JP2016000707A - Insulin resistance improving agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide formulations which can safely and effectively improve insulin resistance leading to development of diseases including a type 2 diabetes mellitus or metabolic syndrome.SOLUTION: The invention relates to a composition containing press residues of apple fruits and rosemary extract. The invention relates to an insulin resistance improving agent, in which rosemary leaf extract is preferable as a rosemary extract, and preferably it is extracted using C1-4 alcohol as an extracting solvent. The composition containing 5 to 15-fold press residues of apple fruits at a mass ratio to the rosemary extract is administered at doses of 10-50 mg/kg per day.

Description

  The present invention relates to a preparation that can safely improve insulin resistance.

  Type 2 diabetic patients account for 90-95% of all diabetic patients. The disease progresses very slowly and there are no subjective symptoms at the time of onset. Often, hyperglycemia and glucose intolerance are found during routine checkups for lifestyle-related disease tests, or after progressing, the patient is aware of polyuria and dry mouth as subjective symptoms.

  Various causes of type 2 diabetes have been pointed out, one of which is insulin resistance. Insulin resistance refers to a state in which, despite insulin being secreted, the response to insulin is slowed and the increased blood glucose level does not decrease. Insulin resistance is common in obese individuals but the cause at the molecular level is unknown.

  According to many research results, insulin resistance has revealed not only signal transduction after insulin receptor but also abnormality of insulin receptor itself. The early failure of insulin resistance is compensated by more insulin secretion from the pancreatic beta cells. Therefore, I do not notice the progression until it becomes obvious diabetes. I finally realize that I have diabetes when my β-cell secretion cannot keep up with the demand for final insulin.

  Increased β-cell apoptosis and decreased regenerated β-cells make it difficult to supply the required amount of insulin, and insulin resistance causes retention in the liver and adipose tissue when more insulin is needed and cannot be supplied Carbohydrates and lipids are released into the blood, and free fatty acids are released into the blood due to the progress of lipolysis in adipose tissue. In addition to hyperglycemia and dyslipidemia, free fatty acids are also released into non-adipose tissue ( (Liver, skeletal muscle, pancreas, heart, kidney, etc.) and become lipotoxic (cell dysfunction).

  Insulin resistance has been claimed to be exclusively associated with diabetes, but recent studies have shown that it is also closely associated with the development of many other diseases. Of particular note is its relevance to metabolic syndrome. And the key to prevention and treatment is improvement of insulin resistance and response to visceral fat.

  One of the metabolic syndromes closely related to visceral fat accumulation is nonalcoholic fatty liver. Fructose, glucose liquid sugar, corn syrup, and fructose alone have been widely added to foods instead of sugar because they have a light sweetness as a sweetener and are inexpensive. This is one of the causes of non-alcoholic fatty liver. The present inventor has so far considered the use of natural products for the prevention and treatment of non-alcoholic fatty liver onset, has been researching the treatment of visceral fat and has published the results (Non-Patent Documents 1 to 3).

  In the treatment of insulin resistance, α-glucosidase inhibitors, PPARγ activators, AMP-activated protein kinase activators and the like are often used in combination. However, these synthetic drugs have strong side effects, and since insulin resistance is closely related to lifestyle and requires constant treatment, insulin resistance improving substances are being searched for from naturally derived compounds.

  For example, Patent Document 1 discloses a composition containing an acetogen fiber such as apple pectin, which treats, prevents, or improves metabolic dysfunction associated with insulin resistance.

  Patent Document 2 discloses a food product which may contain rosemary extract as an antioxidant and may be functional in reducing insulin resistance. Patent Document 3 discloses a specific product. A composition comprising a bitter taste receptor ligand having a structure, which may further comprise a rosemary extract compound and is said to be capable of treating insulin resistance or the like, is disclosed.

