JP6865459B2 - Insulin resistance improver - Google Patents

Description

The present invention relates to an insulin sensitizer effective for the treatment of type 2 diabetes, and more particularly to an insulin sensitizer containing a specific combination of plum vinegar polyphenol or a plurality of aglycones constituting the same as an active ingredient.

Diabetes is a disease in which the concentration of glucose in the blood is abnormally high, and type 1 accounts for about 10% of patients due to the death of insulin-secreting β-cells in the islets of Langerhans in the pancreas due to different causes. It is broadly classified into two types: diabetes and type 2 diabetes, which accounts for about 90% of patients due to decreased insulin secretion or improved insulin resistance (see Non-Patent Document 1).

Type 2 diabetes is associated with weight loss by diet and exercise therapy, self-injection of insulin, administration of insulin secretagogue, and glucose absorption inhibitors (α-glucosidase inhibitors) such as miglitol (see Non-Patent Document 2). It is mainly treated by methods such as administration and administration of an insulin resistance improving agent.

Of these, the insulin sensitizer is a drug that improves insulin resistance in the liver, muscle, adipose tissue, and the like. Insulin resistance is a state in which a normal amount or more of insulin is required to obtain the action of insulin at the cell, organ, or individual level, that is, a state in which sensitivity to insulin is reduced.

Examples of the insulin sensitizer include thiazolidinedione-based insulin sensitizers such as pioglitazone (see Non-Patent Document 3), metformin (see Non-Patent Document 4), and buformin (see Non-Patent Document 5). .) And other biguanide insulin resistance improvers are used. In addition to these insulin sensitizers, various studies have been conducted to date.

Specifically, those containing a compound having a lophenol skeleton as an active ingredient (see Patent Document 1) and those containing an extract of a lily family plant such as aloe vera as an active ingredient (see Patent Document 2). ), Those containing a compound having a cyclolanostane skeleton as an active ingredient (see Patent Document 3), those containing a sphingolipid such as sphingomyelin as an active ingredient (see Patent Document 4), fibrates. Examples thereof include those containing an extract of aloe vera microaloe as an active ingredient (see Patent Document 5) and those containing an extract such as lemon fruit as an active ingredient (see Patent Document 6).

On the other hand, umezu, which is generated in large quantities as a by-product (waste) during the production of ume products such as umeboshi, contains polyphenols (umezu polyphenols), and it has already been reported that this umezu polyphenols have various health-promoting effects. Has been done.

Specifically, glucose absorption inhibitory (α-glucosidase inhibitory) effect (see Patent Document 7), anti-fatigue effect (see Patent Document 8), blood pressure increase inhibitory effect (see Patent Document 9), antibacterial effect. (See Patent Document 10) and antiviral activity (see Patent Document 11) have been reported. However, no report has been made on the effect of umezu polyphenols on improving insulin resistance.

Japanese Patent No. 4165658 Japanese Patent No. 4169777 Japanese Patent No. 4176140 Japanese Patent No. 5154218 Japanese Patent No. 5317175 Japanese Patent No. 5563181 Japanese Patent No. 5282932 Japanese Patent No. 5634928 Japanese Unexamined Patent Publication No. 2012-171936 Japanese Patent No. 5867802 Japanese Unexamined Patent Publication No. 2014-214121

"Diabetes", [online], [Searched March 11, 2016], Internet <https://ja.wikipedia.org/wiki/Diabetes> "Miglitol", [online], [Searched March 11, 2016], Internet <https://ja.wikipedia.org/wiki/Miglitol> "Pioglitazone", [online], [Searched March 11, 2016], Internet <https://ja.wikipedia.org/Pioglitazone> "Metformin", [online], [Searched on March 11, 2016], Internet <https://ja.wikipedia.org/Metformin> "Buformin", [online], [Searched March 11, 2016], Internet <https://ja.wikipedia.org/ Buformin>

An object of the present invention is to provide an insulin resistance improving agent which is safe and highly effective and can further promote the use of umezu produced as a by-product in the production of processed ume foods. Another object of the present invention is to provide pharmaceuticals, quasi-drugs, food compositions, and feed compositions having strong insulin resistance improving activity.

