HK1122985B - Agent for improving insulin resistance - Google Patents

Description

Insulin resistance improving agent

Technical Field

The present invention relates to an insulin resistance-improving agent containing 3-O-beta-D-glucopyranosyl-4-methylergost-7-en-3-ol as an active ingredient, and a food or drink containing the agent. More particularly, it relates to an insulin resistance-improving agent having an effect of regulating the production of adipocyte cytokines such as free fatty acid, plasminogen activator inhibitor, tumor necrosis factor, monocyte chemoattractant protein-1, and resistin, which are factors involved in the onset and severity of insulin resistance-related pathologies, and a food or beverage containing the agent.

Background

Insulin is a kind of hormone produced by β cells in pancreatic islets (islets of langerhans) of the pancreas, and plays a role not only in sugar metabolism but also in fat metabolism and protein metabolism via an insulin receptor present in an insulin target tissue such as skeletal muscle, liver, fat, and the like, and plays an important role in maintaining homeostasis in a living body. The effect of insulin in each target tissue is: promoting uptake of glucose in blood by muscle cells or fat cells, promoting glycogen production in liver and muscle tissues, inhibiting gluconeogenesis in liver, promoting glucose consumption and fatty acid synthesis in fat cells, and inhibiting lipid decomposition.

Insulin resistance refers to a state in which insulin is required in an amount not less than a normal amount in order to obtain various actions of insulin at a cellular level, an organ level, or an individual level, that is, a state in which insulin is not fully acted due to decreased sensitivity to insulin. The results of current immunological studies suggest that hypertension, diabetes, hyperlipidemia (hypertriglyceridemia, low HDL cholesterolemia), obesity, and the like are pathological conditions based on insulin resistance. If insulin resistance occurs, insulin action in glucose metabolism is insufficient, compensatory hyperinsulinemia occurs in order to maintain blood glucose, hyperglycemia or impaired glucose tolerance is caused, and diabetes progresses due to fatigue of pancreatic β cells. Hyperinsulinemia promotes sympathetic nerve hyperactivity or renal sodium absorption, which causes hypertension, and also induces postprandial hyperlipidemia, hyperuricemia, an increase in plasminogen activator inhibitor (PAI-1), and the like.

On the other hand, insulin resistance induces abnormal fat metabolism due to insufficient insulin action, and Free Fatty Acids (FFA) released from adipocytes increase in liver, promoting synthesis of Triglycerides (TG) in liver, and resulting in hypertriglyceridemia. In addition, lipoprotein lipase (LPL) having high insulin sensitivity generally has reduced activity in an insulin-resistant state, and therefore degradation of TG is reduced, and hypertriglyceridemia is further worsened. In addition, complications such as retinopathy, nephropathy, and gangrene caused by vascular disorders accompanying the progression of diabetes, and the like, as well as myocardial infarction and cerebral infarction, which are arteriosclerotic diseases, progress, and circulatory diseases also progress due to hypertension. As described above, insulin resistance is largely involved in the deterioration of combined morbid states (non-patent document 1).

In recent years, organ-specific gene expression has been analyzed, and as a result: adipose tissue is known to secrete various physiologically active substances, and is not only a simple energy storage tissue but also the largest endocrine organ in the body. The endocrine factors derived from adipose tissue are collectively called adipocyte factors, and play an important role in maintaining homeostasis in metabolism, and insulin resistance is caused by excessive or insufficient production or secretion and problems in balance in obesity, i.e., a state of fat accumulation.

Adipocyte factors are divided into two groups: one group is responsible for insulin sensitivity and one group induces insulin resistance, and representative examples of the former group include adiponectin, leptin, AMPK (AMP-dependent protein kinase), and the like. In particular, adiponectin has been reported to have an insulin resistance-relieving action or a hepatic gluconeogenesis-inhibiting action (non-patent document 2).