Special table 2009-513505 gazette Special table 2008-509213 gazette Special table 2014-501787 gazette

Gao H et al., Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 570948, p. 12 (2012) Wang J et al., Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 590376, p. 12 (2012) Liu C et al., Evidence-Based Complementary and Alternative Medicine, vol. 2013, Article ID 534084, p. 11 (2013)

  As mentioned above, when considering prevention and treatment of various metabolic syndromes, it is important to improve insulin resistance at the same time as reducing visceral fat, but synthetic drugs that can improve insulin resistance safely and effectively There is no. Therefore, by taking casually every day, prevention and improvement of insulin resistance can be achieved before falling into difficult-to-treat type 2 diabetes, and if possible, safe natural products with a long history of edible use are always required. ing. Here, as in the inventions disclosed in Patent Documents 1 to 3, fibers and rosemary extract contained in apples are considered to be effective in improving insulin resistance. According to the experimental findings, these effects were not satisfactory at all.

  Under such circumstances, an object of the present invention is to provide a preparation that can safely and effectively improve insulin resistance that leads to the onset of diseases such as type 2 diabetes and metabolic syndrome.

  This inventor repeated earnest research in order to solve the said subject. As a result, the inventors found that a mixture of apple fruit pressing residue and rosemary extract can effectively improve insulin resistance, and completed the present invention.

  The insulin resistance improving agent according to the present invention is characterized by containing apple fruit pressing residue and rosemary extract.

  In the insulin resistance-improving agent of the present invention, the mass ratio of apple fruit pressing residue to rosemary extract is preferably 5 times or more and 15 times or less. The effect of the insulin resistance improving agent containing apple fruit pressing residue and rosemary extract in such a ratio has been confirmed by the experimental findings of the present inventors.

As the rosemary extract which is one of the active ingredients of the insulin resistance improving agent according to the present invention, those derived from rosemary leaves and those extracted using C _1-4 alcohol as an extraction solvent Is preferred. The effect of the insulin resistance improving agent of the present invention containing such a rosemary extract has been confirmed by the inventor's experimental findings.

  The dose of the insulin resistance improving agent according to the present invention is preferably 10 mg / kg body weight or more and 50 mg / kg body weight or less per day.

  The insulin resistance improving agent according to the present invention can improve insulin resistance that can progress to the onset of lifestyle-related diseases including metabolic syndrome such as diabetes. Moreover, since the active ingredient is a mixture of apple fruit pressing residue and rosemary extract, for example, it can be ingested multiple times per day. This makes it possible to prevent or reduce insulin resistance. Therefore, the present invention is very effective as an agent that can improve insulin resistance, which is said to be one of the causes of lifestyle-related diseases that have become a problem due to westernization of eating habits in recent years.

FIG. 1 shows a control group rat (first group, water control group) fed only with water in addition to food, a rat fed with 10% fructose water instead of water (second group, fructose control group), 10% Rats orally administered 100 mg / kg (Group 3) or 500 mg / kg (Group 4) of the mixture of the present invention in addition to fructose water Rats orally administered 450 mg / kg of apple fruit pressing residue in addition to 10% fructose water It is a graph which shows the weight increase of the rat (6th group) which orally administered 50 mg / kg rosemary extract in addition to (Group 5) and 10% fructose water. FIG. 2 is a graph showing fasting blood glucose level (1), fasting insulin level (2), and fasting free fatty acid (NEFA) level (3) of the rats of Groups 1-6. “*” In FIG. 2 indicates a case where a significant difference is recognized at p <0.05 by a significant difference test by analysis of variance (ANOVA). FIG. 3 shows the insulin resistance index (HOMA-IR Index, Homeostasis model-insulin resistance index) (1) of the above-mentioned rats of Groups 1-6, and the insulin resistance index (Adipo-IR Index) of adipose tissue, It is a graph which shows Adiposesissuinsulin resistance index (2). “*” In FIG. 3 indicates a case where a significant difference is recognized at p <0.05 by a significant difference test by analysis of variance (ANOVA). FIG. 4 is a graph showing changes in liver weight (1), heart weight (2) and kidney weight (3) in the rats of Groups 1-6.

  The insulin resistance improving agent according to the present invention is characterized by containing an apple fruit press residue and a rosemary extract as active ingredients.

