skin aging preventing effect were known, but the adiponectin production promoting activity and the insulin resistance improving effect were not known at all.

  The composition having adiponectin production-promoting activity of the present invention is obtained from a plant of the genus Milk thistle, specifically, a crushed product obtained by crushing seeds, leaves, flowers, stems, etc. Extracts extracted from various seeds of seeds, leaves, flowers, stems, etc. of the milk thistle plant using various solvents, and extracts obtained by concentrating and drying the extracts. Solvent extraction from the seeds of the milk thistle plant Or a product obtained by concentrating and drying the extract.

  In order to obtain a crushed material by crushing seeds, leaves, flowers, stems, etc. of the plant of thistle, it is preferable to dry them beforehand. Drying conditions are not particularly limited, and known methods can be used. For example, methods such as room temperature drying, heat drying, freeze drying, reduced pressure drying, vacuum drying and the like can be used, preferably economical heat drying at 30 to 100 ° C., and more preferably heat drying at 50 to 80 ° C. Examples of the dryer include, but are not limited to, mechanical devices such as a drum dryer, a fluidized bed dryer, a shelf dryer, a vibration dryer, and a rotary dryer.

  Next, the dried product is crushed, and a known crushing method can be employed. Examples of the crusher include, but are not particularly limited to, a dry millstone crusher, a roller mill, a cutter mill, a ball mill, a jet mill, and a hammer mill.

  The crushed plant of the genus Eucommia plant obtained as described above becomes a composition having the adiponectin production promoting activity of the present invention as it is or by adding other components as necessary.

  Moreover, as an extraction solvent used when obtaining an extract from a plant of thistle, for example, water, carbon dioxide, lower monohydric alcohol (methyl alcohol, ethyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2- Butanol, etc.), liquid polyhydric alcohols (glycerin, propylene glycol, 1,3-butylene glycol, etc.), lower esters (such as ethyl acetate), hydrocarbons (benzene, hexane, pentane, etc.), ketones (acetone, methyl ethyl ketone, etc.) , Ethers (diethyl ether, tetrahydrofuran, dipropyl ether, etc.), acetonitrile, and the like, and a single solvent or a mixture of two or more thereof can be used. Methanol, ethanol, hexane and carbon dioxide are preferred.

  The extraction temperature is not particularly limited as long as the extraction solvent is in a liquid state and the milk thistle plant rots and does not deteriorate during extraction, but it is preferably 40 ° C. or less, more preferably 10 ° C. or less. What is necessary is just to select extraction temperature suitably according to the kind of solvent to be used. The extraction time is preferably 5 hours or more, more preferably 1 week or more, and most preferably 20 days or more.

  After the extraction, the mixture of the crushed material and the solvent may be solid-liquid separated by a known method, and only the extract may be recovered. Examples of the solid-liquid separation method include, but are not particularly limited to, centrifugal separation, filter press, and suction filtration. Furthermore, the extract can be concentrated and dried as necessary.

  The extract of the genus Euglena obtained as described above becomes a composition having the activity of promoting adiponectin production of the present invention as it is or by adding other components as necessary.

  The other components that can be included in the composition of the present invention can be mixed as long as they do not reduce the adiponectin production promoting activity in the present invention, and are, for example, conventionally used pharmaceutically acceptable. It can be mixed with additives such as surfactants, solvents, thickeners, stabilizers, preservatives, antioxidants, flavorings and the like.

  Composition forms include, but are not limited to, tablets, liquids, capsules, soft capsules, pastes or troches, gums, or drinkable solutions or emulsions, dry oral supplements, wet oral supplements, etc. is not. Moreover, these forms can be produced by a conventionally known method.

  Next, the insulin resistance improving agent of the present invention comprises the above-described composition having the activity of promoting adiponectin production of the present invention as an active ingredient. The content of the active ingredient may vary depending on the age, weight, etc. of the subject to be ingested, but it is preferably contained so that it can be taken from 0.01 to 100 mg / kg per day for an adult. kg is preferred, and 0.5-5 mg / kg is most preferred.

