JP2003171271A - Medicine for glucose tolerance disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine that effectively acts against glucose tolerance disorder resistant to conventional therapeutic agents and has high safety. <P>SOLUTION: The medicine for glucose tolerance disorder contains at least one selected from the group consisting of leucine, isoleucine and valine as an active ingredient. It can be used for treating and preventing diabetes and glucose tolerance disorder, particularly suitable for hepatopathyic patients and is given them in the form of medicines or of health foods or drinks. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel drug for impaired glucose tolerance, more specifically, for use in treating, improving, preventing (and worsening) preventing and / or preventing impaired glucose tolerance, which comprises a branched chain amino acid as an active ingredient. Related drugs. The drug of the present invention is in the form of a drug (including a drug for liver disease, a nutrient, etc.),
Further, it is used in the form of foods and drinks (including health foods) and food supplements, or in the form used for them.

[0002]

2. Description of the Prior Art It is known that abnormal glucose tolerance such as diabetes frequently appears in many patients with chronic liver damage such as cirrhosis (Exp. Clin. Endocrinol Diabetes (199
5), 103, 63-74. ), And its onset mechanism is believed to be due to insulin resistance in peripheral tissues caused by some cause triggered by liver damage (Hepatol. Res. (2000), 17, 93- See 101.). Also, for the impaired glucose tolerance that frequently occurs in patients with liver damage, it is considered to be dangerous to use the existing antidiabetic drug easily for the following reasons, and there is actually no cure or preventive method for it. Is the current situation. That is, since most of the typical diabetes therapeutic agents, insulin secretagogues (SU agents), biguanide agents, and insulin resistance therapeutic agents (glitazone drugs) having a thiazolidine ring skeleton, are metabolized in the liver, It is extremely difficult to control the drug concentration in the body, and it has been pointed out that the use of the drug may cause serious phytotoxicity, and its use is severely limited.

Under such circumstances, there is a demand for the development of a highly safe drug as a therapeutic or preventive agent for impaired glucose tolerance.

[0004]

The problem to be solved by the present invention is to provide a drug that effectively acts on impaired glucose tolerance, which is difficult to treat with conventional drugs.

It is intended to provide a method for treating, ameliorating and / or preventing the above-mentioned abnormalities by using a pharmaceutical preparation containing at least one or more kinds of branched chain amino acids, or a food or drink (including a food supplement). is there.

[0006]

Means for Solving the Problems As a result of intensive research to solve the above problems, the present inventors have found that glucose tolerance is abnormal by administering or ingesting branched chain amino acids such as leucine, isoleucine and valine. In particular, they found that glucose intolerance in patients with liver damage was effectively improved, and completed the present invention.

Leucine is known to act on pancreatic β cells and has an insulin secretagogue action (Diabetes
Mellitus: A fundamental And Clinical Text, Second
See Edition (2000). ), The effect of insulin on insulin sensitivity in the major target organs of liver, muscle and adipose tissue was not known. In addition, leucine and isoleucine which are other branched chain amino acids, and valine are a mixture or singly thereof, which promotes protein synthesis in liver, muscle, adipose tissue which is the main target organ of insulin, or pancreatic β cell which is an insulin-producing organ. (See Biochem. J. (2000), 351 , 545-550), but its effect on insulin sensitivity is unknown, and the diabetic condition caused by peripheral insulin resistance. The effect on was unknown.

To date, the efficacy of branched-chain amino acids for the treatment or prevention of glucose intolerance has been investigated in a test using rodent model animals, for example, mouse 1 induced by streptozotocin administration.
(Braz., J. Med. Biol. Res., (1987) 20 , 137-
See 144. ), A branched chain amino acid has a therapeutic effect in a mouse type 1 diabetes model induced by EMCV virus infection (Eur. J. Pharm., (2000) 39 ).
See 8 , 409-414. ). This suggests that branched-chain amino acids prevent stress-induced pancreatic β-cell damage, but the effect of improving insulin resistance in peripheral insulin target organs was not clear.

In the present invention, it was confirmed for the first time that branched chain amino acids have such an improving effect.

That is, the present invention provides leucine as an active ingredient.
It exists in a drug for impaired glucose tolerance, which is characterized by containing at least one of isoleucine and valine.

The drug of the present invention can be used in the form of any of pharmaceuticals, foods and drinks, and food supplements, or in any of these forms.

Regarding the isomers of leucine, isoleucine and valine used as the active ingredient in the present invention,
Any of the L-form, D-form and DL-form can be used, but the L-form is preferred from the viewpoint of naturally occurring.

The drug of the present invention is used for treating and improving glucose intolerance.
It is used for progress prevention and prevention.

