JP2016104816A - Food product for inhibiting blood sugar level elevation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a blood sugar level elevation inhibitor, and a composition for preventing or treating lifestyle diseases and disorders related to the diseases.SOLUTION: The present invention relates to a blood sugar level elevation inhibitor containing a compound expressed in Formula (I) and proanthocyanidin, and also relates to a composition for preventing or treating lifestyle diseases and disorders related to the diseases which contains the compound expressed in Formula (I) and proanthocyanidin.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a blood glucose level increase inhibitor containing a compound represented by formula (I) and proanthocyanidins. The present invention also relates to a composition for preventing or treating lifestyle-related diseases and diseases related thereto, comprising a compound represented by formula (I) and proanthocyanidins.

  In recent years, as the eating habits have become westernized, the amount of fat intake per capita has increased, and diseases called lifestyle-related diseases such as diabetes, hyperlipidemia, hypertension and obesity have been rapidly increasing. These diseases are easily combined with each other, and the existence of insulin resistance is considered to be greatly involved in the underlying diseases. Therefore, it may be considered that prevention or treatment of diabetes, that is, suppression of an increase in blood glucose level, also leads to prevention or treatment of other lifestyle-related diseases such as hyperlipidemia, hypertension, obesity and the like. it can.

The total number of diabetic patients caused by insulin resistance and their reserve groups is estimated to exceed 13 million in Japan, and the number is steadily increasing.
Drugs such as thiazolidine derivatives are known as antidiabetic agents. However, drugs such as thiazolidine derivatives are effective for insulin resistance, but have been reported to have side effects of increasing body fat due to long-term use. In order to treat and prevent diabetes, it is necessary to develop a new anti-glycemic agent with few side effects such as increased body fat, and due to the nature of diabetes closely related to lifestyle, It is also desirable to be able to continuously ingest foods and beverages that have an improving action and are inexpensive and easily ingested.

  On the other hand, grape seed extract contains a large amount of antioxidants typified by polyphenols, and particularly contains a high amount of proanthocyanidins having a strong antioxidant power. Proanthocyanidins have been found to be effective in preventing and treating the progression of various complications including diabetic cataract by controlling blood hemoglobin glycation rate to a low level (see, for example, Patent Document 1). . It has also been reported that an anti-arteriosclerotic effect was observed by the combined administration of proanthocyanidins and isoflavones (see, for example, Patent Document 2).

  In addition, as a natural product-derived compound that suppresses an increase in blood glucose level, a specific naringenin glycoside having a sugar chain consisting of 3 molecules of 6 monosaccharides and 1 molecule of 5 monosaccharides isolated from the water-soluble fraction of black tea, It has been found that there is an action of glucose uptake into cells and an action to suppress an increase in blood sugar (see, for example, Patent Document 3).

JP 2000-044772 A JP 2000-325039 A JP 2008-013525 A

  An object of this invention is to provide the blood glucose level raise inhibitor with few side effects, such as an increase in body fat. Another object of the present invention is to provide a composition for preventing or treating lifestyle-related diseases and diseases related thereto.

In order to solve the above-mentioned problems, the present inventor has conducted extensive research and combined a specific compound represented by the formula (I) described below in detail with proanthocyanidins, thereby exhibiting an excellent blood glucose level inhibitory action. I found out that
The present invention based on the above findings by the present inventors is as follows.
[1]
Formula (I):
(Where
One of R ₁ and R ₂ is represented by the following formula (II):
(Where
X _{1 to} X ₅ are each independently H, OH or OMe)
A substituted or unsubstituted benzene ring A, and the other is H or OH;
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a single bond or a double bond)
The blood glucose level raise inhibitor containing the compound and proanthocyanidin represented by these.
[2]
The blood sugar level increase inhibitor according to [1], wherein the proanthocyanidins are grape seed or skin extract.
[3]
The compound of formula (I) is:
R ₁ is a substituted or unsubstituted benzene ring A represented by the formula (II);
R ₂ is H;
The agent for suppressing an increase in blood glucose level according to [1] or [2], wherein ------ is a compound having a single bond.
[4]
[1] to [3] A pharmaceutical or a food or drink comprising the blood sugar level elevation inhibitor according to any one of [1] to [3].
[5]
Formula (I):
(Where
One of R ₁ and R ₂ is represented by the following formula (II):
(Where
X _{1 to} X ₅ are each independently H, OH or OMe)
A substituted or unsubstituted benzene ring A, and the other is H or OH;
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a single bond or a double bond)
A composition for the prevention or treatment of lifestyle-related diseases and diseases related thereto, comprising a compound represented by the formula: and a proanthocyanidin.
[6]
Formula (I):
(Where
One of R ₁ and R ₂ is represented by the following formula (II):
(Where
X _{1 to} X ₅ are each independently H, OH or OMe)
A substituted or unsubstituted benzene ring A, and the other is H or OH;
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a single bond or a double bond)
A composition for the prevention or treatment of diabetes, comprising a compound represented by
[7]
A method for inhibiting an increase in blood glucose level, comprising a step of administering an effective amount of a compound represented by the above formula (I) and proanthocyanidins to a subject.
[8]
A method for preventing or treating lifestyle-related diseases and diseases related thereto, comprising a step of administering to a subject a compound represented by the above formula (I) and proanthocyanidins in a prophylactically or therapeutically effective amount.
[8]
A method for the prophylaxis or treatment of diabetes mellitus and diseases related thereto, which comprises the step of administering to a subject a prophylactic or therapeutically effective amount of a compound represented by the above formula (I) and proanthocyanidins.