As a result of diligent research, the inventors have found that a specific combination of umezu polyphenol or a plurality of aglycones constituting the umezu polyphenol has an excellent effect of improving insulin resistance, and have completed the present invention.

In other words, insulin resistance improving agents of the present invention is to t RANS-p-coumaric acid, two or more aglycone selected Ri by the group consisting of caffeic acid and ferulic acid as an active ingredient. Of these, a combination of trans-p-coumaric acid and ferulic acid, a combination of trans-p-coumaric acid and caffeic acid, or a combination of trans-p-coumaric acid, caffeic acid and ferulic acid is preferable. In addition, the pharmaceutical product, quasi-drug, and feed composition of the present invention contain the insulin sensitizer of the present invention.

As the vinegar polyphenols available insulin resistance improving agent of the present invention, (1) vinegar styrene - a contact step of contacting with divinylbenzene synthetic adsorption resin, (2) a styrene - divinylbenzene synthetic adsorption resin It is preferably obtained by a production method including a water washing step of washing the styrene-divinylbenzene with water and an elution step of (3) eluting the styrene-divinylbenzene synthetic adsorption resin with a mixed solvent of water and an organic solvent.

The production method preferably includes, in addition to the steps (1) to (3), a concentration step of concentrating the eluate obtained by the steps (4) and (3). 3) The mixed solvent of water and the organic solvent used in the elution step is preferably an aqueous ethanol solution.

The fasting blood glucose level increase inhibitor of the present invention separately captures the fasting blood glucose level increase inhibitory action as one aspect of the insulin resistance improving action of the insulin resistance improving agent of the present invention as a trans-. The active ingredient is two or more aglycones selected from the group consisting of p-coumaric acid, caffeic acid and ferulic acid.

In the above, "suppression of fasting blood glucose level increase" means that the increase of fasting blood glucose level is relatively suppressed by ingestion of the fasting blood glucose level increase inhibitor as compared with the case of non-ingestion. Good, including cases that lower high fasting blood glucose levels.

Since the insulin sensitizer of the present invention has an excellent insulin resistance improving effect, the quality of life of the patient can be improved. Further, since the insulin sensitizer of the present invention is derived from food, it is guaranteed to have high safety, and therefore, it can be expected that it can be used for a long period of time. Furthermore, since the insulin resistance improving agent of the present invention uses umezu, which is generated during the production of ume-derived foods such as umeboshi, as a raw material, industrial waste can be reduced.

FIG. 1 is a graph showing the results of confirming the insulin resistance improving effect of umezu polyphenol. FIG. 2 is a graph showing the results of comparing the effects of differences in aglycones, which are constituents of umezu polyphenols, on the improvement of insulin resistance. FIG. 3 is a graph showing the results of comparing the effects of different combinations of aglycones on the improvement of insulin resistance.

1. 1. Insulin resistance improving agent The insulin resistance improving agent of the present invention contains umezu polyphenol or a plurality of aglycones constituting the same as an active ingredient. Here, umezu polyphenol contains many kinds of components, and the structure of these components is dominated by hydroxycinnamic acid derivatives such as glycosides in which the non-sugar portion (aglycone) is hydroxycinnamic acid.

The main components of aglycone constituting umezu polyphenols are trans-p-coumaric acid, caffeic acid and ferulic acid. By combining two or more of these aglycones, they exhibit a better insulin resistance improving effect than when used alone. Specifically, a combination of trans-p-coumaric acid and ferulic acid, a combination of trans-p-coumaric acid and caffeic acid, or a combination of trans-p-coumaric acid, caffeic acid and ferulic acid is shown as a preferable combination. ..

The umezu polyphenol of the present invention is preferably produced by (1) contact step, (2) washing step, and (3) elution step. Further, it is more preferable to include (4) a concentration step. Therefore, each step (1) to (4) will be described in detail below.

(1) Contact step The contact step is a step of bringing umezu into contact with a styrene-divinylbenzene synthetic adsorption resin. The contact between the two can be performed by either a batch method in which umezu and an adsorbent resin are mixed in a large container, or a continuous method using a column in which the adsorbent resin is packed in a column. Above all, the continuous method using a column is preferable because mass processing, labor saving, and automation are possible.

