JP5680498B2 - Composition for improving sugar metabolism - Google Patents

Description

  The present invention relates to a sugar metabolism improving agent comprising panaxatriol (PT), and a sugar metabolism improving composition containing the sugar metabolism improving agent.

  The number of diabetic patients in Japan is estimated to be about 8.2 million, and the number of diabetic reserves is estimated to be about 10.5 million, and the number is increasing year by year. Japanese people are prone to diabetes, that is, they are less likely to consume the food they eat and can easily store them, and the generous gene possession rate is said to be 2 to 5 times that of Westerners. Therefore, prevention or treatment of diabetes is an important problem.

Diabetes is classified into three types, normal type, borderline type, and diabetes type (Japanese Diabetes Society guidelines), and the diabetic reserve arm refers to borderline patients.
The criteria for determining the diabetes type are (1) fasting blood glucose level of 126 mg / dL or higher, (2) postprandial blood glucose level of 200 mg / dL or higher, and (3) blood glucose level after 2 hours in a 75 g glucose tolerance test is 200 mg. / DL or more, (4) There are typical symptoms of diabetes (dry mouth, heavy drinking, polyuria, weight loss, etc.), (5) HbA1c (glycohemoglobin) is 6.5% by mass or more, (6) certain Standards such as the presence of diabetic retinopathy are established.
The boundary type is (1) fasting blood glucose level is 110 mg / dL or more and less than 126 mg / dL, and (2) blood glucose level after 2 hours in a 75 g glucose tolerance test is 140 mg / dL or more and less than 200 mg / dL It corresponds to.

  Currently, as therapeutic agents for diabetes, sulfonylurea agents (SU agents) that promote insulin secretion, phenylalanine derivatives, α-glycosidase inhibitors that suppress sugar absorption, and biquanides that suppress sugar production in the liver ( BG) drugs, thiazolidine derivatives that improve insulin resistance, and the like are known, but few are effective in regulating both fasting blood glucose and postprandial blood glucose. In addition, these drugs are prescribed only when diabetes is diagnosed, and in order to prevent people belonging to the borderline from progressing to diabetes, they can only rely on diet and exercise therapy. Currently.

In addition, improvement of the hyperglycemic state due to diabetes is desired to be fundamentally improved including the constitution, not transient. Excess glucose taken into the body is taken into the liver and muscles from the blood and stored as glycogen. If this glycogen synthesis can be promoted, it is considered that the hyperglycemic state can be improved. Since 70% or more of the glucose metabolism is performed in muscles, improvement of hyperglycemia can be expected by promoting the uptake of glucose into muscles.
Thus, in order to maintain a constitution that actively performs glucose metabolism in muscles, not only the above-mentioned drugs but also improvement of diabetes by food therapy is effective. In addition to the above-mentioned drugs, there are many foods that can be taken as food and suppress postprandial blood glucose levels, but only drugs are present as drugs that suppress fasting blood glucose levels. There is a strong demand for provision.

Glycosides (ginsenoside) contained in ginseng are known to have a blood glucose level regulating action (see Patent Document 1) and an anti-diabetic action (Patent Document 2), and the sugar is released from the glycoside. Protopanaxatriol (PPT), which is an aglycone, has an anti-cancer effect (see Patent Documents 3 to 4), an anti-inflammatory action against skin diseases (see Patent Document 5), and gene expression important for fat metabolism and sugar metabolism. It is known to have various actions such as the activation action of PPARγ to be regulated (Patent Document 6).
Protopanaxatriol (PPT) is a white powder and is insoluble in water, but the solubility can be improved by adding an organic solvent. However, protopanaxatriol (PPT) is structurally unstable and decomposes rapidly in a liquid system, particularly in a low pH system. Moreover, it is a problem in that the decomposition proceeds on a daily basis under a temperature condition of room temperature or higher even in a powder state.

  Therefore, the present situation is that there is a demand for prompt provision of a compound that has a blood glucose level regulating action and a sugar metabolism improving action, is highly safe, can be ingested as a food and drink, and has high stability.

Special table 2008-533132 gazette JP-A 61-24597 JP 2005-504799 A JP 58-57399 A JP 2007-008896 A Korean Published Patent No. 10-2006-0131012

  An object of the present invention is to solve the conventional problems and achieve the following objects. That is, the present invention has an excellent blood glucose level regulating action and sugar metabolism improving action, is highly safe, can be ingested as a food and drink, and contains a highly stable sugar metabolism improving agent, and the sugar metabolism improving agent An object of the present invention is to provide a composition for improving sugar metabolism.

  In order to solve the above-mentioned problems, the present inventors have made extensive studies and as a result, obtained the following findings. That is, the glucose metabolism improving agent comprising panaxatriol (PT) promotes the uptake of sugar into muscle cells, suppresses the increase in postprandial blood glucose level, decreases the fasting blood glucose level, It has been found that it has a regulating action and a metabolism-promoting action of meal-derived sugars, and the present invention has been completed.

The present invention is based on the above findings by the present inventors, and means for solving the above problems are as follows. That is,
<1> A sugar metabolism improving agent comprising a compound represented by the following structural formula (1).
<2> The sugar metabolism-improving agent according to <1>, which has an inhibitory effect on postprandial blood glucose level increase.
<3> The sugar metabolism-improving agent according to any one of <1> to <2>, which has at least one of a fasting blood glucose level lowering action and a serum sugar metabolism-related index regulating action.
<4> The sugar metabolism-improving agent according to any one of <1> to <3>, which has an action of promoting metabolism of sugar derived from a meal.
<5> The sugar metabolism-improving agent according to any one of <1> to <4>, which has an action of promoting sugar uptake into muscle cells.
<6> The sugar metabolism-improving agent according to any one of <1> to <5>, wherein the sugar metabolism-improving action is exerted without being taken simultaneously with a meal.
<7> The sugar metabolism-improving agent according to any one of <1> to <6>, wherein the daily intake is at least 1 mg.
<8> A sugar metabolism improving composition comprising the sugar metabolism improving agent according to any one of <1> to <7>.
<9> A postprandial blood glucose level increase inhibitor comprising the sugar metabolism improving agent according to any one of <1> to <7>.
<10> A fasting blood glucose level-lowering agent comprising the sugar metabolism-improving agent according to any one of <1> to <7>.
<11> A sugar uptake promoter for muscle cells, comprising the sugar metabolism improving agent according to any one of <1> to <7>.
<12> A food or drink comprising the sugar metabolism-improving agent according to any one of <1> to <7>.