The measurement result of HbA1c in Example 1 is shown.

The present invention relates to a blood glucose level increase inhibitor containing a compound represented by formula (I) and proanthocyanidins.
The blood glucose level elevation inhibitor of the present invention may be a combination of naturally occurring compounds.
In addition, in the present invention, by containing the compound represented by the formula (I) and proanthocyanidin, it is more effective in that it can provide a blood sugar level increase inhibitor with little side effect of increased body fat. .

In the present invention, it is possible to provide a composition for preventing or treating lifestyle-related diseases and diseases associated therewith, which comprises a compound represented by the formula (I) and proanthocyanidins. Especially, in this invention, it is a preferable aspect that this composition for prevention or treatment is a composition for treating or preventing diabetes.
The prophylactic or therapeutic composition may comprise a combination of naturally occurring compounds.
In addition, the present invention provides a composition for preventing or treating lifestyle-related diseases and related diseases with few side effects of increased body fat by containing the compound represented by formula (I) and proanthocyanidins. It is more effective in that it can.

Examples of lifestyle-related diseases and diseases associated therewith include hyperglycemia and diseases associated with hyperglycemia such as obesity, hyperlipidemia and diabetes.
Among lifestyle-related diseases, diabetes refers to hyperglycemia or ketoacidosis, as well as chronic general metabolic abnormalities resulting from long-term hyperglycemia or reduced glucose tolerance. Diabetes also includes both type 1 and type 2 (non-insulin dependent diabetes, or NIDDM) disease.

  The composition of the present invention preferably contains the compound represented by formula (I) and proanthocyanidins in a preventive or therapeutically effective amount in the prevention or treatment of lifestyle-related diseases and related diseases. A prophylactically or therapeutically effective amount is within a range that can prevent or treat the disease or condition, the subject and the disease or condition to be prevented or treated, the weight and age of the subject, the severity of the disease or condition, It varies depending on the administration method and can be easily determined by those skilled in the art.

The present invention is directed to administering a composition comprising a compound represented by formula (I) and proanthocyanidins in a prophylactically or therapeutically effective amount to a subject to prevent lifestyle-related diseases and related diseases in the subject. Including prevention or treatment. The composition can also be administered to a subject as a dietary supplement or as an additive to food. The composition comprising the compound represented by formula (I) and proanthocyanidin according to the present invention is a composition comprising a mixture of the compound represented by formula (I) and proanthocyanidin when administered to a subject. It may also be a composition in which a compound represented by formula (I) and proanthocyanidins are administered in combination. When administered in combination, they may be administered simultaneously as a mixture, each may be administered simultaneously as a separate form, or each may be administered separately. In this invention, it is preferable to administer simultaneously as one composition containing the compound represented by a formula (I), and proanthocyanidin.
The present invention also relates to a method for suppressing an increase in blood glucose level by administering a compound represented by the formula (I) and proanthocyanidins, preferably with few side effects of increased body fat.

  An inhibitor of blood sugar level elevation containing a compound represented by formula (I) and proanthocyanidins of the present invention, and a composition for preventing or treating lifestyle-related diseases and related diseases (hereinafter simply referred to as “the composition of the present invention”). The ratio of the compound represented by the formula (I): proanthocyanidin is 1: 10000 to 10000: 1, preferably 1: 1000 to 1000: 1, more preferably Is 1: 100 to 100: 1.

The compound represented by the formula (I) in the composition of the present invention has the following structure.

In formula (I), _one of R ₁ and R ₂ is the following formula (II):
(Where
X _{1 to} X ₅ are each independently H, OH or OMe)
And the other is H or OH (preferably H);
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a single bond or a double bond.

In one embodiment of the present invention, preferably in the above formula (I):
R ₃ is H or OH;
R ₄ is H or OMe;
R ₅ is OH;
R ₆ is H;
In the above formula (II):
X ₁ is H;
X ₂ is H or OH;
X ₃ is H, OH or OMe;
X ₄ is H;
X ₅ is H or OMe.

