JP2006193502A - Adiponectin regulating agent and food, drink, food additive and medicine containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an adiponectin regulating preparation derived from natural materials, having high safety, effective for increasing the adiponectin level and exhibiting adiponectin regulating action. <P>SOLUTION: The adiponectin regulating agent contains an apple extract as an active component. Preferably, the apple extract is a polyphenol derived from an apple. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an adiponectin regulator obtained from an apple, a food and drink containing the same, a food additive, and a medicine.

  There are an estimated 7 million diabetic and obese Japanese patients, and the number is still increasing. General type II diabetes and obesity, which accounts for the majority of diabetes, is a multifactor disease that develops by combining multiple causative genes and overlapping environmental factors such as lifestyle habits. The greatest cause of increased diabetes and obesity is considered to be the increase in insulin resistance due to lifestyle habits, such as the westernization of dietary habits, particularly high fat diet and decreased physical activity.

  Currently, arteriosclerotic diseases occupy a large position alongside cancer in the Japanese cause of death statistics, and many of them suddenly develop in work, causing extremely large losses both socially and at home. Therefore, the establishment of effective preventive and therapeutic measures is an essential issue (Non-patent Document 1).

  Adiponectin was discovered as a secreted protein that is highly expressed specifically in adipocytes. In later studies, anti-arteriosclerosis such as adhesion of monocytes to vascular endothelial cells and suppression of smooth muscle cell proliferation were suppressed. It became clear that it has the effect.

Regarding the relationship with diabetes, adiponectin in blood was correlated with the decrease of adiponectin in the animal model, type II diabetic monkey as insulin resistance progressed, and the glucose uptake index (M value) in the glucose clamp. Has been shown to rise (Non-Patent Document 2). In addition, administration of adiponectin at physiological concentrations to type II diabetic mice (db / db mice, KKA ^y mice) can improve insulin resistance, and can improve insulin resistance in fat-deficient mice. It has been shown that reduced expression or deficiency of adiponectin is responsible for obesity insulin resistance, and thus obesity and type 2 diabetes (Non-Patent Document 3).

  In addition, it has been reported that coronary artery disease patients and obese patients have lower blood levels of adiponectin than healthy individuals.

  As described above, adiponectin, a protein specific to adipose tissue, has been known to have vascular smooth muscle proliferation, migration inhibitory action, anti-arteriosclerotic action, monocyte and macrophage activation inhibitory action, anti-inflammatory action, etc. Furthermore, recent studies have confirmed that they have an effect of suppressing liver fibrosis and promoting normal hepatocyte proliferation.

Therefore, there is an urgent need to establish a fundamental prevention method and treatment method for such lifestyle-related diseases.
Guidelines for the treatment of arteriosclerotic diseases, Japan Atherosclerosis Society, 2002 DIABETES Vol.50: 1126/1133 (2001) Nature Medecine Vol. 7: 941-946 (2001)

  Dissemination of drug treatment is easily dependent on drugs, and there is a possibility that lifestyle improvement will not be sufficiently performed. However, at present, no satisfactory product has been found in that it is derived from natural products, has a wide range of functionalities for lifestyle-related diseases, and has a very low possibility of side effects. An adiponectin regulator that satisfies the properties is highly desired.

  The problem to be solved by the present invention is to provide an adiponectin regulator, food / beverage product, food additive or medicine that has the effect of increasing adiponectin, is naturally derived and highly safe, and has an adiponectin regulating action. .

  As a result of intensive studies to solve the above problems, the present inventors have found that an apple extract has an adiponectin regulating action, and have completed the present invention.

That is, the present invention has the following contents.
(1) An adiponectin regulator comprising an apple extract as an active ingredient.
(2) The adiponectin regulator according to (1), wherein the apple extract is an apple-derived polyphenol.
(3) Food / beverage products containing the adiponectin regulator as described in (1) or (2).
(4) A food additive containing the adiponectin regulator according to (1) or (2).
(5) A medicament comprising the adiponectin modulating agent according to (1) or (2).