  Although the apple which is a raw material of the apple fruit pressurization residue which is one of the active ingredients of the insulin resistance improving agent which concerns on this invention is not restrict | limited, For example, the western apple (Malus pumilla more generally attached | subjected to food) ) As well as Japanese apple (Malus asiatica) fruit. Moreover, the form of the apple fruit to be used is not particularly limited. For example, the apple fruit can be used as it is with the river, or the river from which the river has been removed, or the river and the core have been removed.

  In the present invention, the “apple fruit pressing residue” refers to a remaining koji obtained by squeezing an apple to remove fruit juice. For example, a remaining koji obtained by manufacturing apple juice can be used. Since most of the water-soluble components such as polyphenol are removed together with the fruit juice, the main component is insoluble dietary fiber. “Dietary fiber” is an indigestible or indigestible component that is contained in food and is not degraded by human digestive enzymes. It mainly consists of plant food and the cell walls of fungal plants. It consists of sugars. In addition, apple fruit pressing residue may be marketed as a dry product etc. with product names, such as apple fiber and apple fiber.

  The apple fruit pressing residue in the present invention may be any remaining residue obtained by pressing the apple and removing the fruit juice. For example, in addition to dietary fiber derived from apple, moisture, protein, lipid, mineral, saccharide, ceramide, ursolic acid and It may contain polyphenols. Moreover, since it is difficult to remove fruit juice completely, a part of fruit juice and its dried product may remain in the apple fruit press residue used by this invention. Since there is a possibility that components other than dietary fiber have contributed to the insulin resistance improving action by the apple fruit compressed residue of the present invention, the proportion of dietary fiber in the apple fruit compressed residue is preferably 90% by mass or less, 80 mass% or less is more preferable, 70 mass% or less is more preferable, 60 mass% or less is further more preferable, and 50 mass% or less is further more preferable. On the other hand, as the said ratio, 10 mass% or more is preferable, 20 mass% or more is more preferable, and 25 mass% or more is further more preferable.

  Although the manufacturing method in particular of an apple fruit press residue is not restrict | limited, For example, the residue which pressed the apple fruit for manufacture of apple juice etc. can be used. Furthermore, you may use the said residue dried and water content made 4 mass% or more and 10 mass% or less. The water content can be measured by, for example, a normal pressure heating drying method.

  Rosemary (Rosmarinus officinalis, Lamiaceae) is a small evergreen shrub that is well known as a spice raw material with a thick aromatic leaf and a height of about 2 m. Originated in the Mediterranean region, it is cultivated all over the world, including the United States, England, France and Spain. As ingredients contained in rosemary, many ingredients such as triterpenoid compounds such as phenolic compounds and ursolic acid are known in addition to fats and oils and flavonoids. In addition, the action of the extract on the bile duct and the small intestine and the blood flow increasing action of the coronary arteries have been reported. In European phytotherapy, rosemary leaves are also used for indigestion, rheumatism, and cardiovascular diseases. It is also used as a bath agent. In food, it is used in many fields, including alcoholic beverages, baked confectionery, frozen dairy products, meat and meat product seasonings, condiments, processed vegetables, snacks, and gravy. It is also a medicinal herb that is used as a herbal tea in anticipation of a healthy stomach effect. In China, leaf and branch extracts are also used for headaches.

  As a raw material part of the rosemary extract, leaves and / or branches are preferable, and leaves are more preferable. In addition, since rosemary contains a fragrant oil and fat component, directly using rosemary leaves or the like as a raw material may result in a strong fragrance of the resulting extract that is difficult to take. Therefore, you may use the residue after removing fats and oils components, such as a residue after manufacturing rosemary oil, by steam distillation.