In one embodiment of the present invention, preferably in the above formula (I):
R ₁ is a substituted or unsubstituted benzene ring A represented by the formula (II) (in the formula (II), X _{1 to} X ₅ are each independently H, OH or OMe);
R ₂ is H;
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a single bond;
More preferably, in the above formula (I):
R ₃ is H or OH;
R ₄ is H;
R ₅ is OH;
R ₆ is H;
In the above formula (II):
X ₁ is H;
X ₂ is H or OH;
X ₃ is H, OH or OMe;
X ₄ is H;
X ₅ is H or OMe.
The compounds having this structure (and glycosides thereof) are generally collectively referred to as flavanones. Flavanones are pigment components often found in citrus, and examples include naringenin, naringin, hesperidin, hesperetin, citronin, citronetin, liquiritin, liquiritigenin and the like.
Particularly preferably, the compound of the formula (I) is naringenin or hesperetin.

Naringenin is represented by formula (I): R ₁ is a substituted benzene ring A represented by formula (II) (wherein X ₁ , X ₂ , X ₄ and X ₅ are each H; X ₃ is R ₂ , R ₄ and R ₆ are each H; R ₃ and R ₅ are each OH; ------ is a compound that is a single bond .

Hesperetin is represented by formula (I): R ₁ is a substituted benzene ring A represented by formula (II) (wherein X ₁ , X ₄ and X ₅ are each H; X ₂ is OH; X ₃ is OMe; R ₂ , R ₄ and R ₆ are each H; R ₃ and R ₅ are each OH; ------ is a single bond It is a compound which is.

In one embodiment of the present invention, preferably in the above formula (I):
R ₁ is H;
R ₂ is a substituted or unsubstituted benzene ring A represented by the formula (II);
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a double bond;
More preferably, in the above formula (I):
R ₃ is H or OH;
R ₄ is H or OMe;
R ₅ is OH;
R ₆ is H;
In the above formula (II):
X ₁ is H;
X ₂ is H;
X ₃ is OH or OMe;
X ₄ is H;
X ₅ is H.
The compounds having this structure (and glycosides thereof) are generally collectively referred to as isoflavones. Isoflavones are components that are abundant in leguminous plants such as soybeans, and examples include genistein, genistin, daidzin, daidzein, glycitein, biocanin, and formononetin.

Particularly preferably, the compound of the formula (I) is genistein. Genistein is represented by formula (I): R ₂ is a substituted benzene ring A represented by formula (II) (where X ₁ , X ₂ , X ₄ and X ₅ are each H; X ₃ is R ₁ , R _4, and R ₆ are each H; R ₃ and R ₅ are each OH; ------ is a compound that is a double bond is there.

In one embodiment of the present invention, preferably in the above formula (I):
R ₁ is a substituted or unsubstituted benzene ring A represented by the formula (II);
R ₂ is H;
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a double bond.
The compounds having this structure (and glycosides thereof) are generally collectively referred to as flavones. Flavones are plant pigments found in various plants, and examples include avigenin, luteolin, tangerine, diosmin, flavoxate and the like.

In one aspect of the present invention, composition for preventing or treating lifestyle diseases and diseases associated with this, preferably, the compound represented by formula (I) (formula (I) in: R ₁ has the formula A substituted or unsubstituted benzene ring A represented by (II); R ₂ is H or OH (more preferably H); ------ is a single bond or a double bond (more Preferably a single bond)) and proanthocyanidins.

  The compound represented by the formula (I) may be a derivative in which a part of the structure is altered or modified. Examples of the derivative of the compound represented by the formula (I) include physiologically acceptable salts, glycosides, esters, prodrugs, metabolites, and the like.

  The physiologically acceptable salt of the compound represented by the formula (I) is not particularly limited, and examples thereof include alkali metal (sodium, potassium, etc.) salts, alkaline earth metal (magnesium, calcium, etc.) salts and the like. Examples thereof include base addition salts obtained by adding hydroxides or carbonates of these alkali metals or alkaline earth metals, and alkali metal alkoxides (sodium methoxide, potassium t-butoxide, etc.).

  The glycoside of the compound represented by the formula (I) is not particularly limited, but for example, hexose or glucose of glucose, rhamnose, rutinose (glucose + rhamnose), apiose and the like (preferably glucose or rutinose) An OH group of the compound represented by the formula (I) is present in the OH group of a pentose sugar, a derivative thereof (for example, a modified sugar that has been acetylated, malonylated, etc.) or a combination of two or more thereof. Examples include condensed O-glycosides. Many of the compounds represented by formula (I) are known to exist naturally in the form of glycosides. For example, the glycoside of daidzein is soybean in, the glycoside of hesperitin is hesperidin, and the glycoside of naringenin is naringin.