  Examples of various additives contained in the insulin resistance improving agent of the present invention include surfactants, excipients, colorants, preservatives, coating aids, and combinations thereof. These additives are not particularly limited as long as they are additives in normal pharmaceutical production, and more specific examples include lactose, dextrin, sucrose, mannitol, corn starch, sorbitol, crystalline cellulose, polyvinylpyrrolidone, dextrin, and methylcellulose. , Carboxymethylcellulose salt, stearic acid and its salts, additives such as talc, and combinations thereof. Furthermore, spices, sweeteners and the like may be added. Furthermore, you may add another chemical | medical agent, a food ground material, and a food extract as needed.

  The dosage form of the insulin resistance-improving agent of the present invention is not particularly limited, and is manufactured into an appropriate dosage form according to the Japanese Pharmacopoeia. Specifically, it is produced in dosage forms such as capsules, tablets, powders, sustained-release agents.

  The food-drinks which have the insulin resistance improvement effect | action of this invention contain the composition which has the adiponectin production promotion activity of above-described this invention. The content of the active ingredient may be set according to the form of each food and drink so that the daily intake is 0.01 to 100 mg / kg, more preferably 0.1 to 10 mg / kg. Most preferred is 5-5 mg / kg.

  Examples of other materials that can be mixed in the food and drink having the insulin resistance improving action of the present invention include those that can be generally used as food materials. Examples include polysaccharides obtained from rice, wheat, corn, potato, kelp, proteins obtained from soybeans and dairy products, animal raw materials, glucose, lactose, fructose, sucrose, mannitol, xylitol and various oligosaccharides. Saccharides, as well as combinations thereof, may be mentioned. Furthermore, spices, colorants, sweeteners, acidulants, edible oils, vitamins and other food crushed products, food extracts and the like may be added. These suitable materials and additives are used alone or in combination. Furthermore, you may process to a desired shape by adding water as needed.

  Specific examples of the food and drink of the present invention include confectionery (gum, candy, caramel, chocolate, cookie, snack confectionery, jelly, gummy, tablet confectionery, etc.), noodles (soba, udon, ramen, etc.), and dairy products (milk, Ice cream, yogurt, etc.), seasonings (miso, soy sauce, etc.), soups, beverages (juice, coffee, tea, tea, carbonated drinks, sports drinks, etc.) and general foods and health foods (tablets, capsules, etc.) ), Nutritional supplements (nutrition drinks, etc.), but are not limited to these. Moreover, you may add the extract of this invention to an instant foodstuff. For example, a product obtained by spray-drying or freeze-drying an extract together with powdered cellulose can be easily contained in a food or drink by making it into a powder, granule, tablet, or solution.

  The feed having an insulin resistance-improving action of the present invention contains the above-described composition having the adiponectin production promoting activity of the present invention, and can be applied to all domestic animals, poultry and pets. Examples of livestock and poultry to which the feed of the present invention can be applied include domestic animals such as cows, pigs, horses, goats, sheep and rabbits, and animals such as chickens, turkeys, ducks, and quails. The pet animals to which the present invention can be applied are animals and birds raised for personal hobbies such as dogs, cats, hamsters and small birds. This may be administered alone as a feed composition, or may be added directly to the feed, and the form of use is not particularly limited. When adding to feed, the addition method, addition time, etc. are not specifically limited.

  The content of the active ingredient contained in the feed of the present invention may be set according to the form of each feed so as to be 0.01 to 100 mg / kg as the amount of active ingredient fed per day, and further 0 .1-10 mg / kg is preferred, and 0.5-5 mg / kg is most preferred.