As the styrene-divinylbenzene synthetic adsorption resin, a known resin can be used without particular limitation as long as polyphenols can be selectively adsorbed and eluted. Specifically, Diaion (registered trademark) HP20, HP21, Sepabeads (registered trademark) SP70, SP700, SP825L, SP850, etc. (all manufactured by Mitsubishi Chemical Corporation) can be exemplified. Of these, Diaion (registered trademark) HP20 and Sepabeads (registered trademark) SP70 are preferable.

(2) Water washing step The water washing step is a step of washing the styrene-divinylbenzene synthetic adsorption resin with water. By this step, citric acid, salt and the like contained in umezu are washed with water from a styrene-divinylbenzene-based synthetic adsorption resin.

(3) Elution Step The elution step is a step of eluting a styrene-divinylbenzene-based synthetic adsorption resin with a mixed solvent of water and an organic solvent. The organic solvent is not particularly limited as long as it is mixed with water, and specific examples thereof include alcohols having 1 to 5 carbon atoms and acetone. Of these, ethanol and acetone are preferable, and ethanol is more preferable. The organic solvent may be used alone or in combination of two or more.

As for the mixing ratio of water and the organic solvent, the ratio of the organic solvent is preferably 30 to 90% by volume, more preferably 50 to 60% by volume. If the proportion of organic solvent is lower than 30% by volume, the yield of umezu polyphenols will decrease, and if it is higher than 90% by volume, the solvent may explode, causing safety problems.

(4) Concentration Step The concentration step is a step of concentrating the eluate obtained by the elution step. The form after concentration may be, for example, a highly viscous liquid or a powdery solid, depending on the intended use. The concentration method can be used without particular limitation as long as it is a known method. Specific examples thereof include an ultrafiltration method, a drying method such as spray drying and freeze-drying, and a method of adding a modeling agent such as dextrin to perform modeling treatment.

(5) Others When producing the plum vinegar polyphenol of the present invention, in addition to the above steps (1) to (4), a step of regenerating the styrene-divinylbenzene synthetic adsorption resin with an organic solvent and a mixed solvent are used. Steps such as a step of distilling and regenerating may be added as needed.

2. Pharmaceuticals and the like The pharmaceuticals, quasi-drugs, food compositions and feed compositions of the present invention contain the insulin sensitizer of the present invention. The content of the insulin resistance improving agent in pharmaceutical products, quasi-drugs, food compositions and feed compositions should be freely set in consideration of the improving effect of the insulin resistance improving agent used and its use. Can be done.

(1) Pharmaceuticals Pharmaceuticals are those stipulated in the Pharmaceuticals and Medical Devices Act, and include all medical drugs for humans, over-the-counter drugs for humans (OTC), and veterinary drugs. Further, regarding the form, for example, pills, liquids, powders, granules, tablets, capsule tablets, troches, syrups, dry syrups, suspensions, emulsions, elixirs and other oral preparations and injections. , Suppositories, external liquids, parenteral preparations such as coatings such as ointments, etc., but are not limited thereto.

When the pharmaceutical product of the present invention is produced as an oral preparation, known excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, odorants, coloring agents, etc. At the same time, it may be produced by a known production method.

When the pharmaceutical product of the present invention is produced as a parenteral preparation, distilled water for injection, saline diluent, diluent such as glucose aqueous solution, known fungicides, preservatives, stabilizers, isotonic agents , Stabilizers, preservatives, and soothing agents, and may be produced by a known method.

(2) Quasi-drugs Quasi-drugs are defined in the Pharmaceuticals and Medical Devices Act, and include, for example, nutritional supplements, but are not limited to these. Absent.