The prodrug of the compound represented by the formula (I) is not particularly limited as long as it can be changed into the compound represented by the formula (I) after being administered to a living body. For the purpose of improving absorbability, reducing side effects, etc., a compound represented by the formula (I) which is converted into a prodrug by a known method can be mentioned. Moreover, since the above-mentioned glycoside can be decomposed by an enzyme (glycosidase) in the body and then converted into a compound represented by the formula (I) after administration to a living body, the prodrug of the compound represented by the formula (I) Can be a drug.
One embodiment of the prodrug may be an ester. In addition, the ester may be an ester corresponding to a prodrug, but is not particularly limited as long as it is a compound in which an acid and an alcohol hydroxyl group are bonded, and is preferably an ester of the compound represented by the formula (I). Means a compound having an ester bond with a known acid (not limited to a carboxylic acid ester but also a phosphate ester, a nitrate ester, a sulfate ester, etc.).

  The metabolite of the compound represented by the formula (I) is not particularly limited as long as it is a compound produced in the course of metabolism after the compound represented by the formula (I) is administered to a living body. It may be an intermediate product or a final product. For example, a compound produced from the compound represented by the formula (I) by the action of an enzyme in a living body, an enzyme produced by a microorganism in the living body, or an enzyme produced by the microorganism itself can be mentioned. For example, equol is a metabolite of daidzein, and dihydroflavonol is a metabolite of flavanone.

  As the compound represented by the formula (I), a commercially available product or a chemically synthesized product may be used. When the compound represented by the formula (I) is a compound contained in a natural product such as a plant, the compound represented by the formula (I) can be more easily obtained from the plant or the like. As long as it is a metabolite of the compound represented by the formula (I), it can also be obtained by reacting the compound represented by the formula (I) with a metabolism-related enzyme.

  For example, among the compounds represented by formula (I): Naringenin is present in grapefruit, tomato peel, etc .; Hesperetin is in lemon and orange; Genistein is found in legumes such as soybean; Therefore, it can be obtained by extracting from such plant origin. Of the metabolites of the compound represented by formula (I), equol can be produced and obtained from isoflavones by the action of specific intestinal bacteria.

For example, in the case of naringenin, it can be extracted from a tomato fruit-derived material including tomato skin by the following method.
For example, it is possible to obtain an extract containing naringenin by adding 5 to 20 times the amount of 50 to 90% ethanol to a tomato fruit-derived product containing tomato peel and performing extraction at 40 to 80 ° C. for 1 to 5 hours. it can. Naringenin can be purified by subjecting it to purification with silica gel using an organic solvent such as ethyl acetate or n-hexane as an eluent or purification with an ODS reverse phase resin using water-acetonitrile solvent as an eluent. it can. Whether or not naringenin is contained in the obtained composition can be confirmed by a conventional method such as HPLC using a standard product.

  The tomato fruit origin used as a raw material will not be specifically limited if it contains a tomato peel. The squeeze cake obtained in the process of obtaining the squeezed solution of tomato fruit is generally discarded or used as livestock feed. However, if this squeeze cake is used, the waste raw material can be used effectively, and the high concentration of naringenin Since the composition containing this can be obtained easily and efficiently, it is preferable.

  The tomato juice squeezed liquid used for tomato juice, tomato puree, tomato paste, etc. is obtained by washing and pulverizing the tomato fruit according to a conventional method, preheating it, and then squeezing it. In the process of squeezing, about 1 to 5% of the fruit is generated as a squeezed koji. Juice lees are mainly composed of pericarp and seeds, and they contain not only abundant fibers such as pectin, which is a water-soluble dietary fiber, but also cellulose and hemicellulose, which are water-soluble dietary fibers, as well as polyphenols. Can also be suitably used as a composition containing naringenin.

  The composition of the present invention is not limited to those containing only the compound represented by the formula (I) purified as described above, but includes a crude product of the compound represented by the formula (I). May be. The purified product or the crude product obtained may be used as it is as the composition of the present invention, or may be added to the following pharmaceuticals, foods and drinks, and the like.

  Proanthocyanidins used in the present invention are condensed tannins present in various plant bodies, that is, a compound group in which flavan-3-ols or flavan-3,4-diols are combined by polymerization as a constituent unit, and the acid treatment To produce anthocyanidins such as cyanidin, delphinidin and pelargonidin. There are A and B types depending on the mode of binding.

  Proanthocyanidins include procyanidins, prodelphinidins, propelargonidins and the like, which are polymers of the above structural units (dimers or more). Proanthocyanidins include various derivatives such as stereoisomers, glycosides, gallic acid esters, and caffeic acid esters of the above compounds. In the present invention, proanthocyanidins can be used as proanthocyanidins having various molecular weights (degrees of polymerization). Moreover, the proanthocyanidin composition fractionated according to molecular weight (polymerization degree) can also be used individually or in mixture.

  Proanthocyanidins can be obtained from plant bodies and microorganism bodies by any extraction method, fermentation method, chemical or enzymatic synthesis method, etc. known to those skilled in the art. The proanthocyanidins may be grape seed or skin extracts, or may be commercially available. Commercially available products containing proanthocyanidins include, for example, grape seed-derived proanthocyanidins, trade name “Gravinol” (registered trademark of Kikkoman), apple fruit-derived proanthocyanidins, trade name “Applephenon” (registered trademark of Asahi Breweries) ), Proanthocyanidins derived from coastal pine bark, trade name "Pycnogenol" (registered trademark by Hofer Research), "Flavengenol" (registered trademark by Toyo Shinyaku Co., Ltd.), and the like.

