JP2018035073A - Insulin resistance-improving agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an insulin resistance-improving agent that is safe and effective, and can further promote usage of plum vinegar which is created as a byproduct in producing a plum processed food, and provide a medicine, quasi drug, food composition, feed composition equipped with strong insulin resistance-improving agent activity.SOLUTION: An insulin resistance-improving agent of the present invention has plum vinegar polyphenol or a combination of a plurality of aglycone constituting the polyphenol, which is specifically two kinds or more of aglycone selected from the group consisting of trans-p-coumaric acid, coffeic acid and ferulic acid, as an active ingredient. Now, it is preferable that plum vinegar polyphenol being an active ingredient be obtained by a production method including: (1) a contact process of bringing plum vinegar in contact with styrene-divinylbenzene-based synthetic adsorbent resin; (2) a cleaning process of cleaning styrene-divinylbenzene-based synthetic adsorbent resin with water; and (3) elution process of eluting styrene-divinylbenzene-based synthetic adsorbent resin with mixed solvent of water and organic solvent.SELECTED DRAWING: None

Description

  The present invention relates to an insulin resistance improving agent effective for the treatment of type 2 diabetes, and particularly relates to an insulin resistance improving agent containing, as an active ingredient, a specific combination of ume vinegar polyphenols or a plurality of aglycones constituting the same.

  Diabetes is a disease in which the glucose concentration in the blood is abnormally high, and it is a type 1 that accounts for about 10% of patients due to the death of β-cells secreting insulin in the islets of Langerhans in the pancreas due to different causes It is roughly 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 caused by dietary and exercise weight loss, self-injection of insulin, administration of insulin secretagogues, 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 sensitizer.

  Among these, an insulin resistance improving agent is a drug that improves insulin resistance of liver, muscle, adipose tissue and the like. Insulin resistance refers to a state that requires more than a normal amount of insulin in order to obtain the action of insulin at the cell, organ, and individual levels, that is, a state in which the sensitivity to insulin is reduced.

  As an insulin resistance improving agent, in addition to thiazolidinedione-based insulin resistance improving agents such as pioglitazone (see Non-patent document 3), metformin (see Non-patent document 4) and buformin (see Non-patent document 5). Biguanide insulin resistance improvers such as.) Are used. In addition to these insulin resistance improving agents, various studies have been conducted so far.

  Specifically, those containing a compound having a rophenol skeleton as an active ingredient (see Patent Document 1) and those containing a lily family plant extract such as aloe vera as an active ingredient (see Patent Document 2). ), Containing a compound having a cyclolanostane skeleton as an active ingredient (see Patent Document 3), containing a sphingolipid such as sphingomyelin as an active ingredient (see Patent Document 4), fibrates And those containing an extract of Dunaliella genus microalga as an active ingredient (see Patent Document 5) and those containing an extract of lemon fruit or the like as an active ingredient (see Patent Document 6).

  On the other hand, ume vinegar, which is generated in large quantities as a by-product (waste) during the production of plum products such as plum pickles, contains polyphenol (ume vinegar polyphenol), and it has already been reported that this ume vinegar polyphenol has various health promotion effects. Has been.

  Specifically, glucose absorption inhibition (α-glucosidase inhibition) 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 action (see Patent Document 11) have been reported. However, the insulin resistance improving effect by ume vinegar polyphenol has never been reported.

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. 5643928 JP 2012-171936 A Japanese Patent No. 5867802 JP 2014-214121 A

"Diabetes", [online], [Search March 11, 2016], Internet <https://en.wikipedia.org/wiki/Diabetes> "Miglitol", [online], [searched on March 11, 2016], Internet <https://en.wikipedia.org/wiki/miglitol> "Pioglitazone", [online], [March 11, 2016 search], Internet <https://en.wikipedia.org/Pioglitazone> "Metformin", [online], [March 11, 2016 search], Internet <https://en.wikipedia.org/Metformin> "Buformin", [online], [Search March 11, 2016], Internet <https://en.wikipedia.org/Buformin>

  This invention makes it a subject to provide the insulin resistance improving agent which can accelerate | stimulate more the utilization of the plum vinegar produced as a by-product when manufacturing a plum processed food, and it is safe and effective. Another object of the present invention is to provide a pharmaceutical, a quasi-drug, a food composition, and a feed composition having a strong insulin resistance improving activity.