  ADVANTAGE OF THE INVENTION According to this invention, the said various problems in the past can be solved, the said objective can be achieved, it has the blood glucose level adjustment effect | action and the glucose metabolism improvement effect | action, it is highly safe, and can be ingested as food-drinks. A highly stable sugar metabolism improving agent and a sugar metabolism improving composition containing the sugar metabolism improving agent can be provided.

FIG. 1 is a graph showing changes in fasting blood glucose levels in human tests. The vertical axis represents the blood glucose level (mg / dL), and the horizontal axis represents the number of days elapsed after the start of PT intake. FIG. 2 is a graph showing changes in postprandial blood glucose levels in the placebo ingestion group of the human test. The vertical axis represents the blood glucose level (mg / dL), and the horizontal axis represents the elapsed time (minutes) after the meal. FIG. 3 is a graph showing changes in postprandial blood glucose levels in the panaxatriol (PT) intake group of the human test. The vertical axis represents the blood glucose level (mg / dL), and the horizontal axis represents the elapsed time (minutes) after the meal. FIG. 4 is a graph showing the measurement results of the respiratory quotient of each group in Example 4. The vertical axis represents the respiratory quotient (RQ), and the horizontal axis represents the measurement time (time). FIG. 5A is a graph showing changes with time in ¹³ CO ₂ emission of each group in Example 5. The vertical axis represents emission amount of ¹³ CO ₂ in breath (volume ratio%) and the horizontal axis represents ^glucose-U- 13 _{C 6} after administration time (min). FIG. 5B is a graph showing the accumulated ¹³ CO ₂ emission amount of each group in Example 5. The vertical axis represents AUC ( ¹³ CO ₂ emission increase value).

(Sugar metabolism improving agent)
The sugar metabolism improving agent of the present invention comprises a compound represented by the following structural formula (1).

<Compound represented by Structural Formula (1)>
The compound represented by the structural formula (1) is a compound belonging to danmaran triterpenes. Hereinafter, it may be referred to as “panaxatriol (PT)”.
Panaxatriol (PT) is an aglycon body in which sugar is removed from a plant-derived saponin (glycoside), the side chain is closed.

-How to obtain-
There is no restriction | limiting in particular as an acquisition method of the said panaxatriol (PT), According to the objective, it can select suitably, For example, the method obtained from a commercial item, the method obtained by synthesis, the method obtained from the said plant, etc. Can be mentioned.
There is no restriction | limiting in particular as said plant, Although it can select suitably according to the objective, Araliaceae ginseng is preferable and, among these, the ginseng is more preferable.
The saponin derived from the ginseng ginseng is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ginsenoside-Rg ₁ , notoginsenoside-R ₁ , and ginsenoside-Re.

  Below, an example of the method of obtaining panaxatriol (PT) derived from the ginseng ginseng is demonstrated. The method for obtaining panaxatriol (PT) derived from the ginseng ginseng is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method of extraction and / or purification from ginseng ginseng. It is done.

There is no restriction | limiting in particular as a method obtained by the said extraction, According to the objective, it can select suitably, For example, the method etc. which are obtained by extracting a rice ginseng powder with a water-ethanol solution are mentioned.
The mixing ratio of the water-ethanol solution is not particularly limited and may be appropriately selected depending on the intended purpose. Water: ethanol (V / V) is preferably 9: 1 to 2: 1, and 3: 1 is more preferable.
In the extraction, a method in which hydrochloric acid is contained in the water-ethanol solution and acid hydrolysis is preferable in that an extract containing a high concentration of panaxatriol (PT) can be obtained. There is no restriction | limiting in particular as a density | concentration of the said hydrochloric acid, Although it can select suitably according to the objective, 0.04 mass%-16 mass% are preferable, and 2 mass%-12 mass% are more preferable.
There is no restriction | limiting in particular as temperature of the said acid hydrolysis, Although it can select suitably according to the objective, 60 to 100 degreeC is preferable and 70 to 90 degreeC is more preferable.
There is no restriction | limiting in particular as time of the said acid hydrolysis, Although it can select suitably according to the objective, 0.5 to 24 hours are preferable and 2 to 8 hours are more preferable.
Nanajin participation water decomposition solution obtained by the acid hydrolysis is further neutralized with caustic soda, if necessary, after reducing ethanol concentration, filtered by suction or other methods, the residue is freeze-dried , Drying under reduced pressure, spray drying, etc. can be performed, whereby the panaxatriol (PT) derived from the ginseng can be obtained.

There is no restriction | limiting in particular as a method obtained by the said refinement | purification, According to the objective, it can select suitably, For example, the method etc. which refine | purify using a silica gel column etc. are mentioned.
There is no restriction | limiting in particular as a method refine | purifying using the said silica gel column, According to the objective, it can select suitably, For example, the ethanol solution containing 1 mass%-5 mass% of the processed material obtained by acid hydrolysis Next, after removing insolubles using a filter paper or a centrifuge, it was further concentrated 5 to 10 times using a rotary evaporator and filled with silica gel (for example, silica gel 60N manufactured by Kanto Chemical Co., Inc.). Examples include a method in which the concentrated solution is added to a glass column and column separation is performed using chloroform: ethanol = 10: 1 (V / V) as an eluent.
On normal phase TLC using chloroform: ethanol = 10: 1 (V / V) as a developing solvent, the fraction corresponding to an Rf value of 0.4 is concentrated to obtain highly pure panaxatriol (PT). be able to.