The composition of the present invention may contain 0.1 to 1,000 mg of the compound represented by formula (I) and 0.1 to 1,000 mg of proanthocyanidins.
The composition of the present invention is represented by the formula (I) in a weight ratio of 1: 10000 to 10000: 1, preferably 1: 1000 to 1000: 1, more preferably 1: 100 to 100: 1. A composition comprising 0.1 to 1,000 mg of the compound of formula (I) and 0.1 to 1,000 mg of proanthocyanidins, Also good.

  In addition to the compound of formula (I) and proanthocyanidins, the composition of the present invention may contain one or more additives.

When the composition of the present invention is used as a medicine, a pharmaceutically acceptable excipient can be added to form a pharmaceutical preparation.
The pharmaceutical preparation is not particularly limited, but is externally used for tablets, capsules, granules, fine granules, powders, liquids, syrups, chewable, troches, etc., ointments, gels, creams, patches, etc. The dosage form may be an agent, injection, sublingual, inhalant, eye drop, suppository, and the like. A preferred dosage form is an oral preparation. Moreover, the kit containing naringenin and proanthocyanidins may be used as a pharmaceutical preparation.

Compositions of the present invention include wetting agents, emulsifiers, lubricants such as sodium lauryl sulfate and magnesium stearate, and colorants, release agents, coating agents, sweeteners, fragrances, preservatives and antioxidants. It may be.
Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite and the like, (2) ascorbyl palmitate, Oil-soluble antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like, and (3) citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol And metal chelating agents such as tartaric acid and phosphoric acid.

  Pharmaceutical formulations suitable for oral administration include capsules, cachets, pills, tablets, lozenges, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil It may be in the form of a liquid emulsion, elixir or syrup of the type, and these preparations contain predetermined amounts of naringenin and proanthocyanidins as active ingredients.

  In solid dosage forms for oral administration, (1) a pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate, (2) starch, lactose, sucrose, glucose, mannitol and Bulking agents such as silicic acid, (3) carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, binders such as sucrose and acacia, (4) wetting agents such as glycerol, (5) agar, calcium carbonate, potato Or disintegrants such as tapioca starch, alginic acid, certain silicates and sodium carbonate, (6) dissolution retardants such as paraffin, (7) absorption enhancers such as quaternary ammonium compounds, (8) cetyl alcohol and Humectants such as glycerol monostearate, (9) kaolin and bentonite clay Adsorbents such as, (10) talc, calcium stearate, solid polyethylene glycols, lubricating agents such as sodium lauryl sulfate and mixtures thereof and (11) coloring agents. These excipients can be used in combination of a plurality of kinds as appropriate.

  The pharmaceutical composition may contain excipients other than those described above. In the case of capsules, tablets, and pills, the pharmaceutical preparation may contain a buffer. The solid composition may also be soft and hard gelatin capsules using fillers such as lactose or milk sugar and high molecular weight polyethylene glycols.

The dose of the composition of the present invention can be appropriately set according to the target disease and condition, the degree of the disease, the age, weight, etc. of the subject. Of the compound of formula (I) and proanthocyanidins in a weight ratio of 1: 10000 to 10000: 1, preferably 1: 1000 to 1000: 1, more preferably 1: 100 to 100: 1. The effective dosage of the composition comprising the mixture is in the range of 0.2 to 2,000 mg, preferably for example 0.4 in the mixed composition of the compound of formula (I) and proanthocyanidins consumed with food. About 200 mg / kg body weight.
In one embodiment, the daily dose of the composition of the invention taken at the beginning of the day is 1,000 mg. In another embodiment, the composition of the present invention may be taken in divided doses to give a daily dose of 1,000 mg.
In order to administer 1,000 mg of composition per typical serving, the concentration at which the composition is formulated into the food or drink will vary according to the type of food and drink and the amount of typical food and drink per serving.
For example, the composition of the present invention can be added in an amount of 0.01 to 100 mg per mL of beverage and added in an amount of 0.01 to 100 mg per 1 g of food.
The administration route of the composition of the present invention is not particularly limited and can be administered by oral administration or parenteral administration, but can be conveniently administered by oral administration.

The composition of this invention can be mix | blended with food-drinks from a viewpoint of ingestion ease.
Examples of the food and drink include supplements, foods for specified health use, functional nutritional foods, health foods, functional foods, health supplements, and normal foods and drinks.
The shape of the food and drink includes liquids such as juices, soft drinks, drinks, teas, solids such as biscuits, tablets, granule powders, powders and capsules, semi-fluid forms such as pastes, jellies, soups, seasonings, dressings, etc. Is mentioned. Any of these foods and drinks can be produced by adding the compound represented by the formula (I) and proanthocyanidins using a method known to those skilled in the art.