(3) Food composition The food composition means general foods for humans, foods with health claims (foods for specified health uses, foods with nutritional claims), health foods, nutritional supplements, and the like. As foods, specifically, processed marine products such as kamaboko, chikuwa, and spread, processed meat products such as sausage, ham, and wiener, processed agricultural products such as tofu, fried tofu, and konyaku, western confectionery, Japanese confectionery, bread, and cake. Confectionery such as ki, jelly, pudding, snacks, cooks, gum, candy, ramune, noodles such as raw noodles, Chinese noodles, buckwheat noodles, udon noodles, sauces, soy sauce, dressings, mayonnaise, sauce, honey, powder Processing of seasonings such as candy and water candy, spices such as curry powder, mustard powder, and pepper powder, jams, marmalades, chocolate spreads, pickles, soybeans, sprinkles, and canned and bottled various vegetables and fruits. Dairy products such as vegetables / fruits, cheese, butter, yogurt, fruit juices, vegetable juices, dairy drinks, soft drinks, health teas, medicated liquor drinks, and other nutritional supplements Examples include, but are not limited to, health-oriented foods and drinks such as tablets, beverages, and granules for maintaining health for the purpose of (nutrition supplement) and the like.

(4) Feed composition The feed composition is the feed of animals other than humans. Non-human animals include, for example, pet animals such as dogs and cats, ornamental birds such as canaries and inco, ornamental fish such as goldfish and tropical fish, domestic animals such as cows, pigs, sheep and horses, and poultry such as chickens. Examples include, but are not limited to, farmed fish such as bristle, madai, and flatfish.

Hereinafter, the present invention will be described in more detail based on examples. The scope of claims of the present invention is not limited in any sense by the following examples.

1. 1. Production of umezu polyphenol The umezu polyphenol of the present invention was produced by the following production method. First, Diaion (registered trademark) HP20 resin (styrene-divinylbenzene synthetic adsorbent, manufactured by Mitsubishi Chemical Corporation) was packed in a sealed metallic column (Φ30 cm × 200 cm). A 30 to 40 times amount (volume ratio) of umezu was poured through this column and contacted with the resin, and the umezu polyphenol was adsorbed on the resin (contact step). The column on which the umezu polyphenol was adsorbed was flushed with 4 times the amount (volume ratio) of water with respect to the resin packed in the column, and the citric acid and salt in the column were washed with water (water washing step).

An aqueous ethanol solution (60% by volume) was poured over a washed column to obtain an eluate containing umezu polyphenols. Finally, the eluate was concentrated and dried by a vacuum freeze-dryer to obtain a powder containing umezu polyphenol (concentration step). From 15 tons of umezu, 15.7 kg of this powder was obtained.

Polyphenols in the powder were measured according to the Folin-Ciocalteu method. As a result, it was found that the powder contained 11.5% by weight (hereinafter abbreviated as%) of polyphenol in terms of gallic acid. The total sugar was measured by the phenol-sulfuric acid method, the water content was measured by the dry weight loss method (90 ° C., 7 hours), the ash content was measured by the 550 ° C. ashing method, and the organic acid content was measured by the HPLC method. As a result, it was found that the powder contained 64.5% of total sugar, 3.9% of water, 2.6% of ash, 0.2% of citric acid, and 2.2% of quinic acid in addition to umezu polyphenol.

Furthermore, the constituents of hydroxycinnamic acid, which is an aglycone of umezu polyphenol, were investigated. Specifically, the powder was alkaline-decomposed and then measured by an HPLC method. As a result, it was found that trans-p-coumaric acid was 2%, caffeic acid was 1.1%, ferulic acid was 1.1%, and cis-p-coumaric acid was 0.5%.

2. Effect of Plum Vinegar Polyphenol on Insulin Resistance Improvement Effect in Diet-Induced Obese Mice In order to investigate the effect of intake of plum vinegar polyphenol on insulin resistance induced by obesity, fasting blood glucose with and without the intake of plum vinegar polyphenol of the present invention. The values, fasting insulin concentration, and insulin resistance index (HOMA-IR value) calculated from both values were compared. In addition, in order to confirm that insulin resistance was progressing due to obesity induction, a group fed with a normal diet was provided as a control group. The details of the experiment are described below.

(1) Experimental animals and test materials
A 5-week-old male C57BL / 6JKwl mouse (SPF, Kiwa Experimental Animal Research Institute, Inc., average body weight 16 g, light period: 6:00 to 18:00) was used as an experimental animal. In addition, MF (manufactured by Oriental Yeast Co., Ltd.) was used as the normal diet to be ingested by mice, and HFD-60 (manufactured by Oriental Yeast Co., Ltd.) was used as the high-fat diet. Further, the umezu polyphenol used was the one produced in Example 1, and the cellulose used was the one obtained from Nacalai Tesque Co., Ltd. Table 1 shows the components of the normal diet and the high-fat diet.