On the other hand, the adipocytokines inducing insulin resistance include tumor necrosis factor (TNF-. alpha.), monocyte chemoattractant protein-1 (MCP-1), which is one of inflammatory chemokines, resistin, and the like, in addition to FFA or PAI-1 described above. Among them, it has been reported that the mechanism of action of TNF- α is to inhibit tyrosine phosphorylation of insulin receptor and IRS1 (insulin receptor substrate protein-1) in the insulin signal transduction mechanism, to attenuate insulin action, thereby inducing insulin resistance. It has been reported that in an insulin resistant state, the in vivo level of MCP-1 is increased, and with this, mRNA of a sugar carrier GLUT4 (glucose transporter-4), a nuclear receptor PPAR γ (peroxisome proliferator-activated receptor γ), β 3AR (β 3-adrenergic receptor on kidney) which is one of β -type catecholamine receptors of adipocytes, and a fatty acid binding protein aP2 (fatty acid binding protein 2 of adipocytes) is decreased, and thus MCP-1 is considered to be a causative substance of the decrease in insulin sensitivity (non-patent documents 3, 4, and 5).

As a drug for improving insulin resistance, biguanide agents that mainly inhibit gluconeogenesis in the liver and thiazolidine derivatives that improve insulin sensitivity in muscle or adipose tissue have been developed. These drugs have been recognized as therapeutic agents for diabetes, and are also applicable to the treatment of arteriosclerosis. Thiazolidine derivatives, such as troglitazone and pioglitazone, act as ligands of a transcription factor of the nuclear receptor type, i.e., peroxisome proliferator-activated receptors (PPARs), and promote differentiation of adipocytes, thereby improving insulin resistance.

In addition to this, also disclosed are: an insulin resistance-improving agent containing adiponectin or a gene thereof as an active ingredient (patent document 1), a prophylactic and/or therapeutic agent for a disease caused by insulin resistance containing a substance having affinity with bombesin receptor subtype 3(BRS-3) as an active ingredient (patent document 2), a Free Fatty Acid (FFA) reducing agent containing a pyrrole derivative as an active ingredient (patent document 3), and the like can be used as an insulin resistance-improving agent. Further, as for substances containing substances derived from food as active ingredients, compositions for improving insulin resistance containing acetic acid and its ions or salts as active ingredients (patent document 4), insulin resistance improving agents comprising oils and fats containing specific diglycerides and/or monoglycerides (patent document 5), and the like have been disclosed.

It is known that phytosterols such as β -sitosterol, campesterol, stigmasterol, and the like have an effect of reducing cholesterol in blood by inhibiting the absorption of cholesterol, and practical applications such as addition to edible oil in the form of an oil-and-fat composition are underway. Anti-obesity agents and fat metabolism improvers comprising as an active ingredient a cholestenone compound synthesized from a plant sterol such as β -sitosterol or campesterol (patent documents 6 to 8 and non-patent document 6).

Further, an adiponectin secretion promoter comprising an extract extracted from at least one of rice bran, Hypsizygus marmoreus, Chrysanthemum morifolium, rye, Betula alba and Alpinia zerumbet, and cycloartane-type triterpene or a derivative thereof, cycloartanol and/or (24S) -24, 25-dihydroxycycloartanol, is disclosed (patent document 9).

The genus Aloe of the family Liliaceae is a plant group containing Aloe barbadensis Miller or Aloe arborescens Berger, etc., and it has been known from past experience that it has various effects. For example, an immunosuppressive improver characterized by containing a butanol component of aloe extract or aloin (patent document 10), a substance related to improvement in blood sugar level (patent documents 11 to 14), an obesity prevention improver (patent document 15), and the like have been disclosed, but no improvement in insulin resistance of aloe plants has been reported.

Patent document 1: international publication No. 2003/63894 pamphlet

Patent document 2: japanese laid-open patent publication No. 10-298100

Patent document 3: japanese laid-open patent publication No. 8-12573

Patent document 4: japanese laid-open patent publication No. 2002-

Patent document 5: japanese patent laid-open No. 2001-247473

Patent document 6: japanese laid-open patent publication No. 7-165587

Patent document 7: japanese laid-open patent publication No. 11-193296

Patent document 8: japanese patent laid-open No. 2001-240544

Patent document 9: japanese patent laid-open No. 2005-68132

Patent document 10: japanese laid-open patent publication No. 8-208495

Patent document 11: japanese laid-open patent publication No. 59-214741

Patent document 12: japanese patent laid-open publication No. 2003-286185

Patent document 13: specification of U.S. Pat. No. 4598069

Patent document 14: U.S. patent application publication No. 2003/0207818 specification