  As a result of intensive studies, the inventors have found that a specific combination of ume vinegar polyphenols or a plurality of aglycones constituting the plum vinegar has an excellent insulin resistance improving effect, and have completed the present invention.

  That is, the insulin resistance improving agent of the present invention is selected from the group consisting of ume vinegar polyphenol or a plurality of aglycones constituting it, specifically, trans-p-coumaric acid, caffeic acid and ferulic acid. More than one kind of aglycone is used as an active ingredient. Among 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. Moreover, the pharmaceutical, quasi-drug, and feed composition of the present invention contain the insulin resistance improving agent of the present invention.

  In addition, the ume vinegar polyphenol which is an active ingredient of the insulin resistance improving agent of the present invention includes (1) a contact step in which ume vinegar is brought into contact with a styrene-divinylbenzene synthetic adsorption resin, and (2) a styrene-divinylbenzene synthetic adsorption resin. It is preferable to be obtained by a production method comprising a water washing step of washing the water with water and (3) an elution step of eluting the styrene-divinylbenzene synthetic adsorption resin with a mixed solvent of water and an organic solvent.

  And it is preferable that the said manufacturing method includes the concentration process which concentrates the eluate obtained by the (4) (3) elution process in addition to each process of said (1)-(3), 3) The mixed solvent of water and organic solvent used in the elution step is preferably an aqueous ethanol solution.

  The fasting blood glucose level increase inhibitor of the present invention is a separate invention in which 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 is considered as a separate invention. Two or more aglycones selected from the group consisting of p-coumaric acid, caffeic acid and ferulic acid are used as active ingredients.

  In the above, “suppression of fasting blood glucose level increase” means that the increase in fasting blood glucose level is relatively suppressed by ingestion of the fasting blood glucose level increase inhibitor compared with the case of non-ingestion. Including the case of reducing high fasting blood glucose levels.

  Since the insulin resistance improving agent of the present invention has an excellent insulin resistance improving effect, the quality of life of the patient can be improved. In addition, since the insulin resistance improving agent of the present invention is derived from food, it is guaranteed that it has high safety, so that 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 ume vinegar generated during the production of ume-derived foods such as umeboshi as raw materials, industrial waste can be reduced.

FIG. 1 is a graph showing the results of confirming the insulin resistance improving effect of ume vinegar polyphenol. FIG. 2 is a graph showing the results of comparing the effects of aglycone, which is a constituent component of ume vinegar polyphenol, on the improvement of insulin resistance. FIG. 3 is a graph showing the results of comparing the effects of different aglycone combinations on the improvement of insulin resistance.

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

  The main components of aglycone constituting ume vinegar polyphenol are trans-p-coumaric acid, caffeic acid and ferulic acid. These aglycones show a better insulin resistance improving effect than a single use by combining two or more. 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 ume vinegar polyphenol of the present invention is preferably produced by (1) a contact step, (2) a water washing step, and (3) an elution step. Furthermore, it is more preferable to include the (4) concentration process. Therefore, the steps (1) to (4) will be described in detail below.

(1) Contacting process The contacting process is a process of bringing ume vinegar into contact with a styrene-divinylbenzene synthetic adsorption resin. In addition, both can be contacted by either a batch method in which ume vinegar and an adsorbent resin are mixed in a large container, or a continuous method in which a column in which the adsorbent resin is packed in a column is used. Among these, a continuous method using a column is preferable because it enables mass processing, labor saving, and automation.

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

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

(3) Elution step The elution step is a step of eluting the styrene-divinylbenzene synthetic adsorption resin with a mixed solvent of water and an organic solvent. Although it will not specifically limit as an organic solvent if it mixes with water, Specifically, C1-C5 alcohol, acetone, etc. can be illustrated. Of these, ethanol and acetone are preferable, and ethanol is more preferable. In addition, you may use an organic solvent individually or in combination of multiple.