  Foods and drinks prevent lifestyle-related diseases (for example, obesity, hyperglycemia, hyperlipidemia, diabetes, arteriosclerosis, etc.), suppress blood glucose elevation, improve lifestyle-related diseases, promote lipid metabolism, promote carbohydrate metabolism Moreover, the food / beverage products which attached | subjected the display which has effects, such as a fat accumulation inhibitory effect, an exercise endurance improvement effect, and an exercise | movement substitute effect, may be sufficient. Moreover, the food / beverage products which attached | subjected the display to have a body fat increase inhibitory effect may be sufficient.

The intake of food and drink can be appropriately adjusted according to the use. For example, the compound represented by the formula (I) and proanthocyanidin are each 0.1 to 1000 mg / day, preferably in terms of dry matter. Can be taken in an amount of 10 to 1000 mg / day.
The number of intakes is not particularly limited, but is preferably 1 to 3 times a day, and the number of intakes may be increased or decreased as necessary.

  The food or drink is preferably a tomato processed food or drink, a citrus processed food or drink, a soybean processed food or drink, or a processed grape food. Examples of tomato processed foods and drinks include tomato juice, tomato mix juice, tomato ketchup, tomato sauce, chili sauce, tomato juice drink, solid tomato, tomato puree, tomato paste, tomato soup and the like. Examples of processed citrus foods and drinks include juices using citrus fruits such as lemon, orange and grapefruit, juices mixed with citrus fruits, solid citrus fruits, jam containing citrus fruits, puree, sauces and the like. Examples of processed soybean foods and drinks include soy milk, juice mixed with soy milk, solid soybean, soup containing soybean, sauce, and the like. Examples of processed grape foods and drinks include juices, jams, wines, grape seed oils, etc., and soups, sauces, oil pickles, etc. containing these, using grape seeds or skins as raw materials. These tomato, citrus, soybean or grape processed foods and drinks are added with the compound represented by formula (I) and proanthocyanidins in accordance with the production method (recipe etc.) of ordinary tomatoes, citrus fruits, soybeans or grape processed foods and drinks. Each is prepared according to a normal production method. For example, when it is a processed tomato food containing a high content of naringenin, which is a compound represented by the formula (I), food and drink may be prepared by adding proanthocyanidins.

  In one embodiment of the present invention, the food and drink may be in the form of a beverage or food, such as a cereal food and cake such as a cookie, a chocolate cake with nuts, a cracker, a breakfast bar, an energy bar, and corn flakes. Even baked foods may be fruit juice drinks, vegetable drinks, carbonated drinks, sports drinks, coffee or tea drinks.

  The present invention will be described in detail below with reference to examples, but the technical scope of the present invention is not limited by these descriptions.

[Example 1]
(Inhibition of blood glucose level increase by simultaneous intake of proanthocyanidins and naringenin)
Forty-one male KKAy mice (5 weeks old) (produced by CLEA Japan) were used to confirm the inhibitory effect on blood glucose level increase by naringenin and proanthocyanidins.
5 weeks old male mice were preliminarily raised on a diet AIN-93G (manufactured by Oriental Yeast Co., Ltd.) for 1 week, and then body weight, blood glucose level and HbA1c were measured, and the blood glucose and body weight were grouped so that there was no difference between groups. did.
One group was basically 9 animals, and grouping was performed as follows:
(1) Normal food group (control group);
(2) Actos (registered trademark Takeda Pharmaceutical Company Limited, Actos tablets containing 15 mg / tablet of pioglitazone were pulverized and mixed.) 0.03% mixed group;
(3) Proanthocyanidin water (GSE water: Gravinol SL (registered trademark, manufactured by Kikkoman Foods Co., Ltd.): Proanthocyanidin concentration dissolved in water to be 300 mg / 350 mL) free intake group;
(4) Naringenin (Aldrich) 1% mixed group; and (5) Proanthocyanidin free intake + Naringenin 1% mixed group;
A total of 5 groups (1, 3, 4, 5 groups: 9 animals, 2 groups: 5 animals).
Proanthocyanidins were freely consumed by drinking water. The amount of water consumed per day by the KKAy mice in the control group is about 11 to 17 g, whereas the amount of water consumed per day by the KKAy mice in the group fed with free intake of proanthocyanidin + 1% naringenin is about 5 to 5 g. 7 g, and the intake of proanthocyanidins was about 5 to 7 mg (Table 1).
Proanthocyanidin water ad libitum + Naringenin 1% dietary group showed a slight decrease in food intake during the first week, so all other food intakes were taken free from proanthocyanidin water one week after the start of the study. + Same as the 1% naringenin mixed group. The food intake of the group fed with proanthocyanidin free water + 1% naringenin was about 5 g, and naringenin was about 5 mg.