Patent document 15: japanese patent laid-open No. 2000-319190

Non-patent document 1: insulin resistance and lifestyle diseases, editors and editors of Ishimoto, diagnostics & therapeutics, 2003, pages 1 to 5

Non-patent document 2: science of fat (Adiposcience), volume 1, No. 3, 2004, pages 247 to 257

Non-patent document 3: procedents of the National Academy of sciences, Vol.100, No. 2003, pp.7265-7270

Non-patent document 4: nature (Nature), volume 389, 1997, pages 610 to 614

Non-patent document 5: the Netherlands Journal of Medicine (The Netherlands Journal of Medicine), volume 6, No. 6, 2003, pages 194 to 212

Non-patent document 6: hormone Metabolism Research (Hormone Metabolism Research), volume 37, 2005, pages 79-83

Disclosure of Invention

However, the biguanide agents, which are drugs for improving insulin resistance, have caused gastrointestinal disorders or occasionally lactic acidosis. In addition, thiazolidine derivatives of the same class of drugs cause serious side effects such as retention of body fluids, weight gain, and hepatic dysfunction, and thus care must be taken when using them. And it is practically difficult to use a diabetic drug for insulin resistance in a non-diabetic or hyperglycemic state. Under the circumstances, there is a strong demand for the development of a functional material which is excellent in safety, can be ingested on a daily basis, causes no pain as much as possible, and can improve insulin resistance efficiently.

In order to solve the above problems, the present inventors have focused attention on the development and severity of insulin resistance in the course of studies on insulin resistance improvers, which are drugs involved in the mechanism of diseases such as hypertension, diabetes, hyperlipidemia (hypertriglyceridemia and low HDL cholesterolemia) and obesity, and have conducted intensive studies on novel functional materials capable of improving insulin resistance by controlling these factors, and as a result, have found that: 3-O-beta-D-glucopyranosyl-4-methylergost-7-en-3-ol has an effect of regulating the production of adipocytokines such as free fatty acids, TNF-alpha, MCP-1 and the like, and particularly has an effect of effectively reducing the production of adipocytokines that initiate insulin resistance, and thus it is known that insulin resistance can be improved.

As for the effects of the present invention, patent document 9 only shows the effects of the plant extract on the prevention of differentiation of cultured adipocytes and the effect of ergosterol on the promotion of adiponectin secretion, and nothing is described about the effect of the active ingredient of the present invention on insulin resistance.

Unlike the conventional methods for evaluating insulin resistance, such as glucose clamp method, SSPG (steady state plasma glucose) method, and micromodel method, the present invention has been studied using an insulin resistance test (insulin load test), and has found that 3-O-. beta. -D-glucopyranosyl-4-methylergost-7-en-3-ol can improve insulin resistance more directly without improving insulin secretion performance and the like.

The above-mentioned insulin resistance test has found an extremely advantageous effect, which is not performed in the above-mentioned patent documents 1 to 5, and which is capable of improving insulin resistance without being affected by insulin secretion performance or the like, as compared with the conventional insulin resistance improving effect, and the present invention has been completed.

The present invention aims to provide an insulin resistance-improving agent comprising the above-mentioned 3-O-. beta. -D-glucopyranosyl-4-methylergost-7-en-3-ol as an active ingredient. Another object of the present invention is to provide a functional food or drink, such as a specific health food, containing the insulin resistance-improving agent.

A first invention of the present application for solving the above problems is an insulin resistance-improving agent containing a compound represented by the following chemical formula (1) as an active ingredient.

The second invention of the present application for solving the above problems is an insulin resistance-improving agent comprising an organic solvent extract, a hot water extract or a squeezed liquid of a plant containing a compound represented by the following chemical formula (1) or a fractionated component thereof, which comprises, as an active ingredient, a composition containing at least 0.001% by mass, in terms of dry mass, of the compound represented by the following chemical formula (1), the composition being an organic solvent extract, a hot water extract or a squeezed liquid of the plant or a fractionated component thereof, and it is preferable that the plant is a liliaceae plant.

A third invention of the present application for solving the above problems is a food or beverage containing the insulin resistance-improving agent of the first or second invention, and preferably contains 0.0001% by mass or more of the compound represented by the above chemical formula (1).