  The mixing ratio of water and organic solvent is preferably 30 to 90% by volume, and more preferably 50 to 60% by volume of the organic solvent. If the proportion of the organic solvent is lower than 30% by volume, the yield of ume vinegar polyphenol is lowered, and if it is higher than 90% by volume, the solvent may explode, resulting in a safety problem.

(4) Concentration process A concentration process is a process of concentrating the eluate obtained by the elution process. The form after concentration may be, for example, a liquid with high viscosity or a powdered solid depending on the application. The concentration method can be used without particular limitation as long as it is a known method. Specifically, examples include ultrafiltration methods, drying methods such as spray drying and freeze drying, and methods for performing modeling treatment by adding modeling agents such as dextrin.

(5) Others When producing the ume vinegar polyphenol of the present invention, in addition to the steps (1) to (4), a step of regenerating the styrene-divinylbenzene synthetic adsorption resin with an organic solvent, a mixed solvent, You may add processes, such as a process of distilling and regenerating, as needed.

2. Pharmaceuticals, etc. The pharmaceuticals, quasi drugs, food compositions, and feed compositions of the present invention contain the insulin resistance improving agent of the present invention. The content of the insulin resistance improving agent in pharmaceuticals, quasi drugs, food compositions and feed compositions should be set freely in consideration of the improvement effect of the insulin resistance improving agent used and its use. Can do.

(1) Drugs Drugs are those stipulated in the Pharmaceuticals and Medical Devices Law, and include any of human drugs, general drugs for humans (OTC), and veterinary drugs. In addition, for example, pills, liquids, powders, granules, tablets, capsule tablets, troches, syrups, dry syrups, suspensions, emulsions, elixirs and other oral preparations, injections And non-oral agents such as suppositories, liquids for external use, and coating agents such as ointments, but are not limited thereto.

  In the case of producing the pharmaceutical product of the present invention as an oral preparation, known excipients, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, flavoring agents, coloring agents, etc. At the same time, it may be manufactured by a known manufacturing method.

  Further, when the pharmaceutical product of the present invention is produced as a parenteral agent, diluents such as distilled water for injection, physiological saline diluent, aqueous glucose solution, known disinfectants, preservatives, stabilizers, tonicity agents In addition to the stabilizer, preservative, and soothing agent, it may be produced by a known method.

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

(3) Food composition The food composition means human general foods, health functional foods (specific health foods, nutritional functional foods), health foods, nutritional supplements, and the like. As food, specifically, processed fishery products such as kamaboko, chikuwa, hanpen, processed meat products such as sausage, ham, and wine, agricultural processed products such as tofu, fried chicken, konjac, western confectionery, Japanese confectionery, bread, cake Sweets such as ki, jelly, pudding, snacks, cookie, gum, candy, ramune, noodles such as raw noodles, Chinese noodles, buckwheat, udon, sauce, soy sauce, dressing, mayonnaise, sauce, honey, powder Seasoning such as candy and syrup, curry powder, mustard powder, pepper powder and other spices, jam, marmalade, chocolate spread, pickles, soy sauce, sprinkles, various vegetables and fruit canning Dairy products such as vegetables and fruits, seeds, butter, yogurt, fruit juice, vegetable juice, whey drink, soft drink, health tea, beverages such as medicinal liquor, etc. Nourishing reinforcing tablets for health for the purpose of (supplement), etc., beverages, but such food products such health conscious granules and the like can be exemplified, but the invention is not limited thereto.

(4) Feed composition A feed composition is a food for animals other than humans. Examples of animals other than humans include pets such as dogs and cats, ornamental birds such as canaries and parakeets, ornamental fish such as goldfish and tropical fish, domestic animals such as cows, pigs, sheep and horses, poultry such as chickens, Examples include, but are not limited to, cultured fish such as yellowtail, red sea bream, and flounder.

