JP2008074745A - Inhibitor for blood sugar elevation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an inhibitor for blood sugar elevation having high safety and excellent inhibitory action on a rise in blood sugar. <P>SOLUTION: The inhibitor for blood sugar elevation comprises brassinin or its analog, preferably further comprises phloretin or its glycoside. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a blood sugar increase inhibitor that suppresses an increase in blood sugar after sugar intake.

The hyperglycemia symptom refers to a state in which butto sugar in the blood after meal is increased beyond the normal range, and indicates a state in which the blood glucose level after intake of carbohydrates is increased to 140 mg / dl or more. This hyperglycemia symptom not only triggers diabetes, but also causes and exacerbation factors such as obesity, hyperlipidemia, arteriosclerosis, and so prevention of hyperglycemia is useful for the prevention and treatment of these diseases It is.
As therapeutic agents for postprandial hyperglycemia, α-glucosidase inhibitors, fast-acting insulin secretion promoters, and the like are known, and these are mainly used in critically ill patients in medical institutions. In contrast, non-drug therapy, a collective term for lifestyle improvement such as diet therapy, exercise therapy, and restrictions on drinking and smoking, should be widely applied to patients with hyperglycemic symptoms, from prevention of healthy subjects to treatment of severe cases. Can do.

However, many of the drugs currently used for postprandial hyperglycemia measures are satisfactory in terms of effectiveness, but side effects such as abdominal distension, flatulence, increased flatus, loose stool, diarrhea, abdominal pain, liver dysfunction occur Concerns over long-term use have been pointed out. Also, general therapies such as diet and exercise are extremely difficult to implement in the long term. Therefore, there is a demand for a natural product-derived blood sugar elevation-suppressing material that has few side effects and can be taken daily for a long period of time.
From this point of view, food-derived materials aimed at suppressing a rapid increase in blood sugar after sugar intake have been actively pursued, and many active ingredients having an action to suppress blood sugar increase have been separated and identified. . However, the effectiveness of foods and their active ingredients, which have been found so far and are said to have an anti-glycemic effect, are not always satisfactory, and a long period of time is required before the inhibitory effect is manifested. Many things are required.

On the other hand, brassine and its analogs are indole produced by cruciferous plants such as Chinese cabbage, cabbage, rapeseed, mustard vegetable, broccoli, cauliflower, kale, kohlrabi, hata-daikon, turnip (kabu), rutabaga (kabuha button), etc. It is a derivative and is known as phytoalexin for combating stress such as invasion of microorganisms (Non-patent Document 1). Antibacterial action (Non-Patent Document 2) and anti-cancer action (Non-Patent Document 3) are known as actions of brassin, but it is not known at all to have an action of suppressing an increase in blood sugar after sugar intake.
Soledade C. Pedras, Sabine Montaut et al, J. Org. Chem. Vol. 69, No. 21, p4471-4476, 2004 Mitsuo Takasugi, Nobukatsu Katsui and Akira Shirata, J. Chem. Soc. Chem. Commun., 1986, p1077-1078 Rajendra G. Metha, et al., Carcinogenesis, Vol.16, No.2, 199

  The present invention relates to providing a blood sugar elevation inhibitor having high safety and an excellent blood sugar elevation inhibitory action.

  As a result of searching for various blood glucose-inhibiting materials that can control hyperglycemia after ingesting sugar and can be ingested for a long period of time, the present inventor has found that brassin and its analogs have an excellent anti-glycemic activity.

  The blood sugar elevation inhibitor of the present invention has an excellent blood glucose elevation inhibitory action, can be taken for a long time, and has high safety. Therefore, hyperglycemia after sugar intake and diseases associated therewith, such as diabetes, obesity, Useful for prevention or improvement of hyperlipidemia, arteriosclerosis, etc.

  In the present invention, the brassinin and its analogs are as follows: Chinese cabbage, cabbage, rapeseed, mustard greens, broccoli, cauliflower, kale, kohlrabi, hatsudaikon, turnip (kabu), rutabaga (kabuha button), etc. It is an indole derivative produced by cruciferous plants. Specifically, brassinin (brassinin, 3-S-methyldihiocarbamoyl aminomethyl indole, compound 1), 1-methoxybrassin (1-methoxybrassinin, compound 2), 4-methoxybrassin (4-methoxybrassinin, compound 3), brassin (Brassitin, compound 4), 4-methoxydehydrocyclobrassin (compound 5), isalexin (isalexin, compound 6), brass canate A (brassicanate A, compound 7), rutalexin (compound 8), cyclo Examples include brassunone (cyclobrassinone, compound 9), spirobrassinin (compound 10), brass canal A (compound 11), and braxelexin (compound 12), with brassine being more preferred.