The drug of the present invention is particularly effective for type 1 or type 2 diabetes, or gestational diabetes, and impaired glucose tolerance associated with liver disease and endocrine disease. Further, the drug of the present invention can be preferably used for animals having liver damage, particularly for humans.

It is preferable to use a mixture of isoleucine, leucine and valine as an active ingredient in the drug of the present invention. In this case, in the compounding ratio (weight ratio) of isoleucine, leucine and valine, isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1 to
It is more preferable to use it in a composition range such that 1.3 is obtained.

The drug of the present invention can be suitably used in the form of foods and drinks such as health foods and food supplements, or in the form used therefor.

When the drug of the present invention is used in the form of pharmaceuticals, foods and drinks (including health foods, food supplements, etc.), other components are used in combination as long as the object of the present invention is not impaired. can do. For example, if necessary, supplemental components such as vitamins and minerals that are usually contained in foods and pharmaceuticals can be added.

When the drug of the present invention is used, it is desirable to include all of isoleucine, leucine and valine as active ingredients in the drug. In this case, the daily dose (intake amount) is, for example, As
Isoleucine 2.5-3.0 g, leucine 5.0-6.
0 g, and valine 3.0-4.0 g can be administered or ingested.

When calculating the dose (intake) of the above-mentioned active ingredient used in the present invention, the drug of the present invention (the drug used for the purpose of treatment, prevention, etc. of the disease abnormality targeted by the present invention) Since the above-mentioned calculation range is determined as the active ingredient, the branched chain amino acid to be ingested or administered for another purpose, for example, for the purpose of ordinary diet or for the treatment of another disease, is Need not be included in the calculation.

For example, it is not necessary to calculate by subtracting the amount of isoleucine, leucine and valine per day taken from a normal diet from the daily dose of the active ingredient in the present invention.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below.

The drug of the present invention is particularly preferably a drug (drug for liver disease,
Including nutritional supplements. ) Or in the form used for food and drink (including health foods, food supplements, etc.).

In the present invention, "abnormal glucose tolerance" includes all pathological conditions that are not normal with respect to glucose metabolism. For example, regarding the definition of impaired glucose tolerance, according to the criteria of the Japan Diabetes Society (see Diabetes 42 (5): 385-404, 1999.), the blood glucose level is a fasting value of 110 mg / dl or more, or a 75 g glucose tolerance test ( OGTT) It has been described as a disease state with a 2-hour value of 140 mg / dl or more, but this explanation can be used as the definition of this disease state (disease). Among these are type 1 diabetes and 2
It includes various types of diseases such as type 2 diabetes, gestational diabetes, and liver metabolism and abnormal glucose metabolism associated with endocrine disorders.

The drug of the present invention is particularly effective for the treatment, amelioration and / or prevention of impaired glucose tolerance, which has a liver disorder, for which it is difficult to use conventional diabetic drugs. Further, as shown in Examples below, by using at least one of leucine, isoleucine and valine as an active ingredient, the desired effect can be obtained. Further, since the active ingredient is an amino acid, it is excellent in safety and can be easily used in the form of food and drink (health food etc.).

As described above, the diseases and disorders to which the drug of the present invention is applied (administered or ingested) are impaired glucose tolerance, and the targets to which this drug is applied are its prevention, improvement, prevention of progress (deterioration),
The treatment is not particularly limited as long as it requires treatment and the like, but is applied to mammals, usually humans (patients, healthy subjects) in the above various forms. It is extremely effective in treating, improving and / or preventing impaired glucose tolerance such as diabetes mellitus having liver damage.

There is no particular limitation on the administration form (or ingestion form as food) of the drug of the present invention. Preferably, it can be orally administered (ingested). In this case, the dose varies depending on the symptom, age, and administration method of the patient to be administered, but isoleucine 1.0 to 30.0 is usually taken per day.
g, leucine 1.0 g to 30.0 g, and valine 1.0
It is about 30.0 g. In the case of a general adult, isoleucine is preferably 2.0 to 10.0 per day.
g, leucine 2.0 to 10.0 g, and valine 2.0 to
About 10.0 g, more preferably isoleucine 2.5
-3.0 g, leucine 5.0-6.0 g, and valine 3.0-4.0 g.

On the other hand, drip administration, injection administration (intravenous administration)
It is also possible to administer parenterally (ingestion), etc., and in that case, the dose (intake) should be about 10 to 20 times less than the preferable dose (intake) range for oral administration (intake). Can be administered (ingested).