The fourth invention of the present application for solving the above problems is the use of the compound represented by the above chemical formula (1), or an organic solvent extract, a hot water extract, a squeezed liquid of a plant containing at least 0.001% by mass of the compound in a dry mass, or a fractionated component thereof for the preparation of an insulin resistance-improving agent, and it is preferable that the plant is a plant of the family liliaceae.

A fifth invention of the present application for solving the above problems is a method for improving insulin resistance, characterized in that: a compound represented by the above chemical formula (1), or an organic solvent extract, a hot water extract, a squeezed liquid or a fractionated component thereof of a plant containing at least 0.001% by mass of the compound in a dry mass is administered to a subject to be improved in insulin resistance, and it is preferable that the plant is a Liliaceae plant.

The insulin resistance-improving agent and the food and drink containing the insulin resistance-improving agent of the present invention can be safely administered or ingested and are effective in preventing lifestyle-related diseases which may be caused by insulin resistance. The active ingredient of the insulin resistance-improving agent of the present invention can be safely ingested from dietary experiences, and can be easily prepared from readily available plants of the family Liliaceae, such as aloe vera.

Brief Description of Drawings

Fig. 1 is a graph showing a blood glucose level fluctuation in an insulin tolerance test.

Best Mode for Carrying Out The Invention

The following is a detailed description of preferred embodiments of the invention. However, the present invention is not limited to the following preferred embodiments, and can be freely modified within the scope of the present invention. In the present specification, the percentages are expressed by mass unless otherwise specified.

In the present invention, the insulin resistance-improving action (insulin sensitivity-enhancing action) means an action of preventing or improving various health disorders caused by low insulin sensitivity, for example, lifestyle-related diseases. Specifically, the composition effectively inhibits the increase or production of adipocytokines that induce insulin resistance, such as plasminogen activator inhibitor (PAI-1) or Free Fatty Acid (FFA), tumor necrosis factor (TNF-. alpha.), MCP-1, and resistin, and has an improving effect on the prevention of the onset and severity of insulin resistance-related conditions, and has an effect on the prevention, amelioration, or treatment of a risk reduction in insulin resistance-related conditions, such as hyperinsulinemia, hyperlipidemia, impaired glucose tolerance, diabetes, hypertension, obesity, and arteriosclerosis. Therefore, the insulin resistance-improving agent of the present invention can be defined as an insulin sensitivity-promoting agent, an adipocytokine production-regulating agent, and particularly as an adipocytokine production-inhibiting agent that induces insulin resistance.

The methods for evaluating insulin resistance include glucose clamp method, SSPG (steady state plasma glucose) method, micromodel method, method for determining HOMA-IR (steady state model evaluation of insulin resistance) index by calculating blood glucose level and blood insulin concentration in the fasting state, and insulin tolerance test, and any of these methods can be used for evaluating insulin resistance.

The compound having the structure represented by the above chemical formula (1) has an action of improving insulin sensitivity, and as a result, can prevent or improve a disease state caused by insulin resistance. Therefore, it is useful as an insulin resistance improving agent or an active ingredient of a food or drink containing the agent. Insulin sensitivity can be assessed by measuring the response of blood glucose values to decrease following administration of insulin.

The compound (hereinafter referred to as "the compound of the present invention") used as an active ingredient of the insulin resistance-improving agent of the present invention (hereinafter referred to as "the drug of the present invention") is a compound having a structure represented by the above chemical formula (1), i.e., 3-O- β -D-glucopyranosyl-4-methylergost-7-en-3-ol. The compound of the present invention has a structure in which the 3-hydroxyl group of 4-methylergost-7-en-3-ol is subjected to dehydration condensation with the 1-hydroxyl group of D-glucose.

The purity of the compound of the present invention which can be used as an active ingredient of the insulin resistance-improving agent of the present invention is most preferably 100%, and can be appropriately set within the range having an effect of improving insulin resistance.

The composition used as an active ingredient of the insulin resistance-improving agent of the present invention (hereinafter referred to as "the composition of the present invention") is an extract of a plant of the family liliaceae or a fractionated component thereof containing at least the above-mentioned compound of the present invention in an amount of 0.001% by mass, preferably 0.01% by mass or more, more preferably 0.1% by mass or more in a dry mass basis. The upper limit of the content of the compound of the present invention is not particularly limited, but is preferably 10% by mass, and may be 50% by mass, 70% by mass, or 90% by mass.