  The adiponectin regulator comprising the apple extract of the present invention as an active ingredient can raise adiponectin with very few side effects.

  In addition, foods and drinks, food additives and medicines containing the above-mentioned adiponectin modulator as an active ingredient can raise adiponectin with very few side effects.

  Reduced or deficient adiponectin expression has been shown to be responsible for obesity insulin resistance and thus obesity and type II diabetes. Furthermore, it has been reported that coronary artery disease patients and obese patients have lower blood levels of adiponectin than healthy individuals. Therefore, the adiponectin regulator in the present invention refers to a substance that normally regulates the blood concentration of adiponectin.

  The apple-derived polyphenol in the present invention contains the derived polyphenol as an active ingredient in the apple extract. The adiponectin regulator in the present invention may be either an apple extract or an apple-derived polyphenol, but is preferably an apple-derived polyphenol. Apple-derived polyphenols with a high degree of purification have high processing applicability, such as being less likely to cause turbidity and turbidity when added to foods and drinks, and also capable of suppressing the influence of flavor on foods and drinks themselves.

  The apple extract containing apple-derived polyphenol used in the present invention is extracted by known extraction means from fruits of the family Rosaceae, for example, cultivars such as Fuji, Mutsu, Tsugaru, Starking Delicious, and original apples Is obtained.

  Although both mature and immature fruits can be used as fruits, immature fruits are particularly preferred because they contain more polyphenol compounds and contain a large amount of various active ingredients having a wide range of physiological effects.

  The apple-derived polyphenol contained in the apple extract of the present invention is composed of a polyphenol fraction purified from an apple fruit or an unripe fruit juice juice extract, but the polyphenol fraction is purified, It is carried out by treating the juice juice and the extract with an adsorbent, and polyphenol is contained in a fraction adsorbed on the adsorbent (hereinafter referred to as an adsorbed fraction). The adsorbent is not particularly limited as long as it adsorbs polyphenol. For example, hydrophilic vinyl polymer resin (“Toyopearl HW40” manufactured by Tosoh Corporation), styrene-divinylbenzene resin (“Separbeads SP-850” manufactured by Mitsubishi Chemical Corporation). ) And gel type synthetic resin (“Diaion HP-20” manufactured by Mitsubishi Chemical Corporation).

  The polyphenol fraction is purified by eluting the adsorbed fraction adsorbed on the adsorbent with an alcohol solvent such as water-containing ethanol. The polyphenol fraction can then be concentrated to obtain a liquid formulation, and further, a powder formulation can be obtained by spray drying or freeze-drying the liquid formulation.

  As an extraction method of an apple extract that is a raw material for apple-derived polyphenols, for example, the washed raw material is crushed at pH 3.2 to 4.6, preferably pH 3.5 to 4.3, and pectinase is added to the obtained fruit juice. Clarification is performed at 10 to 100 ppm, preferably 20 to 30 ppm at ˜75 ° C., preferably 30 to 60 ° C., and after centrifugation, diatomaceous earth (trade name “Silica 300S” at 5 to 75 ° C., preferably 15 to 25 ° C. Further, clarification is performed by filtration to obtain a clarified fruit juice. Alternatively, partitioning with an organic solvent such as hexane and chloroform and filtration can be performed to obtain an apple extract as a clarified extract.

  In order to obtain an apple-derived polyphenol from an apple extract, the clarified extract is then 0 to 40 ° C, preferably 15 to 25 ° C, pH 1.5 to 4.2, preferably pH 3.0 to 4.0. Is passed through an adsorption column (trade name “Separbeads SP-850”, manufactured by Mitsubishi Chemical Corporation) to adsorb polyphenols. Subsequently, pure water is passed through to remove non-adsorbing substances (saccharides, organic acids, etc.) in the column, and then the adsorbed fraction is eluted with 10 to 90%, preferably 30 to 80% ethanol. Ethanol is distilled off from the obtained adsorbed fraction under reduced pressure at 25 to 100 ° C., preferably 35 to 90 ° C., and the concentrated solution may be used as it is as a liquid apple-derived polyphenol. Or powder auxiliary agents, such as dextrin, may be added, spray-drying or freeze-drying may be carried out, and it may be set as the extraction powder product of an apple origin polyphenol.