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

1. Production of Plum Vinegar Polyphenol The plum vinegar polyphenol of the present invention was produced by the following production method. First, Diaion (registered trademark) HP20 resin (styrene-divinylbenzene-based synthetic adsorbent, manufactured by Mitsubishi Chemical Corporation) was packed in a sealed metallic column (Φ30 cm × 200 cm). Pour vinegar of 30-40 times volume (volume ratio) was made to contact with this column, and the plum vinegar polyphenol was made to adsorb | suck to resin (contact process). The column adsorbed with ume vinegar polyphenol was poured 4 times the volume (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 into a washed column to obtain an eluate containing ume vinegar polyphenol. Finally, the eluate was concentrated and dried with a vacuum freeze dryer to obtain a powder containing ume vinegar polyphenol (concentration step). In addition, 15.7 kg of this powder was obtained from 15 tons of plum vinegar.

  The polyphenol in the powder was 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. Further, total sugar was measured by the phenol sulfuric acid method, moisture was measured by the loss on drying method (90 ° C., 7 hours), ash was measured by the ashing method at 550 ° C., and the organic acid content was measured by the HPLC method. As a result, the powder was found to contain 64.5% total sugar, 3.9% moisture, 2.6% ash, 0.2% citric acid, and 2.2% quinic acid in addition to plum vinegar polyphenols.

  Furthermore, the structural component of hydroxycinnamic acid which is an aglycon of ume vinegar polyphenol was examined. Specifically, the powder was alkali-decomposed and then measured by the 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 ume vinegar polyphenol on insulin resistance in diet-induced obese mice Fasting blood glucose with and without ingestion of ume vinegar polyphenol of the present invention to investigate the effect of ume vinegar polyphenol intake on insulin resistance induced by obesity Value, 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 has progressed due to the induction of obesity, a group fed with a normal diet was provided as a control group. The details of the experiment are described below.

(1) Laboratory animals and test substances
Five-week-old male C57BL / 6JKwl mice (SPF, Kiwa Laboratory Animal Research Co., Ltd., average body weight 16 g, light period: 6:00 to 18:00) were used as experimental animals. Moreover, MF (made by Oriental Yeast Co., Ltd.) was used for the normal food ingested by the mouse, and HFD-60 (made by Oriental Yeast Industry Co., Ltd.) was used for the high fat diet. Furthermore, the ume vinegar polyphenol used what was manufactured in Example 1, and the cellulose used what was obtained from Nacalai Tesque Corporation. In addition, Table 1 shows the components of the normal diet and the high fat diet.

(2) Experimental method 1) Acclimatization and grouping For 7 days from the start of the experimental test, mice (22 mice) were bred and acclimatized with a normal diet at the breeding facility, and on the 7th day there was significant difference in body weight and food intake between groups The group was divided into 4 groups of 5-6 animals to avoid any difference. Specifically, normal diet group (Normal, n = 5), high fat diet + 1% cellulose group (HF, n = 6), high fat diet + 0.25% plum vinegar polyphenol (hereinafter referred to as UP if necessary) (Omitted) + 0.75% cellulose group (UP0.25%, n = 5), high fat diet + 1% plum vinegar polyphenol group (UP1%, n = 6).

2) Obesity induction and measurement Each group of mice had a normal diet (MF), a high fat diet mixed with 1% cellulose in a high fat diet (HFD-60), 0.25% plum vinegar polyphenol and 0.75 in a high fat diet. A feed mixed with 1% cellulose, and a diet mixed with 1% plum vinegar polyphenol in a high fat diet 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 using a blood glucose meter (Glutest Neo Super, Sanwa Chemical Laboratories) after blood was collected from the tail vein after the mice were fasted for 16 hours. For the “fasting blood glucose level”, the same sample was measured three times, and the average value was calculated.

  For fasting insulin concentration, mice were fasted for 16 hours, then laparotomized under anesthesia, and blood was collected from the aorta. The collected blood was allowed to stand at room temperature for 30 minutes, and then centrifuged at 3000 rpm × 20 minutes to obtain serum. Serum insulin concentration was measured using ELISA method (ultra-sensitive mouse insulin measurement kit, Morinaga Biochemical Laboratory). For the “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) was 1 ng / mL = 26 μIU / mL.