In the present invention, the drying quality can be specified as follows: the mass of the compound measured after drying according to the drying method specified in the conventional test method "drying weight loss test method" modified by the prescription of the japanese pharmacopoeia (jp 111 a 3/30/2001), for example, about 1g of the compound of the present invention is dried at 105 ℃ for 4 hours, placed and cooled in a desiccator, and the mass is measured by weighing.

The compounds of the invention or compositions containing the compounds can be prepared, for example, as follows: a fraction containing the compound of the present invention is extracted from a plant belonging to the family Liliaceae, a plant containing the compound or a part thereof or a crushed material thereof with an organic solvent or hot water and concentrated.

The plant belonging to Liliaceae is a plant belonging to the genus Aloe or Allium. Examples of the plants belonging to the genus Aloe include Aloe barbadensis, Aloe ferox Miller, Aloe africana Miller, Aloe arborescens, and Aloe spicata Baker. In the preparation of the compound of the present invention or the composition containing the compound of the present invention, the whole of the above-mentioned plant may be used, and mesophyll (transparent gel fraction) is preferably used. The above plant or a part thereof is preferably crushed with a homogenizer or the like to form a liquid, and extracted with an organic solvent or hot water. The organic solvent comprises: alcohols such as methanol, ethanol and butanol; esters such as methyl acetate, ethyl acetate, propyl acetate, and butyl acetate; ketones such as acetone and methyl isobutyl ketone; ethers such as diethyl ether and petroleum ether; hydrocarbons such as hexane, cyclohexane, toluene, and benzene; halogenated hydrocarbons such as carbon tetrachloride, methylene chloride and chloroform; heterocyclic compounds such as pyridine, glycols such as ethylene glycol; polyhydric alcohols such as polyethylene glycol; nitrile solvents such as acetonitrile and mixtures of these solvents. These solvents may be anhydrous or in an aqueous state. Among these solvents, ethyl acetate/butanol mixture (3: 1) or chloroform/methanol mixture (2: 1) is preferable.

The extraction method may be a method used for extracting a general plant component. Generally, the method comprises using 1 to 300 parts by mass of an organic solvent per 1 part by mass of fresh plants or dried plants, and refluxing the mixture under heating at a temperature of not more than the boiling point of the solvent while stirring or shaking the mixture, or performing ultrasonic extraction at room temperature. The extract can be used to separate insoluble substances by filtration or centrifugation to obtain crude extract. The crude extract can be purified by various chromatographies such as normal phase or reverse phase silica gel column chromatography. In normal phase silica gel column chromatography, the compound of the present invention is eluted with chloroform/methanol at a ratio of about 5: 1 when a gradient of chloroform/methanol mixture is used as the elution solvent. In reverse phase silica gel column chromatography, if a gradient of methanol/water mixture is used as the elution solvent, the compound of the present invention is eluted with methanol having a concentration of about 95%. The resulting fraction can be further purified by HPLC or the like.

Whether or not the compound of the present invention is contained in the compound obtained as described above or a composition containing the compound can be confirmed, for example, by a method described in examples below, using an insulin resistance-improving effect or an inhibitory effect on the production of adipocytokine that induces insulin resistance as an index. For example, a glycoside obtained by binding glucose to the aglycone moiety, and a 4-methylergost-7-en-3-ol as the aglycone moiety may be mentionedBy passing¹³C-nuclear magnetic resonance spectroscopy (NMR), and the like.

The compounds of the present invention may be prepared by condensing D-glucose with 4-methylergost-7-en-3-ol. 4-Methyleergost-7-en-3-ol can be obtained by extraction and purification from plants. The condensation of D-glucose with 4-methylergost-7-en-3-ol can be carried out by combining the methods shown in the 4 th edition of Experimental chemistry lecture 26, 1992 (pages 272, 297 and 342, respectively). That is, D-glucose is fully acetylated and then the anomeric position is converted to the α -bromide. 4-Ethylergost-7-en-3-ol was reacted with α -bromide in diethyl ether to effect β -glycosylation, and then acetyl group was hydrolyzed in sodium methoxide-methanol to obtain the objective substance.