<Ingestion>
There is no restriction | limiting in particular as an ingestion method of the said sugar metabolism improving agent, ingestion amount, the frequency | count of ingestion, ingestion time, and ingestion object, According to the objective, it can select suitably.
There is no restriction | limiting in particular as said ingestion method, Although it can select suitably according to the objective, The method of ingesting orally is preferable at the point which is easy to continue since it can ingest easily.
The intake amount is not particularly limited and may be appropriately selected in consideration of various factors such as the age, weight, constitution, symptom, and presence / absence of administration of a drug containing another component as an active ingredient. However, the daily intake is preferably at least 1 mg, more preferably 2 to 20 mg. Within the preferred range, it is advantageous in that both postprandial blood glucose level and fasting blood glucose level can be suppressed, and taking ability can be improved.
Moreover, there is no restriction | limiting in particular as said frequency | count of ingestion, Although it can select suitably according to the objective, Once a day is preferable at the point with the convenience.
There is no restriction | limiting in particular as said intake time, According to the objective, it can select suitably. In order to reduce the troublesomeness of the user for taking it, the intake time should not be limited at the same time as the meal or after the meal, and the sugar metabolism improving effect is exhibited even if it is not taken at the same time as the meal. However, if the form of intake is a dosage form that can be ingested as a normal food without any problems, the effect of improving glucose metabolism does not differ depending on the time of intake. It is not related to simultaneous intake.
The animal species to be ingested are those that are suitably applied to humans, but as long as their effects are exerted, animals other than humans (eg, mice, rats, hamsters, birds, dogs, Cats, sheep, goats, cows, pigs, monkeys, etc.).

<Sugar metabolism improving effect>
The sugar metabolism-improving action of the sugar metabolism-improving agent is not particularly limited and can be appropriately selected according to the purpose. However, the action of suppressing the increase in postprandial blood glucose level by the action of promoting sugar uptake into cells, It preferably has at least one of a blood glucose level lowering action and a meal-derived sugar metabolism promoting action.

-Sugar uptake into cells-
There is no restriction | limiting in particular as said cell, According to the objective, it can select suitably, For example, although a muscle cell, a liver cell, a fat cell etc. are mentioned, Among these, it is preferable that it is a muscle cell. Since the muscle cell is a cell responsible for 70% or more of sugar metabolism, it can be expected to function efficiently as a sugar uptake organ. On the other hand, since liver and fat cells have a risk of developing into symptoms such as fatty liver and obesity, improvement of the hyperglycemic state can be expected, but it is desirable that muscle cells become the main body of glucose uptake if possible.
The details of the action mechanism of the sugar uptake-promoting action are not clear, but the sugar metabolism-improving agent promotes translocation of GLUT4 localized in the cell onto the cell membrane. It is estimated that.

-Evaluation method of sugar uptake promoting action-
The method for evaluating the sugar uptake promoting action is not particularly limited and can be appropriately selected according to the purpose. For example, the sugar metabolism improving agent is added to the culture medium of cultured cells and sensitized for a certain period of time. Then, the labeled sugar is taken in, the cultured cells are solubilized, and the label in the cultured cells is measured.
There is no restriction | limiting in particular as said cultured cell, According to the objective, it can select suitably, For example, L6 cell which is a rat skeletal muscle origin cell, C2C12 cell which is a mouse | mouth skeletal muscle origin cell, etc. can be used.
The medium for culturing the L6 cells is not particularly limited and may be appropriately selected according to the purpose. For example, 10% by mass FBS (fetal bovine serum) and 1% by mass AB (anti-biotic solution) are used. Examples thereof include DMEM (Dulbecco's modified Eagle medium). The method for inducing differentiation of the L6 cells is not particularly limited and may be appropriately selected according to the purpose. For example, a method of culturing in MEM containing 2% by mass FBS and 1% by mass AB Etc.
There is no restriction | limiting in particular as said sugar label, According to the objective, it can select suitably, For example, RI label etc. are mentioned. The method for incorporating the RI-labeled sugar is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method of adding RI-labeled sugar to the medium. There is no restriction | limiting in particular also as said sugar, According to the objective, it can select suitably, For example, glucose etc. are mentioned.
There is no restriction | limiting in particular as a method of solubilizing the said cell, According to the objective, it can select suitably, For example, the method using 0.05N sodium hydroxide etc. are mentioned.
When the sugar label is an RI label, the method for measuring its radioactivity is not particularly limited and can be appropriately selected according to the purpose. For example, a scintillation cocktail can be added to a vial in which solubilized cells are collected. Examples include a method in which Picoflour (manufactured by Perkin Elmer) is added and measurement is performed using a scintillation counter.

-Postprandial blood glucose level-
The postprandial blood glucose level refers to a blood glucose level 30 minutes to 120 minutes after the meal.
The postprandial blood glucose level can be appropriately selected depending on the age, the elapsed time after the meal, etc. In humans, it is preferably less than 180 mg / dL at 30 minutes after meal, and less than 140 mg / dL at 120 minutes after meal. .

-Evaluation method of postprandial blood glucose level-
The method for evaluating postprandial blood glucose level is not particularly limited and can be appropriately selected according to the purpose. For example, there are a method for evaluating with a hyperglycemic model mouse, a method for evaluating a human with a starch diet, and the like. Can be mentioned.
The blood glucose level measurement method is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a method of measuring with a simple blood glucose meter (eg, Freestyle manufactured by Nipro Corporation), cyclic Examples include a method of measuring with a GB sensor (manufactured by Sanko Junyaku Co., Ltd.).

---- Evaluation method using hyperglycemia model mice ---
The method for evaluating with the hyperglycemic model mouse is not particularly limited and can be appropriately selected according to the purpose. For example, the method is bred for a certain period of time with a high-fat diet mixed with the sugar metabolism-improving agent. A method of measuring the blood glucose level later is included.
There is no restriction | limiting in particular as said hyperglycemia model mouse, According to the objective, it can select suitably, For example, a KKAy mouse | mouth (Clea Japan Co., Ltd.), a ZDF rat (Nippon Charles River Co., Ltd.), etc. are mentioned.
There is no restriction | limiting in particular as said high fat meal, According to the objective, it can select suitably, For example, a commercial item (Quick Fat, Japan Claire Co., Ltd.) etc. can be used.
There is no restriction | limiting in particular as said breeding period, According to the objective, it can select suitably, For example, 4 days-35 days etc. are mentioned.