Such a brassin or an analog thereof is extracted by a known organic chemical synthesis method (see Non-Patent Documents 1 and 3) or from a natural product or callus containing the brassin or an analog thereof, or a precursor thereof. Furthermore, it can be obtained by combining organic chemical synthesis methods as required (see Non-Patent Documents 1 to 3).
As a natural product or callus containing brassinin or an analog thereof, or a precursor thereof, for example, cruciferous plants, specifically, Chinese cabbage, cabbage, rapeseed, mustard vegetable, broccoli, cauliflower, kale, kohlrabi, Examples include Tsukandaiko, Turnip, and Rutabaga.

The blood sugar elevation inhibitor of the present invention preferably further contains phloretin or a glycoside thereof from the viewpoint of enhancing the blood glucose elevation inhibitory action and stably lowering the blood sugar level.
Phloretin, as shown below, is 3- (4-hydroxyphenyl) -1- (2,4,6-trihydroxyphenyl) -1-propane (3- (4-Hydroxyphenyl) -1- ( 2,4,6-trihydroxyphenyl) -1-propanone, compound 13), and examples of the glycoside thereof include phlorizin (compound 14). Phloretin is contained in apples and pears as phlorizin.

Such phloretin or a glycoside thereof is a known organic chemical synthesis method (Sato S, Akiya T, Nishizawa H, Suzuki T .: Carbohydrate Research 341 (8): 964-970, 2006), natural products containing them. (Ki Won Lee, Young Jun Kim, Dae-Ok Kim, Hyong Joo Lee, Chang Yong Lee: J Agric Food Chem. 51, 6516-6520, 2003), or a combination of these Can do.
Examples of the natural product or callus containing phloretin or a glycoside thereof include rose family plants, specifically apple, pear and cherry.

If the brassinin or its analog obtained by the said synthesis | combination or extraction, and a phloretin or its glycoside conform to the specification accept | permitted on a pharmaceutical or foodstuff and exhibit the effect of this invention, it is a crude refined | purified substance Further, the purity of these compounds or extracts may be increased by appropriately combining known separation and purification methods.
Examples of the extraction include a solvent extraction method that uses a polar solvent or a nonpolar solvent such as water, hot water, and alcohol. Examples of the purification means include organic solvent precipitation, centrifugation, ultrafiltration membrane, high performance liquid chromatograph, column chromatograph and the like.

  As shown in Examples described later, brassin has an action of significantly suppressing an excessive increase in blood glucose after sugar intake, and this action is enhanced when phloretin or a glycoside thereof is combined. Therefore, brassin or an analog thereof, and a combination of these with phloretin or a glycoside thereof can be used as an inhibitor of blood sugar elevation using this as an active ingredient. It can also be used to produce a blood sugar elevation inhibitor. The suppression of blood glucose elevation prevents and improves hyperglycemia after sugar intake and associated diseases such as insulin resistance, diabetes, obesity, hyperlipidemia, arteriosclerosis caused by increased oxidative stress in the body Or it can be used as a food and drink, a quasi-drug, a pharmaceutical product, etc. for treatment. Brassine or its analogs are various types of drugs such as hyperglycemia after sugar ingestion and diseases associated therewith, such as insulin resistance, diabetes, obesity, hyperlipidemia, arteriosclerosis caused by increased oxidative stress in the body. Foods and drinks that display an indication that they are used to prevent or improve postprandial hyperglycemia, such as foods for the sick, with the concept of physiological functions that promote prevention, treatment, and improvement of lifestyle-related diseases. It can be used as a special-purpose food or drink such as food for specified health use.

  Examples of the dosage form when the suppression of blood glucose elevation according to the present invention is used as a pharmaceutical include oral administration such as tablets, capsules, granules, powders, syrups, etc., or injections, suppositories, inhalants, transdermal agents, and external use. Parenteral administration by an agent or the like. In order to prepare pharmaceutical preparations of such various dosage forms, the brassinin of the present invention or an analog thereof can be used alone or other pharmaceutically acceptable excipients, binders, extenders, disintegrations. Agents, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, carriers, diluents and the like can be used in appropriate combinations. Of these dosage forms, the preferred form is oral administration.

  When used as a preparation for oral administration, the content of the brassinine of the present invention or an analogue thereof in the preparation is generally 0.0001 to 40% by weight, particularly 0.001 to 4% by weight of the total composition as a dry product. Is preferred. In addition, the content of phloretin or a glycoside thereof is generally 0.0001 to 40% by mass, particularly preferably 0.001 to 4% by mass of the total composition as a dried product.