The compound of the present invention can be used as it is as an active ingredient of the insulin resistance improving agent of the present invention or a food or beverage containing the agent. The plant organic solvent extract, hot water extract, squeezed liquid or fractions thereof (hereinafter referred to as "extract and the like") containing the compound of the present invention can also be used as an insulin resistance-improving agent or an active ingredient of a food or drink containing the agent.

In the present invention, the squeezed liquid is obtained by adding a crushed plant material to a squeezing machine, recovering a plant squeezed stock solution, and removing insoluble components (impurities) with a filter or a filter cloth or the like. For example, when aloe vera belonging to the Liliaceae family is used as the plant, the aloe vera pressed liquid can be prepared by crushing the mesophyll gel fraction from which the outer skin of the aloe vera leaf has been removed with a crusher, feeding the crushed fraction into a press, recovering the aloe vera stock solution, and removing impurities from the aloe vera stock solution with a filter or a filter cloth or the like. In this case, the total content of aloin and aloe-emodin contained in the outer skin of aloe vera leaf is preferably 5ppm or less.

The extract and the like contained in the insulin resistance-improving agent are preferably contained in an amount of at least 0.001 mass%, more preferably 0.01 to 1 mass%, and particularly preferably 0.05 to 1 mass%, in terms of dry mass, of the compound of the present invention. The extract and the like contained in the food and drink preferably contain at least 0.0001% by mass, more preferably 0.001 to 1% by mass, and particularly preferably 0.005 to 1% by mass of the compound of the present invention in terms of dry mass. The extract may be in the form of a solution, or may be freeze-dried or spray-dried by a conventional method, and stored or used in the form of powder.

The insulin resistance-improving agent of the present invention can be administered orally or non-orally to mammals including humans, either directly or in combination with a pharmaceutically acceptable carrier for formulation, a composition containing the compound of the present invention or an extract thereof, etc. In the insulin resistance-improving agent of the present invention, the compound of the present invention may be prepared as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include both metal salts (inorganic salts) and organic salts, a list of which is described in "Remington's Pharmaceutical Sciences, 17 th edition, page 1418, 1985". Specifically including, but not limited to: inorganic acid salts such as hydrochloride, sulfate, phosphate, diphosphate and hydrobromide, and organic acid salts such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, pamoate (pamoate), salicylate and stearate. Can also be made into salt with metal such as sodium, potassium, calcium, magnesium, aluminum, etc., and salt with amino acid such as lysine, etc. Solvates such as hydrates of the above compounds or pharmaceutically acceptable salts are also included in the present invention.

The formulation form of the insulin resistance-improving agent of the present invention is not particularly limited, and may be appropriately selected depending on the purpose of treatment, and specifically, it may be a tablet, a pill, a powder, a solution, a suspension, an emulsion, a granule, a capsule, a syrup, a suppository, an injection, an ointment, a patch, an eye drop, a nasal drop, or the like. In the case of preparing a preparation, additives such as excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, diluents, surfactants, and solvents for injection, which are commonly used in general insulin resistance-improving drugs, can be used as a carrier for the preparation. The compound of the present invention or an extract containing the compound may be used in combination with other drugs having an insulin resistance-improving effect, as long as the effect of the present invention is not impaired.

The amount of the compound of the present invention or an extract containing the compound contained in the insulin resistance-improving agent of the present invention is not particularly limited and may be appropriately selected, and for example, the amount of the compound of the present invention is at least 0.001% by mass, preferably 0.01 to 1% by mass, and particularly preferably 0.05 to 1% by mass in the preparation.

The insulin resistance-improving agent of the present invention can prevent, improve or treat various diseases, complications and the like caused by insulin resistance, and reduce the risk of such diseases, complications and the like. The insulin resistance-improving agent of the present invention can be preferably used for patients in a state where insulin resistance is lower than that of normal persons. Insulin resistance refers to a state in which the plasma insulin value is 10 to 15 muU/ml or more and the HOMA index is 1.73 or more in the normal fasting state.