(2) Experimental method 1) Acclimation and grouping Mice (22 animals) were bred in a breeding facility for 7 days from the start of the experimental test and acclimated, and on the 7th day, the weight and food intake were significant between the groups. They were divided into 4 groups of 5-6 animals so that there would be no difference. Specifically, normal diet group (Normal, n = 5), high-fat diet + 1% cellulose group (HF, n = 6), high-fat diet + 0.25% umezu polyphenol (hereinafter, UP if necessary) It was divided into a + 0.75% cellulose group (UP0.25%, n = 5) and a high-fat diet + 1% umezu polyphenol group (UP1%, n = 6).

2) Induction and measurement of obesity For each group of mice, a high-fat diet (MF), a high-fat diet (HFD-60) mixed with 1% cellulose, a high-fat diet with 0.25% umezu polyphenol and 0.75 A feed mixed with% cellulose and a high-fat diet mixed with 1% umezu polyphenol were fed for 5 weeks. During breeding, body weight and food intake were measured every 3 days. Five weeks after the start of the experiment, after fasting for 16 hours, the fasting blood glucose level and the fasting insulin concentration were measured, and the HOMA-IR value was calculated.

The fasting blood glucose level was measured by fasting the mice for 16 hours, collecting blood from the tail vein, and using a blood glucose meter (Glucest Neo Super, Sanwa Kagaku Kenkyusho). The "fasting blood glucose level" was calculated by measuring the same sample three times and calculating the average value.

The fasting insulin concentration was determined by fasting the mice for 16 hours, then opening the abdomen under anesthesia and collecting blood from the aorta. The collected blood was allowed to stand at room temperature for 30 minutes and then centrifuged at 3000 rpm for 20 minutes to obtain serum. The serum insulin concentration was measured using the ELISA method (ultra-sensitive mouse insulin measurement kit, Morinaga Biochemical Research Institute). For "fasting insulin concentration", the same sample was measured three times, and the average value was calculated.

Furthermore, the HOMA-IR value was calculated according to the following formula (I). The conversion formula from insulin concentration to enzyme unit (IU) used was 1 ng / mL = 26 μIU / mL.

3) Statistical processing Average weight gain (g / 5week), average dietary intake (g / day), fasting blood glucose level (mg / dL), fasting insulin concentration (ng / mL), and HOMA-IR value The value and standard deviation were calculated. In addition, it was confirmed by t-test whether the values of each group showed a significant difference with respect to the high-fat diet group.

(3) Experimental results The experimental results are shown in Table 2 and FIG. Table 2 is a table summarizing the calculated values, and FIG. 1 is a graph of the fasting blood glucose level, the fasting insulin concentration, and the HOMA-IR value shown in Table 2. From Table 2 and FIG. 1, it was found that the addition of umezu polyphenols tended to reduce the fasting blood glucose level, fasting insulin concentration, and HOMA-IR level in a concentration-dependent manner as compared with the high-fat diet group. It was. In particular, in the umezu polyphenol 1% group, the HOMA-IR value, which is an index of insulin resistance, was significantly reduced (p <0.05) as compared with the high-fat diet group, and decreased to the same level as the normal diet group. I found out.

3. 3. Aglycone-improving effect on insulin resistance in diet-induced obese mice Aglycones constituting umezu polyphenols were ingested by mice together with a high-fat diet, and the effects of these substances on insulin resistance were compared with umezu polyphenols. Specifically, the experiment was conducted as follows.

(1) Experimental animals and test substances The same experimental animals, normal diet, high-fat diet, and cellulose as in Example 2 were used. The umezu polyphenol used was the one prepared in Example 1, and the trans-p-coumaric acid, caffeic acid, and ferulic acid were obtained from Wako Pure Chemical Industries.