As the extraction solvent, a water-soluble organic solvent and a mixed solvent of water and a water-soluble organic solvent are preferable. The water-soluble organic solvent is not particularly limited, and may be appropriately selected, for example, from what can be obtained a rosemary extract capable of exhibiting an excellent insulin resistance improving action in combination with apple pressing residue. , 1-propanol, 2-propanol, n-butanol, isobutanol, s-butanol, C _1-4 alcohol of t-butanol; water-soluble ether solvents such as diethyl ether and tetrahydrofuran; water-soluble such as dimethylformamide and dimethylacetamide And water-soluble sulfoxide solvents such as dimethyl sulfoxide. Among these, C _1-4 alcohol is preferable from the viewpoint of safety and the like, C _1-2 alcohol is more preferable, and ethanol is more preferable.

  When a mixed solvent of water and a water-soluble organic solvent is used, the concentration of the water-soluble organic solvent with respect to the whole may be adjusted as appropriate. For example, it can be 50 v / v% or more, preferably 60 v / v% or more. 70 v / v% or more is more preferable, 80 v / v% or more is further preferable, and 90 v / v% or more is particularly preferable. The upper limit is not particularly limited, but can be, for example, 99 v / v% or less.

  The amount of the extraction solvent used is not particularly limited and may be adjusted as appropriate. For example, it can be about 2 mass times or more and 20 mass times or less with respect to rosemary. The ratio is preferably 5 times or more, more preferably 7 times or more, more preferably 15 times or less, and more preferably 12 times or less.

  The extraction temperature can also be adjusted as appropriate, and can be, for example, 10 ° C. or higher and 80 ° C. or lower. In addition, when extracting above the boiling point of a solvent, it is preferable to seal or pressurize an extraction container. Further, the extraction solvent may be heated to reflux. Further, the extraction temperature may be changed in stages.

  The extraction time can also be adjusted as appropriate. For example, the extraction time can be about 1 hour or more and 50 hours or less in total.

  The extracted liquid mixture can be used as it is, but normal post-treatment may be performed. For example, the extraction residue and the extraction solvent may be separated by filtration or centrifugation, or the separated extract may be dried by appropriately combining heating drying, reduced pressure drying, freeze drying, and the like. In addition, when drying by heating, it is preferable to concentrate at 60 ° C. or less, preferably 50 ° C. or less, while reducing the pressure, so that the active ingredient is not decomposed.

  As the rosemary extract, rosemary oil containing a large amount of oil and fat components derived from rosemary is well known and generally commercially available. According to the experimental knowledge of the present inventor, rose that does not contain oil and fat components. A remarkable insulin resistance improving effect was obtained by combining Marie extract with apple fruit press residue. Therefore, the rosemary extract used in the present invention preferably does not contain an oil or fat component.

  Rosemary extract that does not contain fat and oil components is mainly extracted when the oil and fat components are removed from the rosemary by steam distillation, etc., or when extraction is performed without removing the fat and oil components. Partial purification may be performed to remove the fat and oil component. For example, if the extract is concentrated or an insoluble component that precipitates by adding a poor solvent to the extract is filtered and washed, the main oil component can be removed because it is liquid at room temperature. However, since it may be difficult to completely remove the fat and oil component, the ratio of the fat and oil component contained in the rosemary extract used in the present invention can be 0.001% by mass or more and 10% by mass or less. 0.01 mass% or more and 5 mass% or less are preferable, 0.1 mass% or more and 2 mass% or less are more preferable, and 1 mass% or less is more preferable. In the present invention, the “oil / fat component” refers to water-insoluble components such as phospholipids, long-chain fatty acids, higher alcohols, etc., in addition to esters of general fatty acids and glycerin. Rosemary oil is rich in monoterpene hydrocarbons such as pinene, camphene and limonene.