3) Statistical processing Average weight gain (g / 5week), average food intake (g / day), fasting blood glucose (mg / dL), fasting insulin concentration (ng / mL), HOMA-IR Values and standard deviations were calculated. Moreover, it was confirmed by the t test whether the value of each group showed a significant difference with respect to a 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 described in Table 2. From Table 2 and Figure 1, it can be seen that the addition of ume vinegar polyphenol tends to decrease all of fasting blood glucose level, fasting insulin level, and HOMA-IR level in a concentration-dependent manner compared to the high fat diet group. It was. In particular, in the ume vinegar polyphenol 1% group, the HOMA-IR value, which is an index of insulin resistance, was significantly decreased (p <0.05) compared to the high fat diet group, and decreased to the same level as the normal diet group I understood.

3. Effect of aglycone in improving insulin resistance in diet-induced obese mice The aglycone constituting ume vinegar polyphenol was ingested together with a high-fat diet in mice, and the effects of these substances on insulin resistance were compared with ume vinegar polyphenol. Specifically, the experiment was performed as follows.

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

(2) Experimental method 1) Acclimatization and grouping 37 mice acclimatized in the same manner as in Example 2 were added to the normal diet group (n = 4), high fat diet group (n = 5), 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), high fat diet + 0.02% coumaric acid + 0.011% caffeic acid + 0.011% ferulic acid group (3 mixed groups, n = 5).

  In addition, as described in Example 1, the concentration of aglycone contained in each group was such that ume vinegar polyphenol contained 2% trans-p-coumaric acid as aglycone, 1.1% caffeic acid, and 1.1% ferulic acid. Set based on being. In addition, the 6 groups ingesting the high fat diet were adjusted by adding cellulose so that the caloric intake was the same.

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

  The “fasting blood glucose level” was measured using a glucose oxidase / peroxidase (GOD / POD) method (glucose CII-Test Wako, Wako Pure Chemical Industries), which is a more accurate measurement method. For the “fasting blood glucose level”, the same sample was measured three times, and the average value was calculated. Further, the fasting insulin concentration was measured in the same manner as in Example 2, and the average value 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 described in Table 3. 2 and Table 3 indicate that fasting blood glucose levels are significantly reduced in the ume vinegar polyphenol, trans-p-coumaric acid, caffeic acid, ferulic acid intake group, and the three-mixed group compared to the high fat diet group. It was. In addition, it was found that the fasting insulin concentration was lower in the ferulic acid intake group than in the high-fat diet group, and significantly decreased in the three-mixed group. Furthermore, HOMA-IR values were found to be lower in the coumaric acid intake group than in the high-fat diet group, and significantly decreased in the 1% ume vinegar polyphenol, ferulic acid, three-mixture intake group.

  From the above results, among the three types of aglycone molecules (trans-p-coumaric acid, caffeic acid, and ferulic acid) constituting ume vinegar polyphenol, ferulic acid had the highest effect of improving insulin resistance. In other words, it suggests that the active body of insulin resistance improving effect of ume vinegar polyphenol is a ferulic acid derivative. It was thought that the improvement effect of was shown.

  Moreover, it seems that some ferulic acid derivatives in ume vinegar polyphenols have poor digestion efficiency and are not easily 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, ferric acid absorption efficiency is higher in the single intake group, fasting blood glucose level, fasting The decrease in insulin concentration and HOMA-IR value is thought to have increased.

  Trans-p-coumaric acid, an aglycone molecule constituting ume vinegar polyphenol, showed a tendency to reduce fasting blood glucose and to resist HOMA-IR levels. Caffeic acid also showed an effect of lowering fasting blood glucose. Ingestion of three types of aglycone molecules at the same time showed a stronger effect of improving insulin resistance than when ingested alone, so these three types of aglycone molecules work cooperatively to improve insulin resistance. It has been suggested.

4). Insulin resistance improvement effect of multiple aglycones in diet-induced obese mice From Example 3, among the main aglycones constituting ume vinegar polyphenol, ferulic acid improves insulin resistance the most, and if three kinds of aglycones are combined, more Insulin resistance was found to improve.

  Therefore, a combination of multiple aglycones was given to a mouse along with a high-fat diet, and the effect of differences in aglycone combinations on insulin resistance was investigated. Specifically, the experiment was performed as follows.