When the drug of the present invention is used in the form of a drug or food or drink, it can be prepared by a conventional method. In the case of a pharmaceutical product, various pharmacologically acceptable substances for formulation (as an auxiliary agent) can be included. The substance for formulation can be appropriately selected depending on the dosage form of the formulation, for example, excipient, diluent, additive, disintegrant, binder, coating agent, lubricant, glidant, lubricant, flavoring agent. , Sweeteners, solubilizers, and the like. Furthermore, specific examples of the substance for formulation include magnesium carbonate, titanium dioxide, lactose,
Mention may be made of mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol.

In the present invention, it can be used together with other drug components (pharmaceutical active substances), for example, in the form of a mixture or a combination. In such a case, the active ingredient aimed at in the present invention, preferably L-isoleucine, L -Leucine and L
-A mixture of valine is contained in the drug of the present invention as long as it contains the above-mentioned preferred ratio and exhibits the desired pharmacological activity. The individual amino acids used as the active ingredient in the present invention can be used in the form of salts for some or all of them.

The drug of the present invention is in the form of various pharmaceutical preparations known or to be developed in the future, as described above, for example, oral administration, intraperitoneal administration, transdermal administration, intravenous administration,
It can be prepared into various administration forms such as inhalation administration. In order to prepare the drug of the present invention in the form of these various pharmaceutical preparations, a known method or a method developed in the future can be appropriately adopted.

Examples of the form of these various pharmaceutical preparations include suitable solid or liquid preparation forms such as granules and powders,
Coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops, injectable solutions,
There may be mentioned, for example, formulations which prolong the release of the active substance.

It goes without saying that the drug of the present invention in the above-exemplified formulation form should contain the above-mentioned components in an amount effective for exerting a medicinal effect. The fact that it should contain a medicinally effective amount of the above components also applies to use in foods and drinks.

There is no particular difficulty in using the present invention in foods and drinks, and for example, it can be mixed with juice, milk, confectionery, jelly and the like for eating and drinking.

When the drug of the present invention is used as a food supplement, it can be prepared in the form of tablets, capsules, powders, granules, suspensions, chewable agents, syrups and the like.

[0035]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

(Example 1) Blood glucose change in rats and Leu loading 7-week-old SD male rats were fed with 0.05% phenobarbital.Na water, and 0.5 ml / kg of carbon tetrachloride was added as a 50% olive oil solution to the back. Rats were chronically injured by subcutaneous administration twice a week for 15 weeks or longer. The animals were fasted 17 hours before the start of the experiment, and 4 g / kg of glucose was orally administered 60 minutes before the start of experiment, and 1.5 g / kg of L-leucine (Leu) at the start of the experiment (0 min) or physiological saline as a control. . After starting the experiment, -60, 0, 3
Blood was collected from the tail vein at time 0, 60, 90, and 150 minutes, and blood glucose was measured by an enzyme method using Drychem 5000. The result is shown in FIG.

As shown in FIG. 1, as a result of the glucose tolerance test (OGTT), the change in blood glucose level was kept low by oral administration of Leu, and improvement in glucose tolerance was observed.

(Example 2) Blood glucose changes in rats and BCAA loading 7-week-old SD male rats were fed 0.05% phenobarbital.Na water, and 0.5 ml / kg of carbon tetrachloride was used as a 50% olive oil solution in the back. Rats were chronically injured by subcutaneous administration twice a week for 15 weeks or longer. The animals were fasted 17 hours before the start of the experiment, and 4 g / kg glucose was orally administered 60 minutes before the start of the experiment, and 1.5 g / kg of branched chain amino acid (BCAA) at the start of the experiment (0 minutes) or physiological saline as a control. . As BCAA, L-isoleucine (Ile): L-leucine (Leu): L-valine (Va
l) = 1: 2: 1.2 (w / w) mixture was used. After the start of the experiment, blood samples were collected from the tail vein at -60, 0, 30, 60, 90, 120, 180 and 240 minutes, and blood glucose was collected.
It was measured by the enzymatic method using 00. The result is shown in FIG.

As shown in FIG. 2, as a result of the glucose tolerance test (OGTT), the change in blood glucose level was kept low by oral administration of BCAA, and improvement of glucose tolerance was observed.

(Example 3) Blood glucose change in rats and Leu load 7-week-old SD male rats were given 0.05% phenobarbital.Na water, and 0.5 ml / kg of carbon tetrachloride was used as a 50% olive oil solution in the back. Rats were chronically injured by subcutaneous administration twice a week for 15 weeks or longer. The animals were fasted 17 hours before the start of the experiment, and 4 g / kg of glucose was orally administered 60 minutes before the start of experiment, and 1.5 g / kg of L-leucine (Leu) at the start of the experiment (0 min) or physiological saline as a control. . After starting the experiment, -60, 0, 3
Blood was sampled from the tail vein at 0, 60, 90, 120, 180, and 240 minutes, and blood glucose was measured by an enzyme method using Drychem 5000. The result is shown in FIG.