  The ratio between the apple fruit pressed residue and the rosemary extract in the present invention may be appropriately adjusted within the range in which the insulin resistance improving action is exhibited, for example, the mass ratio of the apple fruit pressed residue to the rosemary extract It can be 5 times or more and 15 times or less. The mass ratio is preferably 6 times or more, more preferably 7 times or more, further preferably 8 times or more, further preferably 14 times or less, more preferably 13 times or less, and further preferably 12 times or less. In addition, since the said mass ratio changes with the drying degree of an apple fruit pressing residue or a rosemary extract, after adjusting the water content of an apple fruit pressing residue and a rosemary extract to 5 mass% or more and 6 mass% or less It shall be calculated by

  The dosage form of the insulin resistance improving agent according to the present invention is not particularly limited. For example, the apple fruit press residue and the dried rosemary extract may be simply mixed, or the apple fruit press residue and the rosemary extract may be dispersed or dissolved in water. . In addition, rosemary leaves may be used as bathing agents, and rosemary-derived essential oils and extracts may be used as perfumes for external preparations, soaps, cosmetics, etc. Such an insulin resistance ameliorating agent is highly effective when orally administered, and is preferably an oral agent from the viewpoint of ease of ingestion and administration.

  Although it does not restrict | limit especially as an oral formulation, For example, a tablet, a powder, a capsule, a sugar-coated tablet, a granule etc. can be mentioned. For the insulin resistance improving agent according to the present invention, a pharmaceutically acceptable additive may be used in accordance with the dosage form. Examples of such additives include excipients, bases, preservatives, auxiliaries, stabilizers, wetting agents, pH adjusting agents, antioxidants, colorants, sweeteners and the like. However, the dried apple fruit residue and rosemary extract, which are the active ingredients of the insulin resistance improving agent according to the present invention, can be granulated without adding excipients or the like. In addition, the suspension may be a beverage or may be added to a general diet.

  The insulin resistance improving agent according to the present invention can be administered to animals other than humans in addition to humans. However, it is preferably used for humans.

  What is necessary is just to adjust suitably the administration frequency and dosage of the insulin resistance improving agent which concerns on this invention according to a patient's symptom, age, sex, a state, etc. Based on the animal experiment data described below, for example, the dosage for humans is preferably about 10 mg / kg body weight or more and 50 mg / kg body weight or less per day in a dried apple fruit press residue-rosemary extract mixture. More preferably, it is about 15 mg / kg body weight or more and about 40 mg / kg body weight or less. The number of administrations per day is preferably 1 or more and 5 or less, more preferably 1 or more and 3 or less.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.

Example 1: Apple pressing residue according to the present invention: Preparation of rosemary extract mixture Pressing residue (stock) produced when pressing fruit of Japanese apple (Malus asiatica) and Western apple (Malus pumila) to produce apple juice Beverage from Akita New Bio Farm) was dried in warm air at 90 ° C. for 3 days under normal pressure, and the moisture content was adjusted to a range of 5 to 6% by mass to obtain apple fruit pressing residue.

  The composition analysis of the obtained apple fruit pressing residue was requested to the Japan Food Analysis Center. The results are shown in Table 1.

  As the above result, the obtained apple fruit pressing residue contained about 30% by mass of dietary fiber. Moreover, about 10-20 mass% of pectin was contained.

  In addition, a powdered rosemary extract (product name “Rosemary extract” manufactured by Sabinsa Japan Corporation) commercially available as a health food material was purchased and used. The said extract is what was heated and extracted from the rosemary leaf using ethanol as a solvent, and the fat and oil component was removed.

  As a result of preliminary experiments using mice, when the breeding content and the amount of exercise were raised without any particular designation or restriction, a mixture of apple fruit pressing residue: rosemary extract mixing ratio of 10: 1 by mass ratio was obtained. It was recognized that the insulin resistance improving action was most excellent. Therefore, the mixture which mixed the said apple fruit pressing residue and rosemary extract by 10: 1 (mass ratio) was used in the following experiments.

Example 2: Test for improving insulin resistance using experimental animals A male Sprague-Dawley rat (hereinafter referred to as "SD rat") weighing approximately 170 g (obtained from Chongqing Medical University Experimental Animal Center (China)) was tested at room temperature 21 ± Under the conditions of 1 ° C. and humidity of 55 ± 5%, the animals were preliminarily raised for 1 week in a 12-hour bright and dark breeding room with free access to normal feed (obtained from Chongqing Medical University Animal Center (China)) and water.