  The daily dose for adults to obtain the effect of regulating adiponectin with the adiponectin modulating agent of the present invention is 100 to 2500 mg, preferably 150 to 1500 mg as apple extract or apple polyphenol. It is preferably 150 to 1000 mg, particularly 150 to 750 mg.

  When using the adiponectin regulating agent of the present invention, in terms of absorption of polyphenols, the blood concentration of polyphenols is higher when the amount of apple extract per day or the amount of polyphenol derived from apples is ingested less frequently. It is easy to develop a similar action.

  The adiponectin regulating agent of the present invention can be used by adding as a food additive to foods in general, including beverages, such as soups, beverages (juice, liquor, mineral water, coffee, tea, non-alcoholic beer, etc.) Suitable for confectionery (gum, candy, chocolate, snacks, jelly, etc.), noodles (soba, udon, ramen, etc.), alcoholic beverages (beer, sparkling liquor, cocktail, Chuhai, shochu, sake, whiskey, brandy, wine, etc.) Used for.

  The pharmaceutical dosage form containing the adiponectin modulating agent of the present invention is not particularly limited, but for example, solid preparations such as tablets, powders, fine granules, granules, capsules, pills, liquid preparations, suspensions, syrups, Oral administration agents such as liquids such as emulsions can be mentioned. This orally administered agent includes excipients, disintegrants, binders, lubricants, surfactants, alcohols, water, water-soluble polymers, sweeteners, flavoring agents, It can be produced by a commonly used method by adding a sour agent, a pharmaceutical carrier and the like.

Examples Next, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

(Production Example 1)
300 kg of apple fruit from Aomori Prefecture was crushed and pressed to obtain 210 kg of fruit juice. The obtained fruit juice was clarified with 30 ppm of pectinase, and after centrifugation, clarification was performed by filtration through diatomaceous earth (silica 300S, manufactured by Chuo Silica Co., Ltd.) to obtain a clarified fruit juice. The clarified juice was passed through an adsorption column (Separhees SP-850, manufactured by Mitsubishi Chemical Corporation) to adsorb polyphenols. Subsequently, pure water was passed through to remove non-adsorbed substance chambers (sugars, organic acids, etc.) in the column, and then eluted with 80% alcohol. Alcohol was concentrated under reduced pressure from the obtained fraction to prepare about 2 kg of an extracted powder product. When the extracted powder product was assayed using reversed-phase high performance liquid chromatography, chlorogenic acids (about 20%), fluorethylene glycosides (about 5%), flavonols (about 15%), proanthocyanidins (about 50%) %) And other browning substances (about 10%). Furthermore, these procyanidins are analyzed by a matrix-assisted laser ionization-time-of-flight mass spectrometer (MALDI-TOF / MS, manufactured by Applied Biosystems). It was confirmed to be an oligomer or polymer from the body to the 15-mer. (M. Ohnishi-kameyama et al. Mass Spectrometry, 11, 31, -36, 1997)

(Comparative Example 1) Tablet 140 g of lactose and 17 g of corn starch were mixed, and this mixture was granulated with a paste prepared in advance from 70 g of corn starch. 1 g of magnesium stearate was added to the obtained granules and mixed well, and the mixture was tableted with a tableting machine to produce 1000 tablets.

Example 1 Tablet
150 g of apple polyphenol obtained in Production Example 1, 90 g of lactose, and 17 g of corn starch were mixed, and this mixture was granulated with a paste prepared in advance from 70 g of corn starch. 1 g of magnesium stearate was added to the obtained granules and mixed well, and the mixture was tableted with a tableting machine to produce 1000 tablets.