Drinking amount (g) (shown as mean ± standard error)
* Indicates a significant difference in the risk rate of 5% according to the Fisher's PLSD method of each group with respect to the control group (the same applies hereinafter).

(Measurement item and measurement method)
The test period is 4 weeks (28 days), and body weight, food intake and water consumption are measured. As needed, blood glucose level is Antsense III (manufactured by Horiba), and HbA1c is DCA2000 + (manufactured by Siemens). It was measured. After completion of the test, fat (subcutaneous, mesentery, perirenal, epididymis), gastrocnemius muscle and liver were removed and the weight of the adipose tissue was measured.
Regarding the body weight of the KKAy mice, a large increase was observed in the Actos 0.03% diet group (Table 2). On the other hand, the weight gain of the group fed with proanthocyanidin free water + naringenin 1% was smaller than that of the group containing Actos 0.03%.

Body weight (g) (shown as mean ± standard error)

  Regarding the total weight of adipose tissue, a large increase was observed in the Actos 0.03% diet group, but no increase in adipose tissue was observed in the other groups. In the dietary group of free intake of proanthocyanidin + 1% naringenin, an increase in adipose tissue weight was not observed as in the Actos 0.03% dietary group, but an increase in body weight was observed (Table 3).

Various tissue weights (g)

In the group containing the free intake of proanthocyanidin + naringenin 1%, the blood glucose level and the inhibitory effect on HbA1c elevation were observed by simultaneous intake of proanthocyanidin and naringenin (Table 4, FIG. 1). ). On the other hand, the blood glucose level and HbA1c increase inhibitory effect were not observed in the proanthocyanidin water free intake group, and the blood glucose level and HbA1c increase inhibitory effect were weak in the naringenin 1% mixed group. It was found that by taking proanthocyanidins and naringenin, a stronger blood glucose level and HbA1c increase-inhibiting effect were seen than when they were taken alone.
HbA1c (hemoglobin A1c) is a kind of glycohemoglobin. The amount of blood HbA1c is proportional to the blood glucose level from the time of erythrocyte production to the present, and is also used as a diagnostic criterion for diabetes.

Blood glucose level at any time (mg / dL) (shown as mean ± standard error)

[Example 2]
(Inhibition of blood glucose level increase by simultaneous intake of proanthocyanidins and hesperetin)
Forty blood KKKy mice (10 weeks old) (produced by CLEA Japan) were used to confirm the blood glucose level increase inhibitory effect of hesperetin and proanthocyanidins.
The body weight and blood glucose level of 10-week-old KKAy mice were measured and divided into groups so that there was no difference between groups in blood glucose and body weight.
One group was basically 10 animals, and grouping was performed as follows:
(1) Control group (0.5% CMCNa solution gavage group);
(2) GSE 10 mg / day gavage group (equivalent to GSE intake in Example 1 (per body weight));
(3) Hesperetin (manufactured by Aldrich) 52 mg / day gavage group (equivalent to naringenin intake (per body weight) in Example 1); and (4) GSE 10 mg / day + Hesperetin 52 mg / day gavage group;
A total of 4 groups. Each sample of groups 2 to 4 was dissolved in a 0.5% CMCNa (sodium carboxymethylcellulose) solution, and 0.4 mL of each group was forcibly orally administered.

(Measurement item and measurement method)
The test was conducted for 11 days, and body weight, food intake and water consumption were measured, and blood glucose level was measured using Antsense III (manufactured by Horiba, Ltd.) as needed.
Regarding the body weight of the KKAy mice, no difference was observed in each group (Table 5).

Body weight (g) (shown as mean ± standard error)

  Regarding the blood glucose level, a decrease in blood glucose level was not observed in the GSE or hesperetin alone group compared to the control group, but a decrease in blood glucose level was observed in the GSE and hesperetin simultaneous intake group (Table 6).

Blood glucose level at any time (mg / dL) (shown as mean ± standard error)

From Example 1 and Example 2, it was clarified that a synergistic blood glucose elevation inhibitory effect can be obtained by simultaneously taking naringenin or hesperetin (both flavanones) and proanthocyanidins. This combination of naringenin or hesperetin and proanthocyanidins cannot be found in nature in a single raw material.

Example 3
(Inhibition of blood glucose level increase by simultaneous intake of proanthocyanidins and genistein)
Using 40 males (13 weeks old) KKAy mice (manufactured by CLEA Japan), the effect of inhibiting the increase in blood glucose level by genistein and proanthocyanidins was confirmed.
The body weight and blood glucose level of 13-week-old KKAy mice were measured and divided into groups so that there was no difference between the groups in blood glucose and body weight.
One group was basically 10 animals, and grouping was performed as follows:
(1) Control group (0.5% CMCNa solution gavage group);
(2) GSE 10 mg / day gavage group (equivalent to GSE intake in Example 1 (per body weight));
(3) genistein (Funakoshi Co., Ltd.) 52 mg / day gavage group (equivalent to naringenin intake (per body weight) in Example 1); and (4) GSE 10 mg / day + genistein 52 mg / day gavage group;
A total of 4 groups. Each sample in groups 2 to 4 was dissolved in 0.5% CMCNa solution, and 0.4 mL of the solution in each group was orally administered by gavage.