  The 51 SD rats preliminarily raised as described above were arbitrarily divided into 6 animals and 45 animals, and 6 animals were used as a water control group (Group 1), and the breeding was continued under the same conditions as in the preliminary breeding. The remaining 45 animals were raised for 13 weeks under the same conditions except that 10% fructose water was used instead of water. Next, 45 animals reared with fructose water were divided into 5 groups of 9 animals each to make groups 2-6. The second group (fructose control group) was continuously given 10% fructose water. The third group was given 100 mg / kg of the inventive mixture of Example 1 above in addition to 10% fructose water. The fourth group was given 500 mg / kg of the inventive mixture in addition to 10% fructose water. In addition to 10% fructose water, only the apple fruit pressing residue was given to the fifth group (apple fruit pressing residue control group) at 450 mg / kg (corresponding to the content in 500 mg of the mixture of the present invention). The sixth group (rosemary extract control group) was given 50 mg / kg of the rosemary extract alone (corresponding to the content in 500 mg of the mixture of the present invention) in addition to 10% fructose water. The mixture of the present invention, apple fruit pressing residue and rosemary extract were suspended in 5% aqueous gum arabic solution and orally administered daily for 4 weeks using rat sonte.

  The SD rats in each group were allowed to freely receive solid feed and water or 10% fructose water during the breeding period. In order to avoid stress and monitor the intake of fructose more precisely, two or one animal was bred per gauge. During the breeding, water or fructose water and feed intake were measured daily. They were fasted overnight at the end of the fourth week, but they received water ad libitum.

  After the breeding, each SD rat was anesthetized with ether, anticoagulated with heparin, and a blood sample was collected. Plasma was separated from the blood sample, and blood glucose level, insulin level and free fatty acid (NEFA) level were measured. The measurement of blood glucose level was commissioned to Shanghai Biotechnology Research Institute in Shanghai, the measurement of insulin level was commissioned to Morinaga Biochemistry Laboratory Co., Ltd., and the free fatty acid level was commissioned to Wako Pure Chemical Industries, Ltd. In addition, the insulin resistance index of the liver uses HOMA-IR (Homeostasis model-Insulin Resistance) Index: [Fasting insulin value (μIU / mL) × Fasting blood glucose level (mmol / L)] / 22.5 Asked. The insulin resistance index of adipose tissue was determined using Adipo-IR Index: fasting insulin value (mmol / L) × fasting free fatty acid value (pmol / L). After the above measurement, the administration of water, fructose water, and specimens was resumed. After 1 week, the animals were fasted overnight with free intake of water, and the body weight of each rat was measured. did.

  FIG. 1 shows changes in body weight during the breeding period. Fig. 2 (1) shows fasting blood glucose levels, Fig. 2 (2) shows fasting insulin values, and Fig. 2 (3) shows fasting NEFA values. FIG. 3 (1) shows the insulin resistance index (HOMA-IR Index) of the liver, and FIG. 3 (2) shows the insulin resistance index (Adipo-IR Index) of the adipose tissue. FIG. 4 shows changes in the weight of each organ. In addition, the significant difference test in each experimental data analysis was calculated | required by ANOVA using statistical software StatView (SAS company, Version 5.0.1). “*” In each figure indicates a case where a significant difference is recognized at p <0.05 by a significant difference test by ANOVA.