--- Method for evaluating a human being loaded with a starch diet ---
There is no restriction | limiting in particular as a method to load and evaluate the said human being with a starch diet, According to the objective, it can select suitably, For example, a fasting blood glucose level is high (120 mg / dL-140 mg / dL) to a test subject. Measure a change in blood glucose level for up to 120 minutes every 30 minutes after a meal by ingesting a prescribed meal for a certain period of time, taking a sugar metabolism-improving agent once a day when it is not taken at the same time as the meal The method of doing is mentioned.
There is no restriction | limiting in particular as said test period, According to the objective, it can select suitably, For example, 4 to 16 weeks etc. are mentioned.
The determined meal is not particularly limited and may be appropriately selected according to the purpose. A meal having a high starch content such as rice or pasta is preferable.

-Fasting blood glucose level-
The fasting blood sugar level refers to the blood sugar level of blood collected by fasting after waking up in the morning. Strictly speaking, it is desirable that the blood glucose level is measured by collecting blood after an interval of 10 hours or more from a meal.
The fasting blood glucose level can be appropriately selected depending on age and the like, but is preferably less than 110 mg / dL for humans.

-Evaluation method of fasting blood glucose level-
The method for evaluating the fasting blood glucose level is not particularly limited, and can be appropriately selected according to the purpose.For example, except that the measurement time is fasting, the human is loaded with a starch diet. The evaluation can be performed by the same method as that used for evaluation.

-Sugar metabolism-related indicators-
There is no restriction | limiting in particular as said glucose metabolism related parameter | index, According to the objective, it can select suitably, For example, a blood parameter | index etc. are mentioned.
The blood index is not particularly limited and can be appropriately selected according to the purpose. Examples thereof include HbA1c (glycohemoglobin), glycoalbumin, 1 / 5AG (1,5 anhydroglucitol), insulin and the like. Can be mentioned.
The method for measuring the blood index is not particularly limited and can be appropriately selected depending on the purpose. For example, using blood collected during an evaluation test in which the human being is loaded with a starch diet, It can be measured according to a conventional method.

--HbA1c--
The HbA1c (glycohemoglobin) refers to a state in which hemoglobin (Hb) in erythrocytes and glucose are bound. That is, as the blood glucose level increases, the value of HbA1c increases. Since the reaction rate between the hemoglobin (Hb) and glucose is slow, the value does not depend on the temporary physiological condition, and reflects the average blood glucose over the past one to two months.
The normal value of the HbA1c is 4.3% by mass to 5.8% by mass, and if it is 6.5% by mass or more, the suspicion of diabetes becomes extremely high.

--Glycoalbumin--
The glycoalbumin refers to a state in which albumin in blood and glucose are bound. That is, as the blood glucose level increases, the value of glycoalbumin increases.
Since the albumin has a short half-life compared to the HbA1c, it reflects the past average blood glucose that is closer to the HbA1c, that is, the average blood glucose one to two weeks before.
The normal value of the glycoalbumin is 11.6% by mass to 16.4% by mass.

--1, 5AG-
The 1 · 5AG is a polyol having a structure similar to glucose and is abundant in the body. The 1 · 5AG is supplied from food, and the excess 1 · 5AG is excreted into the urine. Under normal conditions, the 1.5AG is reabsorbed by renal tubules, but when glucose is excreted (urine sugar) due to hyperglycemia, the reabsorption of 1.5AG is subject to competitive inhibition, and urine The blood concentration is reduced by being lost. As described above, the 1.5 AG is increased or decreased under the influence of urine sugar, so that it becomes an index of blood glucose from the present to the latest.
However, when the HbA1c is at a level of 10% by mass or more, the 1.5AG is discharged out of the body. In this case, it is suitable to use the HbA1c as an index.
The normal value of 1.5G is 14 μg / mL to 46 μg / mL.

-Promotion of dietary sugar metabolism-
There is no restriction | limiting in particular as sugar derived from a meal, According to the objective, it can select suitably, For example, sucrose, maltose, lactose, glucose, fructose, galactose etc. are mentioned.

  There is no restriction | limiting in particular as a method of evaluating the said glucose metabolism promotion effect, According to the objective, it can select suitably, For example, the method of measuring a respiratory quotient (RQ), the method of measuring a carbon dioxide discharge, etc. Can be mentioned. Animals normally use carbohydrates or lipids as energy sources, but by measuring the respiratory quotient, the consumption rate of carbohydrates or lipids can be calculated. The respiratory quotient indicates that the higher the value, the more the carbohydrate is metabolized as a nutrient source.

<Application>
The above-mentioned glucose metabolism improving agent has an excellent inhibitory effect on postprandial blood glucose level increase, fasting blood glucose level lowering effect, glucose metabolism related index regulating effect, glucose uptake promoting activity into muscle cells, and dietary glucose metabolism promotion Since it has an effect | action, it can utilize suitably as a glucose metabolism improvement composition mentioned later, a postprandial blood glucose level rise inhibitor, a fasting blood glucose level lowering agent, and a sugar uptake promoter.

(Sugar metabolism improving composition)
The sugar metabolism improving composition of the present invention contains the aforementioned sugar metabolism improving agent, and further contains other components as necessary.
There is no restriction | limiting in particular as content of the said sugar metabolism improving agent in the said sugar metabolism improving composition, According to the objective, it can select suitably. The sugar metabolism improving composition may be the sugar metabolism improving agent itself.