  Other materials that can be mixed in the feed of the present invention include, for example, corn, milo, soybean, soybean meal, wheat, barley, rice, buckwheat, fish meal, skim milk powder, beet pulp pellets, bran pellets, grain screening pellets, alfalfa pellets , Tapioca pellets, corn cob meal, cotton hull pellets, sweet potato chips, homini feed, beer koji, hay cube, mini cube, alfalfa baled hay, sudan grass, rice straw, ryegrass straw, fescue straw, timothy hay, oat hay, Molasses, lupine, canola, rapeseed meal, cottonseed, corn gluten meal, corn gluten feed, soy hull pellets, whey powder, brewer's yeast, cholesterol, and other pharmaceutically acceptable vitamins And minerals, feed additives, veterinary drugs and the like, and are not particularly limited.

  Hereinafter, the present invention will be described in more detail with reference to examples.

In addition, the measurement of adiponectin production promotion activity was performed as follows. That is, in each well of a 24-well titer plate, 2 mL of 10% FBS-containing DMEM medium (GIBCO, glucose 4.5 mg / mL) and preadipocyte cell line 3T3-L1 cells (Human Science Promotion Foundation) .5 × 10 ⁴ cells added to the culture to confluence. Add 6% FBS-containing DMEM medium (containing 4.5 mg / mL glucose) and specimen (so that the final solid content of each composition is 50 μg / mL) to each well with cells attached to the bottom for 6 days Cultured. As a positive control, a mixed solution of an insulin solution (final concentration 3.3 μg / mL), a dexamethasone solution (final concentration 0.33 μM), and an isobutylmethylxanthine solution (final concentration 0.167 mM) was used. Each negative solvent was used as a negative control.

  After culturing for 6 days, the supernatant of each well was collected, and the amount of adiponectin in the supernatant was quantified by ELISA. For ELISA measurement, Quantikine Mouse Adiponectin / Acrp30 Immunoassay (R & D Systems) was used and operated according to the attached instructions.

Example 1 [Preparation of Milk Thistle Extract]
Milk thistle seeds or leaves were dried with hot air at 80 ° C. and crushed with a blender with a rotary blade to obtain a powder. 120 ml of ethanol was added to 12 g of this crushed material, followed by extraction treatment at 4 ° C. for 12 hours. Moreover, it replaced with ethanol and performed the same extraction process using each solvent of water, methanol, and hexane. Each of these extracts was centrifuged (3000 rpm, 10 minutes) to recover the supernatant, and the supernatant was concentrated under reduced pressure to obtain a composition having adiponectin production promoting activity of the present invention.

  The results are shown in Table 1. From the results in Table 1, it can be seen that the seeds or leaves of the milk genus plant and the hexane extract have strong adiponectin production promoting activity.

Example 2
Adiponectin using 3T3-L1 cells in the same manner except that the ethanol extract concentrate of milk thistle seed obtained in Example 1 above was added so that the final solids concentration would be 12.5, 25, 50, 100 μg / mL. Was produced in the medium, and the amount of adiponectin was measured. The results are shown in Table 2. From the results of Table 2, it was revealed that the ethanol extract fraction of milk thistle seeds increased the activity of promoting adiponectin production in a concentration-dependent manner. Moreover, when the cells before disruption were observed under a microscope, it was confirmed that oil droplets were accumulated in the cells and differentiation was induced.

Claims (7)

A composition having adiponectin production-promoting activity, which is obtained from a plant of the genus Asteraceae. The composition having adiponectin production promoting activity according to claim 1, wherein the plant of the genus Milkiax is a milk thistle. The method for producing a composition having adiponectin production promoting activity according to claim 1 or 2, wherein an extract is obtained from a asteraceae plant using the solvent. The method for producing a composition having adiponectin production promoting activity according to claim 3, wherein the solvent is one solvent selected from the group consisting of methanol, ethanol, hexane, and carbon dioxide, or a mixture of two or more. An insulin resistance improving agent comprising the composition according to claim 1 or 2. A food / beverage product having an insulin resistance improving action, comprising the composition according to claim 1. A feed having an insulin resistance improving effect, comprising the composition according to claim 1.