(Test Example 1) Fat accumulation inhibitory action of apple polyphenol (human)
Next, a clinical trial examined the action of apple polyphenols to suppress fat accumulation.

[Method]
1) Subjects Among the male and female over 20 years old who volunteered to participate in this study among paid volunteers, in a preliminary study conducted 4 weeks before the start of the study, the body mass index showed 22 <BMI ≤ 30 I chose a name. However, those who are taking medicines and health foods that may affect lipid metabolism, those who have a history of food allergies, 200 ml within 1 month of this study, or 400 ml within 3 months Excluded were those who collected blood (such as blood donation) exceeding the limit, or those judged by the investigator to be inappropriate for study participation. Based on the results of preliminary examinations (blood, physical examination) and CT examinations conducted before ingestion by doctors who do not participate directly in the trial, the age, weight, height, body mass index, blood pressure, They were divided into two groups so that backgrounds such as neutral fat, total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) waist / hip were aligned. In addition, this study was conducted in accordance with the purpose of the Declaration of Helsinki, with sufficient explanations of research content and methods, etc., with the consent of documents.

2) Test meal The test meal was a tablet containing apple polyphenol produced in Example 1 (150 mg / 1 tablet) and a control meal not containing the polyphenol produced in Comparative Example 1 (placebo tablet). . In addition, before conducting the test, the investigator confirmed that there was no distinction between the test beverage and the placebo tablet due to sensory aspects such as flavor and aroma and packaging.

3) Ingestion method and schedule The study was a parallel two-group comparative study using a double-blind method with random assignment. The test period was set to a total of 20 weeks, including a pre-observation period of 4 weeks, an intake period of 12 weeks, and an observation period of 4 weeks after the end of intake. Subjects were divided into two groups and ingested test tablets as follows.

Group A: Apple polyphenol-containing test tablets (150 mg / tablet) 4 tablets each before dinner (4 tablets / day in total), the following groups of apple polyphenol test tablets
Group B: 4 placebo tablets (150 mg / tablet) each before dinner (4 tablets / day in total), the following placebo tablet intake group The subjects except for taking test tablets daily, Instruction was given not to change daily life such as eating, smoking and exercising.

4) Blood test All subjects had adiponectin, Na, Ca, Cl, K, GPT (ALT), LDH, total bilirubin, UIBC, Fe, and γ-GTP on the start of intake and 12 weeks after intake (end of intake). Measurement items of total protein, urea nitrogen, blood cell components (white blood cell, red blood cell, hemoglobin content, hematocrit value, MCV, MCH, MCHC, platelet count) were carried out. In order to avoid external effects such as food and exercise, all tests were fasted for 12 hours or longer, maintained at rest for 10 minutes or more after visiting the hospital, and blood was collected in the sitting position.

(result)
The results are shown in Table 1. Regarding adiponectin, a significant decrease was observed 12 weeks after ingestion in the placebo capsule ingestion group (p <0.001). In comparison between groups, a significant difference was observed between the placebo capsule intake group and the apple polyphenol test capsule intake group (p <0.01). In addition, no abnormality was observed from various blood tests. During the intake period, no complaining complaints were found.

  Since the adiponectin regulator which uses an apple extract as an active ingredient has few side effects and can regulate adiponectin, this invention is useful.

  In addition, foods and drinks, food additives, and medicines containing the above-mentioned adiponectin regulator as an active ingredient can adjust the amount of adiponectin in the blood because the amount of adiponectin in the blood is extremely small.

Claims (5)

An adiponectin regulator comprising an apple extract as an active ingredient. The adiponectin regulator according to claim 1, wherein the apple extract is an apple-derived polyphenol. Food-drinks containing the adiponectin regulator of Claim 1 or 2. The food additive containing the adiponectin regulator of Claim 1 or 2. The pharmaceutical containing the adiponectin regulator of Claim 1 or 2.