The other components of the composition for improving sugar metabolism are not particularly limited and may be appropriately selected depending on the purpose within a range not impairing the effects of the present invention. For example, pharmacology such as ethanol, water, starch, etc. Pharmaceutically acceptable carriers, auxiliary raw materials or additives used for foods and drinks described below.
There is no restriction | limiting in particular also as content of the said other component, According to the objective, it can select suitably.

<Use>
The sugar metabolism-improving composition may be used singly or in combination of two or more, and may be used in combination with a pharmaceutical having other ingredients as active ingredients. Moreover, the said sugar metabolism improvement composition may be used in the state mix | blended in the pharmaceutical which uses another component as an active ingredient.

<Application>
The use of the composition for improving sugar metabolism can be suitably used, for example, for the prevention or treatment of diabetes. Moreover, it can utilize suitably also for the food / beverage products mentioned later.

(Postprandial blood glucose level rise inhibitor, fasting blood glucose level lowering agent, and sugar uptake promoter)
<Postprandial blood glucose level rise inhibitor>
The postprandial blood glucose level increase inhibitor of the present invention contains the aforementioned sugar metabolism improving agent, and further contains other components as necessary.
There is no restriction | limiting in particular as content of the said glucose metabolism improving agent in the said postprandial blood glucose level rise inhibitor, According to the objective, it can select suitably. Moreover, the postprandial blood glucose level increase inhibitor may be the sugar metabolism improving agent itself.

The other components are not particularly limited and may be appropriately selected depending on the purpose. For example, the other components may be selected from pharmacologically acceptable carriers according to the dosage form of the postprandial blood glucose level increase inhibitor. It can select suitably, For example, ethanol, water, starch, etc. are mentioned.
There is no restriction | limiting in particular also as content of the said other component, According to the objective, it can select suitably.

<Fasting blood glucose level lowering agent>
The fasting blood glucose level-lowering agent of the present invention contains the aforementioned sugar metabolism-improving agent, and further contains other components as necessary.
There is no restriction | limiting in particular as content of the said sugar metabolism improving agent in the said fasting blood glucose level lowering agent, According to the objective, it can select suitably. Further, the fasting blood glucose level-lowering agent may be the sugar metabolism improving agent itself.

The other components are not particularly limited and may be appropriately selected depending on the purpose. For example, the other components may be selected from among pharmacologically acceptable carriers depending on the dosage form of the fasting blood glucose level-lowering agent. It can select suitably, For example, ethanol, water, starch, etc. are mentioned.
There is no restriction | limiting in particular also as content of the said other component, According to the objective, it can select suitably.

<Sugar uptake promoter>
The sugar uptake promoter of the present invention contains the aforementioned sugar metabolism improving agent, and further contains other components as necessary.
There is no restriction | limiting in particular as content of the said sugar metabolism improving agent in the said sugar uptake promoter, According to the objective, it can select suitably. The sugar uptake promoter may be the sugar metabolism improving agent itself.

The other components are not particularly limited and may be appropriately selected depending on the purpose. For example, the other components may be appropriately selected from pharmacologically acceptable carriers according to the dosage form of the sugar uptake promoter. For example, ethanol, water, starch and the like can be mentioned.
There is no restriction | limiting in particular also as content of the said other component, According to the objective, it can select suitably.

<Use>
The postprandial blood glucose level elevation inhibitor, the fasting blood glucose level lowering agent, and the sugar uptake promoter may be used singly or in combination of two or more. You may use together with the medicine made into an active ingredient. Moreover, the postprandial blood glucose level rise inhibitor, the fasting blood glucose level lowering agent, and the sugar uptake promoter may be used in a state of being blended in a medicine containing other components as active ingredients.

<Application>
Examples of the use of the postprandial blood glucose level increase inhibitor, the fasting blood glucose level lowering agent, and the sugar uptake promoter can be suitably used for the prevention or treatment of diabetes. Moreover, it can utilize suitably also for the food / beverage products mentioned later.

(Food)
The food / beverage products of this invention contain the said sugar metabolism improving agent, and also contain another component as needed.
Here, the food and drink are those which are less likely to harm human health and are taken by oral or gastrointestinal administration in normal social life. It is not limited to the category of goods, etc., and means, for example, a wide range of foods that are taken orally, such as general foods, health foods, health functional foods, quasi drugs, and pharmaceuticals.

There is no restriction | limiting in particular as a compounding quantity of the said sugar metabolism improving agent in the said food / beverage products, It can mix | blend suitably according to the kind of food / beverage products used as long as the effect of this invention is not impaired.
The food or drink may contain only the sugar metabolism improving agent, and the food or drink may be the sugar metabolism improving agent itself.

<Type of food and drink>
There is no restriction | limiting in particular as said kind of food / beverage products, According to the objective, it can select suitably, For example, drinks, such as a soft drink, a carbonated drink, a nutritive drink, a fruit drink, a lactic acid drink; Ice cream, ice sherbet, Frozen confectionery such as shaved ice; noodles such as buckwheat, udon, harusame, gyoza peel, sushi mai, Chinese noodles, instant noodles; rice cake, candy, gum, chocolate, tablet confectionery, snack confectionery, biscuits, jelly, jam, cream, baked Confectionery such as confectionery and bread; crab, salmon, clams, tuna, sardines, shrimp, skipjack, mackerel, whale, oyster, saury, squid, red scallop, scallop, abalone, sea urchin, salmon roe, tocobushi, etc .; Processed fishery and livestock products such as sausages; dairy products such as processed milk and fermented milk; salad oil, tempura oil, margarine, ma Oils and processed oils such as nauses, shortenings, whipped creams, dressings; seasonings such as sauces and sauces; curry, stew, oyakodon, rice cakes, miscellaneous cooking, Chinese rice cakes, bowls, tempura, eel rice, hayashi rice, oden, Retort pouch foods such as Mabodorf, beef bowl, meat sauce, egg soup, omelet rice, dumplings, shumai, hamburger, meatballs; various forms of health foods, nutritional supplements, pharmaceuticals, quasi drugs, and the like.