(2) Experimental method 1) Acclimation and grouping 37 mice acclimatized in the same manner as in Example 2 were subjected to a normal diet group (n = 4), a high-fat diet group (n = 5), and a high-fat diet + 1% UP. Group (n = 6), high-fat diet + 0.02% coumaric acid group (n = 5), high-fat diet + 0.011% caffeic acid group (n = 5), high-fat diet + 0.011% ferulic acid group (n = 5) It was divided into 7 groups: n = 5), high-fat diet + 0.02% coumaric acid + 0.011% caffeic acid + 0.011% ferulic acid group (3 types mixed group, n = 5).

As for the concentration of aglycone contained in each group, as described in Example 1, umezu polyphenol contains trans-p-coumaric acid 2%, caffeic acid 1.1%, and ferulic acid 1.1% as aglycone. It was set based on the fact that there is. In addition, the 6 groups fed with a high-fat diet were adjusted by adding cellulose so that their calorie intakes were the same.

2) Obesity induction, measurement and statistical processing After inducing obesity in the mice of each group in the same manner as in Example 2, the fasting blood glucose level and the fasting insulin concentration were measured to calculate the HOMA-IR value. Moreover, the calculated value was statistically processed in the same manner as in Example 2.

The "fasting blood glucose level" was measured using a more accurate measurement method, the glucose oxidase / peroxidase (GOD / POD) method (glucose CII-Test Wako, Wako Pure Chemicals). The "fasting blood glucose level" was calculated by measuring the same sample three times and calculating the average value. Moreover, the fasting insulin concentration was measured in the same manner as in Example 2, and the average value thereof was calculated.

(3) Experimental results The experimental results are shown in Table 3 and FIG. Table 3 is a table summarizing the calculated values, and FIG. 2 is a graph of the fasting blood glucose level, the fasting insulin concentration, and the HOMA-IR value shown in Table 3. From FIG. 2 and Table 3, it was found that the fasting blood glucose level was significantly reduced in the plum vinegar polyphenol, trans-p-coumaric acid, caffeic acid, ferulic acid intake group, and the triple-mixed group as compared with the high-fat diet group. It was. It was also found that the fasting insulin concentration was lower in the ferulic acid intake group than in the high-fat diet group, and was significantly reduced in the three-kind mixed group. Furthermore, it was found that the HOMA-IR value was lower in the coumaric acid intake group than in the high-fat diet group, and significantly decreased in the 1% umezu polyphenol, ferulic acid, and triple intake group.

From the above results, among the three types of aglycone molecules (trans-p-coumaric acid, caffeic acid, and ferulic acid) constituting the umezu polyphenol, ferulic acid had the highest effect of improving insulin resistance. That is, it is suggested that the active body of the insulin resistance improving effect of umezu polyphenol is a ferulic acid derivative, and ferulic acid generated by decomposition in the digestive tract after ingestion of umezu polyphenol is absorbed in the body and insulin resistance. It was considered that the improvement effect was shown.

In addition, some ferulic acid derivatives in umezu polyphenols have poor digestibility and are difficult to be absorbed by the body. Therefore, in the 0.011% ferulic acid alone intake group and the 1% plum vinegar polyphenol group adjusted so that the ferulic acid content is the same, the ferulic acid absorption efficiency is higher in the single intake group, and the fasting blood glucose level and fasting It is probable that the decrease in insulin concentration and HOMA-IR value increased.

Trans-p-coumaric acid, an aglycone molecule that constitutes umezu polyphenols, showed a tendency to lower fasting blood glucose and resist HOMA-IR values. Caffeic acid also showed an effect of lowering fasting blood glucose. When three types of aglycone molecules were ingested at the same time, they showed a stronger insulin resistance improving effect than when they were ingested alone. Therefore, these three types of aglycone molecules work cooperatively to improve insulin resistance. It has been suggested.

4. Insulin resistance improving effect of multiple aglycones in diet-induced obese mice From Example 3, among the main aglycones constituting umezu polyphenols, ferulic acid most improves insulin resistance, and it is better to combine three types of aglycones. It was found that insulin resistance improved.

Therefore, we examined the effect of different combinations of aglycones on insulin resistance by ingesting mice with a high-fat diet in combination of multiple aglycones. Specifically, the experiment was conducted as follows.

(1) Experimental animals and test substances The same experimental animals as in Example 3, high-fat diet, cellulose, trans-p-coumaric acid, caffeic acid, and ferulic acid were used.