As shown in FIG. 3, as a result of the glucose tolerance test (OGTT), the change in blood glucose level was kept low by oral administration of Leu, and improvement in glucose tolerance was observed. At this time, the plasma insulin level was measured using the ELISA method (insulin measurement kit; Morinaga Institute of Bioscience). As shown in Figure 4, Leu
No significant difference in insulin level was observed between the oral administration group and the physiological saline administration group.

(Example 4) Blood glucose change in BCAA-loaded rats 7-week-old SD male rats were donated with 0.05% phenobarbital.Na water, and 0.5 ml / kg of carbon tetrachloride was added as a 50% olive oil solution to the back. Rats were chronically injured by subcutaneous administration twice a week for 15 weeks or longer. The animals were fasted 17 hours before the start of the experiment, and 4 g / kg glucose was orally administered 60 minutes before the start of the experiment, and 1.5 g / kg of branched chain amino acid (BCAA) at the start of the experiment (0 minutes) or physiological saline as a control. . As BCAA, L-isoleucine (Ile): L-leucine (Leu): L-valine (Va
l) = 1: 2: 1.2 (w / w) mixture was used. After the start of the experiment, blood samples were collected from the tail vein at -60, 0, 30, 60, 90, 120, 180, and 240 minutes, and blood glucose was collected.
It was measured by the enzyme method using 5000. The result is shown in FIG.

As shown in FIG. 5, as a result of the glucose tolerance test (OGTT), the change in blood glucose level was kept low by oral administration of BCAA, and improvement in glucose tolerance was observed. At this time, the plasma insulin level was measured using the ELISA method (insulin measurement kit; Morinaga Institute of Bioscience). As shown in Figure 6, Leu
No significant difference in insulin level was observed between the oral administration group and the physiological saline administration group.

From the above, a drug containing a branched chain amino acid provided by the present invention is used for treating glucose intolerance,
It is clear that it is effective for prevention and the like. Further, since the active ingredient is a branched chain amino acid, it is highly safe and has almost no side effects. Therefore, it can be used in the form of foods and drinks and is more useful than existing diabetic therapeutic agents.

[0045]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a drug suitable for treating, ameliorating, preventing the progress, preventing, etc. of impaired glucose tolerance such as diabetes in patients with diabetes or liver damage. It is excellent in safety, and because it is a pharmaceutical product and the active ingredient is a branched chain amino acid, it is highly safe and has few side effects, which is advantageous in use as compared with existing antidiabetic agents.

[Brief description of drawings]

FIG. 1 is a graph showing changes in blood glucose during Leu loading in CCl ₄ -induced chronic liver injury rats in Example 1. ●: LC / Leu; ○: LC / saline. LC: Liver cirrhosi
s.

FIG. 2 is a diagram showing changes in blood glucose during BCAA loading in CCl ₄ -induced chronic liver injury rats in Example 2. ●: glucose + BCAA; ◯: glucose + saline.

FIG. 3 is a graph showing changes in blood glucose during Leu loading in CCl ₄ -induced chronic liver injury rats in Example 3. ●: glucose + Leu; ■: glucose + saline.
*: P <0.05.

FIG. 4 is a graph showing changes in plasma insulin level during Cle ₄ -induced chronic liver injury rat during Leu loading in Example 3. ●: glucose + Leu; ■: glucose + saline.

FIG. 5 is a graph showing changes in blood glucose during BCAA loading in CCl ₄ -induced chronic liver injury rats in Example 4. ●: glucose + BCAA; ■: glucose + physiological saline;
*: P <0.05.

FIG. 6 is a graph showing changes in plasma insulin levels during CCAA ₄ challenge in rats with CCl ₄ -induced chronic liver injury in Example 4. ●: glucose + BCAA; ■: glucose + saline.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 3/10 A23L 2/00 F

Claims (7)

[Claims] 1. A drug for impaired glucose tolerance, which comprises at least one of leucine, isoleucine and valine as an active ingredient. 2. The drug according to claim 1, which is in the form of any of pharmaceuticals, foods and drinks, and food supplements, or in a form used in any of these. 3. The drug according to claim 1, wherein leucine, isoleucine and valine are L-forms. 4. Treatment, improvement, prevention of progression of glucose intolerance and / or
Alternatively, the drug according to claim 1, which is used for prevention. 5. A living body having a liver disorder, wherein the living body is used.
The drug according to any of the above. 6. A compounding ratio of isoleucine, leucine and valine in terms of weight ratio, isoleucine / leucine / valine = 1.
/1.9-2.2/1.1-1.3
The drug according to any of the above. 7. The composition according to claim 1 used in a health food.
The listed drug.