<Other ingredients>
There is no restriction | limiting in particular as said other component, According to the objective, it can select suitably, For example, the auxiliary | assistant raw material or additive etc. which are normally used in manufacturing food-drinks are mentioned.
The auxiliary raw material or additive is not particularly limited and may be appropriately selected depending on the intended purpose. For example, glucose, fructose, sucrose, maltose, sorbitol, stevioside, rubusoside, corn syrup, lactose, citric acid , Tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, Arabia Examples include gum, carrageenan, casein, gelatin, pectin, agar, vitamin Bs, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, pigments, fragrances, preservatives and the like.
There is no restriction | limiting in particular as content of the said other component, According to the objective, it can select suitably.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples at all.

(Example 1: Blood glucose level of hyperglycemia model mouse)
<Method>
By using a diet containing panaxatriol (PT) (manufactured by LKT Laboratories) at a ratio shown in Table 1 below for a commercially available high fat diet (trade name: Quick Fat, manufactured by CLEA Japan, Inc.), by free intake, Hyperglycemia model mice (KKAy mice (CLEA Japan, Inc., 8 weeks old, 5 mice / group) were bred for 5 days (hereinafter sometimes referred to as “PT combination group”). As a control, a feed containing no panaxatriol (PT) was used (hereinafter, sometimes referred to as “PT-free group”).
The blood glucose level at 10:00 am was measured before (initial value) and after (after raising) the breeding with the panaxatriol (PT) -containing high fat diet. The blood glucose level was measured with a cyclic GB sensor (manufactured by Sanko Junyaku Co., Ltd.). The average value measured twice as postprandial blood glucose level of each individual is shown in Table 1 below. Statistical analysis was performed by Dunnett's multiple test.

<Result>
From Table 1, in the PT non-blending group (control), when the initial value was compared with 5 days after breeding, a significant increase in postprandial blood glucose level was observed in 5 days. On the other hand, in the administration group containing 0.0001% by mass of PT, the increase in postprandial blood glucose level was significantly suppressed at a risk rate of less than 10% compared to the PT non-combination group (control). In the administration group containing 0.001% by mass, an increase in postprandial blood glucose level was significantly suppressed at a risk rate of less than 5% compared to the PT non-administration group (control), and in the administration group containing 0.01% by mass The increase in postprandial blood glucose level was significantly suppressed at a risk rate of less than 1% with respect to the PT-free group (control).
From these results, it was confirmed that the KKAy mouse had an effect of suppressing an increase in postprandial blood glucose level by blending PT with 0.0001% by mass or more.

(Example 2: Uptake of sugar into rat skeletal muscle-derived cells)
<Method>
DMEM containing rat skeletal muscle-derived cells (L6 cells, manufactured by Dainippon Pharmaceutical Co., Ltd.) containing 10% by mass FBS (fetal bovine serum, manufactured by GIBCO) and 1% by mass AB (anti-biotic solution, manufactured by SIGMA) (Dulbecco's modified Eagle medium, manufactured by SIGMA) was suspended in 15 mL, dispensed into a 75 cm ² culture flask, and then statically cultured at 37 ° C. in a 5% CO ₂ environment. After reaching subconfluence (80%), the cells were seeded at a density of 50,000 cells / well in a 24-well plate (manufactured by Sumitomo Bakelite Co., Ltd.). After reaching confluence, the cells were cultured for 3 days and then replaced with MEM (minimal essential medium, manufactured by Nacalai Tesque, Inc.) containing 2% by mass FBS and 1% by mass AB to induce differentiation of L6 cells. 8 days after differentiation induction, panaxatriol (PT) (dissolved in ethanol) was added to 1 ppm or 10 ppm. A well containing no PT was used as a control. Next, desensitization was performed by replacing with MEM containing 2% by mass BSA (bovine serum albumin, manufactured by SIGMA) to which panaxatriol (PT) was added to 1 ppm or 10 ppm after 30 hours. After 18 hours, the 2% by mass BSA-containing MEM was removed, and KRH buffer (50 mM HEPES (manufactured by SIGMA), pH 7.4, 137 mM sodium chloride (manufactured by Wako Pure Chemical Industries, Ltd.), 4.8 mM potassium chloride ( Wako Pure Chemical Industries, Ltd.), 1.85 mM calcium chloride (Wako Pure Chemical Industries, Ltd.), 1.3 mM magnesium sulfate (Wako Pure Chemical Industries, Ltd.)) were added at 30 μL / well. Then, 6 μL of RI-labeled 2-deoxyglucose (2-DG, manufactured by American Radiolabeled Chemicals) was added (the final concentration was 6.5 mM (0.5 · Ci)) and reacted. Five minutes after the start of the reaction, the cells were washed four times with ice-cooled KRH buffer to remove 2-DG that was not incorporated into L6 cells. After removing the KRH buffer, the cells were solubilized with 250 μL of 0.05N sodium hydroxide (Wako Pure Chemical Industries, Ltd.) and collected in a vial. Further, it was washed twice with 200 μL of KRH buffer, and similarly recovered in a vial. 3 mL of liquid scintillation cocktail Picofloor (Perkin Elmer Co., Ltd.) was added to the vial from which the cells were collected, and radioactivity was measured using a liquid scintillation counter (LSC-5100, manufactured by Aloka).
Evaluation was made with n = 4, and the average value was obtained. All statistical analyzes were performed by Student's t-test, with P <0.05 giving a significant difference. The specific activity when the radioactivity in the case of no addition is defined as 100 is shown in Table 2 below.

<Result>
From Table 2, an increase in glucose uptake into the cells was observed by adding PT to L6 cells.
These results suggest that the panaxatriol (PT) -containing sugar metabolism-improving agent of the present invention has an action of promoting sugar uptake in the muscle which is the central organ of sugar uptake in the living body.