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

(2) Experimental method 1) Acclimatization and grouping 31 mice acclimated in the same manner as in Example 3 were treated with a high fat diet group (n = 5), 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 mixed groups, n = 6), high fat diet + 0.011% ferulic acid + 0.02% coumaric acid group (n = 5) The high fat diet 0.011% ferulic acid + 0.011% caffeic acid group (n = 5) and the high fat diet 0.02% coumaric acid 0.011% caffeic acid group (n = 4).

  In addition, as described in Example 1, the concentration of aglycone contained in each group was such that ume vinegar polyphenol contained 2% trans-p-coumaric acid as aglycone, 1.1% caffeic acid, and 1.1% ferulic acid. Set based on being. Each group was adjusted by adding cellulose so that the calorie intake was the same.

2) Induction of obesity, measurement and statistical processing After mice of each group were fed as in Example 3, fasting blood glucose levels and fasting insulin concentrations were measured to calculate HOMA-IR values. The calculated values were 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 described in Table 4. From Table 4 and FIG. 3, the fasting blood glucose level was the same as that of the ferulic acid group or lower than that of the ferulic acid in the three mixed groups and any two mixed groups. In particular, the three-mixed group showed a tendency to lower fasting blood glucose (P <0.1) than the ferulic acid group, and significantly decreased fasting blood glucose in the coumaric acid + ferulic acid group than in the ferulic acid group (P <0.05). ) Was confirmed.

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

  Furthermore, the HOMA-IR value showed a tendency to decrease compared to the ferulic acid group in the three kinds mixed group and any two kinds mixed group (P <0.1). In particular, the HOMA-IR value of the three mixed groups (P <0.05), the coumaric acid + ferulic acid group (P <0.01), and the coumaric acid + caffeic acid group (P <0.01) is significantly higher than that of the ferulic acid group. It was confirmed that it decreased.

  From the above results, among the three types of aglycones (trans-p-coumaric acid, caffeic acid, ferulic acid) constituting ume vinegar polyphenol, the ferulic acid + coumaric acid group had the highest effect of improving insulin resistance. That is, it was thought that coumaric acid greatly improved the insulin resistance improvement of ferulic acid. Moreover, a certain significant difference was recognized also in the coumaric acid + caffeic acid group and the 3 types mixed group.

Claims (13)

  An insulin resistance improving agent comprising 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, comprising trans-p-coumaric acid and ferulic acid as active ingredients.   The insulin resistance improving agent according to claim 1, comprising trans-p-coumaric acid and caffeic acid as active ingredients.   The insulin resistance improving agent according to claim 1, comprising trans-p-coumaric acid, caffeic acid and ferulic acid as active ingredients.   An insulin resistance improving agent comprising ume vinegar polyphenol as an active ingredient.   A pharmaceutical comprising the insulin resistance-improving agent according to any one of claims 1 to 5.   A quasi-drug containing the insulin resistance-improving agent according to any one of claims 1 to 5.   A food composition comprising the insulin resistance-improving agent according to any one of claims 1 to 5.   A feed composition comprising the insulin resistance improving agent according to any one of claims 1 to 5. A method for producing an insulin resistance improver comprising ume vinegar polyphenol as an active ingredient,
(1) a contact step of bringing ume vinegar into contact with a styrene-divinylbenzene synthetic adsorption resin;
(2) a water washing step of washing the styrene-divinylbenzene synthetic adsorption resin with water;
(3) an elution step of eluting the styrene-divinylbenzene synthetic adsorption resin with a mixed solvent of water and an organic solvent;
The manufacturing method of the insulin resistance improving agent containing this.   (4) The method for producing an insulin resistance improving agent according to claim 10, further comprising a concentration step of concentrating the eluate obtained by the elution step.   (3) The method for producing an insulin resistance improving agent according to claim 10 or 11, wherein the mixed solvent of water and an organic solvent used in the elution step is an ethanol aqueous solution.   A fasting blood glucose level increase inhibitor comprising as an active ingredient two or more aglycones selected from the group consisting of trans-p-coumaric acid, caffeic acid and ferulic acid.

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