(Measurement item and measurement method)
The test was conducted for 11 days, and body weight, food intake and water consumption were measured, and blood glucose level was measured using Antsense III (manufactured by Horiba, Ltd.) as needed.
Regarding the body weight of the KKAy mice, no difference was observed in each group (Table 7).

Body weight (g) (shown as mean ± standard error)

  Regarding the blood glucose level, a decrease in blood glucose level was not observed in the GSE alone group compared to the control group. A decrease in blood glucose level was confirmed in the genistein alone intake group, but a greater drop in blood glucose level was observed in the simultaneous intake group of GSE and genistein than in the genistein alone intake group (Table 8).

Blood glucose level at any time (mg / dL) (shown as mean ± standard error)

  It was clarified that the simultaneous intake of genistein (isoflavones) and proanthocyanidins has a synergistic effect on suppressing the increase in blood sugar. This combination of genistein and proanthocyanidins cannot be found in nature in a single raw material.

Example 4
(Manufacture of tomato processed foods and drinks containing Naringenin and Proanthocyanidins)
The production example of tomato processed food / beverage products which uses naringenin and proanthocyanidin as a part of raw material below is shown.

1. Tomato Juice Season packed tomato juice production methods include tomato washing, sorting, crushing, heating, squeezing, blending, degassing, sterilizing, filling, cooling and boxing processes. In addition, after adding naringenin and proanthocyanidins with the composition shown in Table 9, salt was added only in the case of salt, and after degassing under reduced pressure by mixing nitrogen gas, the dissolved oxygen concentration was adjusted to 3 ppm or less. , Sterilized by heating at 121 ° C. for about 1 minute, cooled to 90 ° C., and filled into cans. Moreover, the manufacturing method of a concentrated reduction product opens a tomato concentrate in an opening process, and dilutes with water to a normal salt-free soluble solid content (4.5 or more). Thereafter, naringenin and proanthocyanidins are added and prepared, and then manufactured through deaeration, sterilization, filling, cooling, and boxing processes.

2. Vegetable mixed juice Tomato juice obtained by diluting squeezed tomato juice or tomato concentrate to the specified salt-free soluble solid content (4.5 or more) with the composition shown in Table 10, various vegetable juices and Naringenin And proanthocyanidins are added and prepared, and then manufactured through deaeration, sterilization, filling, cooling, and boxing processes.

3. Tomato sauce All raw materials shown in Table 11 were mixed, nitrogen gas was mixed and degassed under reduced pressure to make the dissolved oxygen concentration 3 ppm or less, then filled into No. 2 can, 110 ° C, 30 minutes retort sterilization To do.

A production example of a processed food or drink using the compound represented by the formula (I) other than naringenin and proanthocyanidin as a part of the raw material can be produced by the same procedure as in Example 4 above.

This application claims the priority based on the Japan patent application 2011-99664 for which it applied on April 27, 2011, The content is integrated here as a reference.

Claims (6)

Formula (I):
(Where
One of R ₁ and R ₂ is represented by the following formula (II):
(Where
X _{1 to} X ₅ are each independently H, OH or OMe)
A substituted or unsubstituted benzene ring A, and the other is H or OH;
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a single bond or a double bond)
The blood glucose level raise inhibitor containing the compound and proanthocyanidin represented by these.   The blood sugar level increase inhibitor according to claim 1, wherein the proanthocyanidins are grape seed or skin extract. The compound of formula (I) is:
R ₁ is a substituted or unsubstituted benzene ring A represented by the formula (II);
R ₂ is H;
The blood glucose level elevation inhibitor according to claim 1 or 2, wherein ------ is a compound that is a single bond.   The pharmaceutical or food-drinks containing the blood glucose level raise inhibitor of any one of Claims 1-3. Formula (I):
(Where
One of R ₁ and R ₂ is represented by the following formula (II):
(Where
X _{1 to} X ₅ are each independently H, OH or OMe)
A substituted or unsubstituted benzene ring A, and the other is H or OH;
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a single bond or a double bond)
A composition for the prevention or treatment of lifestyle-related diseases and diseases related thereto, comprising a compound represented by the formula: and a proanthocyanidin. Formula (I):
(Where
One of R ₁ and R ₂ is represented by the following formula (II):
(Where
X _{1 to} X ₅ are each independently H, OH or OMe)
A substituted or unsubstituted benzene ring A, and the other is H or OH;
R _{3 to} R ₆ are each independently H, OH or OMe;
------ is a single bond or a double bond)
A composition for the prevention or treatment of diabetes, comprising a compound represented by formula (II) and proanthocyanidins.