(Example 3: Human test)
<Measurement of glucose metabolism-related indicators>
-Method-
After suspending 10 g of ginseng powder in 100 mL of a 30% by weight aqueous ethanol solution, saponins such as ginsenoside-Rg ₁ , notoginsenoside-R ₁ , ginsenoside-Re and the like were heated and extracted for 2 hours. Hydrolysis was performed in the presence of hydrochloric acid to prepare an aglycone-containing treated product. The aglycone-containing treated product was isolated using a silica gel column (silica gel 60N manufactured by Kanto Chemical Co., Inc.) to prepare panaxatriol (PT) having a purity of 99% by mass or more.
A capsule containing 8 mg of panaxatriol (PT) prepared in this manner was prepared, and the fasting blood glucose level when continuously ingested for 8 weeks (hereinafter sometimes referred to as “PT intake group”), as well as predetermined The changes in postprandial blood glucose level after ingesting a meal of the menu (a menu loaded with starch meal such as rice balls (350 kcal) using 200 g of cooked rice) were measured. As blood indices, HbA1c level, glycoalbumin level, 1.5 AG, and fasting insulin level in blood were measured.
Blood glucose levels are measured using a simple blood glucose meter (Freestyle, manufactured by Nipro Corporation), measuring fasting blood glucose levels and fasting insulin levels at 9 am, and measuring postprandial blood glucose levels at 9 am After ingesting a predetermined starch meal at 11:30 am, measurements were taken every 30 minutes until 120 minutes later. HbA1c value, glycoalbumin value, and 1.5AG were measured using blood collected at 9:00 am in accordance with the standard method of medical institutions.
The subjects (24) were fasting blood glucose levels of 120 mg / dL to 140 mg / dL, placed in a placebo intake group as a control, 24 were randomly divided into 2 groups, placebo intake group and PT intake Assigned to groups. Moreover, the statistical analysis about the result performed the student t test which compared the placebo intake group and the PT intake group. Moreover, the time slot | zone which ingests a capsule was set to 10:00 am every day, and was set in the time slot | zone which is not taken simultaneously with a meal.
FIG. 1 shows the measurement results of fasting blood glucose level.
FIG. 2 shows changes in postprandial blood glucose levels in the placebo intake group, and FIG. 3 shows changes in postprandial blood glucose levels in the PT intake group.
The measurement results of the blood index in the placebo intake group are shown in Table 3 below, and the measurement results of the blood index in the PT intake group are shown in Table 4 below.

-Result-
As a result of the human test (Example 3), the fasting blood glucose level in the PT ingestion group was significantly reduced as compared with the placebo ingestion group (FIG. 1). The postprandial blood glucose level in the PT ingestion group was significantly reduced 30 minutes, 60 minutes, and 120 minutes after the ingestion compared with the placebo ingestion group, and a clear effect of improving glucose metabolism was observed (FIGS. 2-3). ).
From these results, it became clear that the agent for improving diabetes of the present invention containing panaxatriol (PT) decreases both fasting blood glucose level and postprandial blood glucose level.
Moreover, as a result of confirming the index regarding the glucose metabolism in the blood from Tables 3 to 4, HbA1c in the PT ingestion group significantly decreased after 8 weeks ingestion compared to the placebo ingestion group. Glycoalbumin in the PT intake group was significantly lower than that in the placebo intake group. In addition, glycoalbumin was also significantly decreased between the 0th week and the 8th week of the PT intake group. An increase in 1.5 AG in the PT intake group was observed after the 4th week. In the PT ingestion group, there was no statistically significant change in fasting insulin levels, so panaxatriol (PT) did not increase insulin secretion but improved insulin sensitivity. It is thought that.
From these results, the diabetes-ameliorating agent of the present invention containing panaxatriol (PT) does not need to be taken at the same time as a meal, and is effective when taken once a day. It is considered highly significant above.

(Example 4: Recovery effect of respiratory quotient)
12 hyperglycemia model mice (KKAy mice (CLEA Japan, male, 4 weeks old)) in individual cages under conditions of room temperature 22 ± 1 ° C, humidity 50 ± 5%, 12 hours light / dark cycle Preliminary breeding. During the pre-breeding period, 8 g of CE-2 (manufactured by CLEA Japan, Inc.) per mouse was given per day, and the water supply was freely consumed.
After completion of the pre-breeding period, body weight and blood glucose level were measured and divided into two groups of 6 animals / group so as to be average, and the main breeding was performed by the following method.
The blood glucose level was measured by collecting blood from the mouse tail vein and measuring the whole blood twice using a cyclic GB sensor (manufactured by Sanko Junyaku Co., Ltd.).

-Control group-
A commercially available high-fat diet (trade name: Quick Fat, manufactured by CLEA Japan, Inc.) was given 8 g per mouse per day, and water was freely fed, and this breeding was carried out for 1 week. Hereinafter, it may be referred to as a “control group”.

-Tanachi ginseng treatment group-
After suspending 10 g of ginseng powder in 100 mL of a 30% by weight ethanol aqueous solution, saponins were heated and extracted for 2 hours, and the resulting extract was hydrolyzed in the presence of hydrochloric acid to prepare an aglycone-containing treated product. .
About 0.1 g of the obtained aglycone-containing processed product was precisely weighed, about 8 mL of ethanol (purity 99.5% by mass) was added, and suspended for 15 minutes using an ultrasonic bath. After centrifugation at about 700 × g for 10 minutes, ethanol (purity 99.5% by mass) was added to the supernatant to make exactly 10 mL. When this liquid was measured by gas chromatography under the following conditions, the content of panaxatriol (PT) was 8.0% by mass. The retention time of panaxatriol (PT) under the following conditions was about 29 minutes.
[Analysis conditions]
Gas chromatograph: GC353B manufactured by GL Sciences Inc.
Detector: Hydrogen flame ionization detector (FID)
Injection method: Split injection method (split ratio 1:50)
Column: DB-17MS manufactured by J & W (length 30 m, inner diameter 0.25 mm, film thickness 0.25 μm)
Column temperature: Initial temperature: 310 ° C
Initial temperature holding time: 20 minutes
Temperature increase rate: 10 ° C / min
Achieving temperature: 320 ° C
Achieving temperature holding time: 14 minutes Carrier gas: Helium Flow rate: 1.5 mL / min Inlet temperature: 320 ° C
Detector temperature: 320 ° C
Injection volume: 1 μL

  8 g of feed (aglycone content 0.1% by mass) per mouse per day containing 1% by mass of the aglycone-containing processed product in a commercial high fat diet (trade name: Quick Fat, manufactured by CLEA Japan, Inc.) (PT: about 6.4 mg / day), and water was freely taken. Hereinafter, it may be referred to as “Tanachi ginseng treated product administration group”.