In the case where the suppression of blood sugar elevation of the present invention is used as a food, in addition to various foods such as breads, cakes, noodles, confectionery, jelly, frozen foods, ice creams, dairy products, beverages, etc. Examples include the same forms (tablets, capsules, syrups, etc.) as oral preparations.
In order to prepare various forms of food, the brassinin or its analog of the present invention alone or other food materials, solvents, softeners, oils, emulsifiers, preservatives, fragrances, stabilizers, colorants , Antioxidants, humectants, thickeners, and the like can be used in appropriate combinations. The content of the brassinine of the present invention or its analog in the food is generally preferably 0.0001 to 40% by mass, more preferably 0.001 to 40% by mass as a dry product. In addition, the content of phloretin or a glycoside thereof is generally 0.0001 to 40% by mass, particularly preferably 0.001 to 4% by mass of the total composition as a dried product.

When the suppression of blood sugar elevation of the present invention is used as a pharmaceutical or food, the daily administration or intake amount per adult is preferably 0.01 to 400 mg, particularly 0.1 to 40 mg for brassin, for example. And preferably 0.1 to 4 mg. Moreover, when using together with phloretin or its glycoside, for example, about phloretin, it is preferable to set it as 0.01-400 mg, and it is preferable to set it as 0.1-4 mg especially.
Moreover, it is preferable to administer or ingest before blood sugar intake, and it is preferable to administer or ingest within 5 to 30 minutes before a meal.

1) Experimental materials and methods
(a) Five-week-old male Goto-Kakizaki rats (GK) were purchased and bred for 7 weeks in order to acclimate to the breeding environment. During the breeding period, blood glucose level was measured discontinuously three times or more using the commercially available blood glucose level measuring device Accu-Chek ^(R) (Roche Diagnostics) (non-administration blood glucose level reference value) An evaluation test was conducted after acclimatization to blood glucose level measurement operation. The blood glucose level was measured using peripheral blood obtained by tail vein puncture. All rats were housed under conditions of 25 ± 1 ° C., 55 ± 10% relative humidity, and 12 hours of illumination (7 am-7pm) (rat area breeding room).

(b) Administration method and dose: In the test group, brassinin (LKT Laboratories, Inc.) (2 mg / kg body weight) and phloretin (Sigma Aldrich) (2 mg / kg body weight) were used. ) Using brassine and phloretin in combination, dissolved in phosphate buffer (PBS) (10 ml / kg body weight) and administered orally. PBS (10 ml / kg body weight) was dissolved in PBS (10 ml / kg body weight) in the control group and phloretin (2 mg / kg body weight) was dissolved in PBS (10 ml / kg body weight). Administration was performed using an oral sonde. Glucose load was performed by orally administering glucose (2 g / kg body weight) dissolved in distilled water.

(c) Test method: The blood glucose level was measured using peripheral blood collected from the tail vein before administration (0 minutes), 30 minutes after glucose load, 60 minutes, 90 minutes, 120 minutes, and 180 minutes.
(d) Statistical processing method: The obtained measurement results are expressed as an average value and standard error, and a Student t-test is performed, and significance levels are * p <0.05, ** p <0.01, *** p <0.001.

2) Results As is apparent from Table 1, brassin significantly suppressed the increase in blood sugar after sugar intake. The action of brassin was enhanced by the combined use of brassin and phloretin.

Formulation Example (1) Fruit juice beverage brassine and its analog 0.002% by mass
Phloretin and its glycosides 0.002% by mass
Vegetable juice 40.0% by mass
(Carrot, lemon, parsley, broccoli alone or in mixture)
Fruit juice 40.0% by mass
(Apples, tangerines, Valencia oranges alone or as a mixture)
Acidulant appropriate amount Fragrance appropriate amount Vitamin C appropriate amount

(2) Candy brushin and its analog 0.002 mass%
Phloretin and its glycosides 0.002% by mass
Sucrose ester (emulsifier) 0.2% by mass
Minamata 35.0% by mass
Sugar 35.0% by mass
Wheat flour 5.0% by mass
Condensed milk 17.0% by mass
Milk 6.0% by mass
Butter 2.0% by mass
Perfume

Claims (3)

  A blood sugar elevation inhibitor containing brassin or an analog thereof.   The blood sugar elevation inhibitor according to claim 1, further comprising phloretin or a glycoside thereof.   A food or drink product comprising brassin or an analog thereof and exhibiting a blood glucose elevation-inhibiting action and having a display indicating that it is used for prevention or improvement of postprandial hyperglycemia.