(2) Experimental method 1) Acclimation and grouping 31 mice acclimatized in the same manner as in Example 3 were subjected to a high-fat diet group (n = 5) and a high-fat diet + 0.042% ferulic acid group (n = 6). , High-fat diet 0.011% ferulic acid + 0.02% coumaric acid + 0.011% caffeic acid group (3 types mixed group, n = 6), high-fat diet + 0.011% ferulic acid + 0.02% coumaric acid group (n = 5) , High-fat diet 0.011% ferulic acid + 0.011% caffeic acid group (n = 5), high-fat diet 0.02% coumaric acid 0.011% caffeic acid group (n = 4).

As for the concentration of aglycone contained in each group, as described in Example 1, umezu polyphenol contains trans-p-coumaric acid 2%, caffeic acid 1.1%, and ferulic acid 1.1% as aglycone. It was set based on the fact that there is. In addition, each group was adjusted by adding cellulose so that the caloric intake was the same.

2) Obesity induction, measurement and statistical processing After inducing the diet of the mice in each group in the same manner as in Example 3, the fasting blood glucose level and the fasting insulin concentration were measured to calculate the HOMA-IR value. Moreover, the calculated value was statistically processed in the same manner as in Example 3.

(3) Experimental results The experimental results are shown in Table 4 and FIG. Table 4 is a table summarizing the calculated values, and FIG. 3 is a graph of the fasting blood glucose level, the fasting insulin concentration, and the HOMA-IR value shown in Table 4. From Table 4 and FIG. 3, the fasting blood glucose level showed the same level as or lower than the ferulic acid group in the three-kind mixed group and any two-kind mixed group. In particular, the triple-mixed group showed a tendency to lower fasting blood glucose (P <0.1) more than the ferulic acid group, and the coumaric acid + ferulic acid group significantly lowered fasting blood glucose than the ferulic acid group (P <0.05). ) Was confirmed.

In addition, the fasting insulin concentration tended to decrease in the three-kind mixed group and any two-kind mixed group as compared with the ferulic acid group (P <0.1). In particular, it was confirmed that in the coumaric acid + ferulic acid group and the coumaric acid + caffeic acid group, the fasting insulin concentration was significantly reduced (P <0.01) as compared with the ferulic acid group.

Furthermore, the HOMA-IR value tended to decrease in the three-kind mixed group and any two-kind mixed group as compared with the ferulic acid group (P <0.1). In particular, the HOMA-IR value was significant in the three-kind mixed group (P <0.05), coumaric acid + ferulic acid group (P <0.01), and coumaric acid + caffeic acid group (P <0.01) as compared with the ferulic acid group. It was confirmed that it decreased to.

From the above results, among the three types of aglycones (trans-p-coumaric acid, caffeic acid, and ferulic acid) constituting the plum vinegar polyphenol, the ferulic acid + coumaric acid group had the highest effect of improving insulin resistance. That is, it was considered that coumaric acid greatly improved the improvement of insulin resistance of ferulic acid. In addition, a certain significant difference was also observed in the coumaric acid + caffeic acid group and the three-kind mixed group.

Claims (9)

An insulin sensitizer containing two or more aglycones selected from the group consisting of trans-p-coumaric acid, caffeic acid and ferulic acid as active ingredients. The insulin resistance improving agent according to claim 1, which contains trans-p-coumaric acid and ferulic acid as active ingredients. The insulin resistance improving agent according to claim 1, which contains trans-p-coumaric acid and caffeic acid as active ingredients. The insulin sensitizer according to claim 1, which contains trans-p-coumaric acid, caffeic acid and ferulic acid as active ingredients. A drug for improving insulin resistance, which comprises the insulin sensitizer according to any one of claims 1 to 4. A quasi-drug for improving insulin resistance, which comprises the insulin sensitizer according to any one of claims 1 to 4. A food composition for improving insulin resistance, which comprises the insulin sensitizer according to any one of claims 1 to 4. A feed composition for improving insulin resistance, which comprises the insulin sensitizer according to any one of claims 1 to 4. A fasting blood glucose increase inhibitor containing two or more aglycones selected from the group consisting of trans-p-coumaric acid, caffeic acid and ferulic acid as active ingredients.

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