  As shown in FIG. 1, there was no significant difference in weight gain in each group. As shown in FIG. 2 (1), fasting blood glucose after fasting was significantly reduced in the fructose control group (group 2) in the 500 mg / kg administration group (group 4) of the present invention. Significant changes were observed in the 100 mg / kg administration group of the present invention (Group 3), the apple fruit pressed residue 450 mg / kg only administration group (Group 5), and the rosemary extract only 50 mg / kg administration group (Group 6). I couldn't. Moreover, as shown in FIG. 2 (2), the fasting insulin value was significantly increased in the fructose control group (second group) relative to the water control group (first group). In rats of the 100 mg / kg administration group (Group 3) or 500 mg / kg administration group (Group 4) of the present invention, both significantly reduced insulin levels compared to the fructose control group (Group 2). On the other hand, in the apple fruit pressed residue 450 mg / kg only administration group (group 5) and the rosemary extract only 50 mg / kg administration group (group 6), there was no significant effect on the fructose control group (group 2). I couldn't. As shown in FIG. 2 (3), the fasting NEFA value was significantly increased in the fructose control group (second group) relative to the water control group (first group). Neither the mixture of the present invention, the apple fruit press residue alone, nor the rosemary extract alone affected the NEFA value. As shown in FIG. 3 (1-2), the HOMA-IR Index value representing the insulin resistance index of the liver was significantly increased in the fructose control group (second group) compared to the water control group (first group). The HOMA-IR Index was significantly decreased in the rats of the present invention mixture 100 mg / kg administration group (Group 3) and the present invention mixture 500 mg / kg administration group (Group 4). If the HOMA-IR Index value is 2.5 or more in Japanese, it means that there is insulin resistance, and a value less than 1.6 is a normal value. Therefore, in the rats administered with the mixture of the present invention, the HOMA-IR Index value decreased to near normal values. On the other hand, no significant effect was observed in the fructose control group in the group administered only with apple fruit pressing residue 450 mg / kg (group 5) and the group administered only with rosemary extract 50 mg / kg (group 6). Further, as shown in FIG. 3 (2), the value of Adipo-IR Index representing insulin resistance of adipose tissue was significantly increased in the fructose control group (second group) as compared to the water control group (first group). In the rats of the present invention mixture 100 mg / kg administration group (Group 3) and the present invention mixture 500 mg / kg administration group (Group 4), both were significantly reduced compared to the fructose control group. On the other hand, no significant effect was observed in the fructose control group (group 2) in the group administered only with apple fruit pressing residue 450 mg / kg (group 5) and the group administered only with rosemary extract 50 mg / kg (group 6). It was.

  From the above results, it was found that the mixture of the present invention improves the insulin resistance of the liver and adipose tissue by fructose, while the effect is not seen only with apple fruit pressing residue or rosemary extract alone. Therefore, it can be said that the combination of apple fruit pressing residue and rosemary extract has a synergistic effect on insulin resistance. Further, as shown in FIG. 4, there was no significant difference in changes in liver weight (1), heart weight (2), and kidney weight (3).

  As described above, when a mixture of apple fruit pressing residue and rosemary extract was administered according to the present invention, blood insulin concentration increased due to fructose load and insulin resistance values of liver and adipose tissue increased. On the other hand, it was significantly reduced and improved to a value close to the normal value (control group). However, administration of only apple fruit pressing residue and administration of rosemary extract alone had little effect on the above values. From these results, it was found that it is effective to use a mixture containing both apple fruit pressing residue and rosemary extract to improve insulin resistance. Therefore, in the insulin resistance improving agent according to the present invention, the combination of industrial waste, so-called alcoholic extract of fruit residue used in apple juice or rosemary oil extract residue, brings insulin resistance to near normal value. It can be said that the invention is highly industrially proven to be significantly reduced by experiments.

  From the results of experimental animals, the dose of the mixture according to the present invention, which is expected to have an effect of improving insulin resistance, is determined based on the basic data in the animal experiment of conventional drug development and the numerical value for the clinical trial to humans. In humans, it is estimated to be effective at about 500 mg to 1000 mg twice a day.

Claims (5)

  An insulin resistance improving agent comprising an apple fruit pressing residue and a rosemary extract.   The insulin resistance improving agent according to claim 1, comprising an apple fruit pressing residue having a mass ratio to the rosemary extract of 5 to 15 times.   The insulin resistance improving agent according to claim 1 or 2, wherein the rosemary extract is derived from leaves of rosemary. The insulin resistance improving agent according to any one of claims 1 to 3, wherein the rosemary extract is extracted using C _1-4 alcohol as an extraction solvent.   The insulin resistance improving agent according to any one of claims 1 to 4, which is administered at a dose of 10 mg / kg body weight or more and 50 mg / kg body weight or less per day.