After this breeding for one week, the breath gas measurement was performed for 24 hours. That is, a mouse is bred in a breath gas analysis chamber (150 mm × 150 mm × 150 mm, manufactured by Muromachi Kikai Co., Ltd.), and the oxygen consumption, carbon dioxide emission, and respiratory quotient (RQ) are measured for a small animal metabolic measurement system MK-5000RQ. It was measured continuously (Muromachi Kikai Co., Ltd.). During the measurement, as in the breeding period, the control group was given 8 g of a commercially available high fat diet per mouse per day, and the group 7 ginseng treated product-containing group contained 1% by mass of the above aglycone. The feed containing the treated product was given 8 g per mouse per day. Both water supplies were free intake.
The respiratory quotient (RQ) is calculated by the following equation.
Respiratory quotient (RQ) = carbon dioxide output per unit time / oxygen output per unit time where RQ = 1.0 for carbohydrates and RQ = 0.7 for lipids. Therefore, how much sugar or lipid is used can be determined from the value of the respiratory quotient.

FIG. 4 shows the measurement result of the respiratory quotient. From these results, an increase in the RQ value was observed in the group of processed ginseng treated products. That is, the intake effect of the ginseng treated product containing panaxatriol (PT) was confirmed to improve the carbohydrate consumption ability.
When the carbohydrate consumption rate was calculated by the following formula, it was 50.7% in the control group, but increased to 60.8% in the Tanachi ginseng treated group, and the carbohydrate consumption rate was increased. It was.
Respiratory quotient (RQ) = 1.0 × (x / 100) + 0.7 × (1−x / 100)
In the above formula, “x” represents a carbohydrate consumption rate (%).

(Example 5: Effect of promoting sugar metabolism on diet-derived sugar)
Sixteen hyperglycemic model mice (KKAy mice (CLEA Japan, male, 4 weeks old)) were preliminarily raised for 1 week in the same manner as in Example 4.
After completion of the preliminary breeding period, the body weight and blood glucose level were measured and divided into two groups of 8 animals / group so as to be average, and the main breeding was carried out by the following method. In addition, the blood glucose level was measured by collecting blood from the tail vein of the mouse and measuring whole blood using a cyclic GB sensor (manufactured by Sanko Junyaku Co., Ltd.).

-Control group-
A commercially available high-fat diet (trade name: Quick Fat, manufactured by CLEA Japan, Inc.) was given 8 g per mouse per day, and water was freely fed, and this breeding was carried out for 1 week. Hereinafter, it may be referred to as a “control group”.

-PT administration group-
8 g per mouse per day is fed with a diet containing 0.1% by mass of panaxatriol (PT) (manufactured by LKT Laboratories) in a commercial high fat diet (trade name: Quick Fat, manufactured by CLEA Japan, Inc.) The water supply was free intake and this breeding was carried out for one week. Hereinafter, it may be referred to as “PT administration group”.

After performing this breeding for 1 week, blood glucose level and body weight were measured, and ¹³ CO ₂ excretion was measured. The blood glucose level of the control group was 335.4 mg / dL, and the blood glucose level of the PT administration group was 199.3 mg / dL.

<Measurement of ¹³ CO ₂ emissions>
The mouse was transferred to an expiration gas analysis chamber (ARCO-2000-ISO System, manufactured by ARCO SYSTEM) and acclimated for 2 hours. Thereafter, at a concentration calculated from [2.0 g D-glucose (manufactured by Nacalai Techs Co., Ltd.) + 72 mg D-glucose-U- ¹³ C ₆ (99%) (manufactured by Cambridge Isotop Lab.) / Kg-weight] the glucose and aqueous solutions of ^glucose-U- 13 _{C 6} were orally administered to mice was measured cumulative ¹³ CO ₂ emissions over 4 hours. The cumulative ¹³ CO ₂ emission amount was indicated by AUC ( ¹³ CO ₂ emission increase value). The AUC ⁽¹³ CO ₂ emissions increase value), ^glucose-U- in 13 _{C 6} graph plotting against time emissions change after administration, based emissions ^glucose-U- 13 _{C 6} before administration It represents the area of the incremental portions to ^glucose-U- 13 _{C 6} administered 4 hours after a line.

FIG. 5A shows the change over time of the ¹³ CO ₂ emission amount, and FIG. 5B shows the result of the cumulative ¹³ CO ₂ emission amount. From these results, a significant increase in ¹³ CO ₂ excretion was confirmed in PT administration (statistical analysis was performed by Student's t-test, with P <0.05 being a significant difference). That is, it was found that the metabolism of sugar taken from meals was promoted.

The sugar metabolism improving agent comprising panaxatriol (PT) of the present invention and the sugar metabolism improving composition containing the sugar metabolism improving agent are excellent in promoting the uptake of sugar into muscle cells and suppressing the increase in postprandial blood glucose level. Since it has an action, a fasting blood glucose lowering action, a glucose metabolism-related index regulating action, and a meal-derived sugar metabolism promoting action, it is a postprandial blood sugar level increase inhibitor, a fasting blood sugar level lowering agent, and a glucose uptake promoter. It can be suitably used as an agent and is effective in the prevention or treatment of diabetes.
Furthermore, since the said sugar metabolism improving agent has high safety | security, it can be utilized suitably for food-drinks.

Claims (1)

Food / beverage products containing the compound represented by following structural formula (1) derived from the acid hydrolyzate of a ginseng , and having a daily intake of 2 mg to 20 mg.