Examples of the various diseases caused by insulin resistance include hypertension, hyperlipidemia, diabetes, and arteriosclerosis. The complications resulting from these diseases can be exemplified by: 1) cerebral apoplexy, nephrosclerosis and renal insufficiency caused by hypertension, 2) arteriosclerosis and pancreatitis caused by hyperlipemia, 3) diabetic retinopathy, nephropathy, neurological disorder and diabetic gangrene caused by diabetes, 4) cardiovascular diseases such as cerebral apoplexy, cerebral infarction, angina pectoris and myocardial infarction caused by arteriosclerosis, uremia, nephrosclerosis and renal insufficiency and the like. The inventors of the present invention found that: the compound of the present invention has an effect of reducing the hemoglobin Alc value and improving hyperglycemia (international publication No. 2005/095436). The disease to which the insulin resistance-improving agent of the present invention is applied is preferably a disease in which the hemoglobin Alc value is not higher than that of a healthy person.

In the present invention, since the effect of inhibiting the production and increase of adipocytokines such as TNF- α, MCP-1, and FFA that cause insulin resistance is expected as an example of the effect of improving insulin resistance, the present invention also has the effect of preventing and/or improving inflammatory diseases of various organs such as rheumatoid arthritis, crohn's disease, nephritis, pancreatitis, hepatitis, and pneumonia, which are diseases caused by the increase of the adipocytokines, vascular disorders, septicemia, cachexia of malignant tumors, and the like. Therefore, the insulin resistance-improving agent of the present invention can be preferably used also for patients in a state in which the production of the above-described adipocytokine is enhanced, or in a state in which the production of the adipocytokine that triggers insulin resistance is enhanced.

The timing of administration of the drug of the present invention is not particularly limited, and an appropriate administration timing can be selected according to the treatment method of a subject disease. The administration form is preferably determined according to the form of the preparation, the age, sex, other conditions of the patient, the degree of symptoms of the patient, and the like. The dose of the drug of the present invention can be appropriately selected depending on the administration method, the age, sex, degree of disease, other conditions, and the like of the patient. The amount of the compound of the present invention as an active ingredient is usually about 0.001 to 50 mg/kg/day, preferably about 0.01 to 1 mg/kg/day. When the extract containing the compound of the present invention is used, the dry mass of the extract is about 0.1 to 1000 mg/kg/day, preferably 1 to 100 mg/kg/day. The above may be administered once or in multiple doses per day.

The compound of the present invention or a composition containing the compound can be contained in a food or drink (drink or food) to produce a food or drink having an insulin resistance-improving effect. The form and properties of the food and drink are not particularly limited as long as the effect of the active ingredient is not impaired, and the food and drink can be prepared by a conventional method using materials used for usual food and drink, in addition to the active ingredient. The amount of the compound of the present invention or an extract containing the compound contained in the food or drink of the present invention is not particularly limited and may be appropriately selected, and for example, the amount of the compound of the present invention may be at least 0.0001% by mass, preferably 0.001 to 1% by mass, and particularly preferably 0.005 to 1% by mass in the food or drink.

The food and drink of the present invention can be used for various purposes utilizing the effect of improving insulin resistance. Examples include: reducing risk factors of lifestyle-related diseases due to insulin resistance, and eliminating effective foods and beverages. The beverage and food of the present invention can prevent diseases caused by insulin resistance, such as hypertension, hyperlipidemia, diabetes, etc., and reduce the risk thereof. The food and drink of the present invention can prevent various complications caused by insulin resistance, for example, stroke, renal sclerosis, renal insufficiency, arteriosclerosis, pancreatitis and the like caused by hypertension, diabetic retinopathy, nephropathy, neuropathy, diabetic gangrene and the like caused by diabetes, cardiovascular diseases such as stroke, cerebral infarction, angina pectoris, myocardial infarction and the like caused by arteriosclerosis, uremia, nephrosclerosis, renal insufficiency and the like; and reduce the risk thereof.

The food and drink of the present invention is expected to have an effect of suppressing the production and increase of adipocytokines that induce insulin resistance, such as TNF- α, MCP-1, and FFA, and therefore has an effect of preventing and reducing the risk of inflammatory diseases of various organs, such as rheumatoid arthritis, crohn's disease, nephritis, pancreatitis, hepatitis, and pneumonia, which are autoimmune diseases caused by the increase of the adipocytokines, vascular disorders, sepsis, cachexia of malignant tumors, and the like. Therefore, the food and drink of the present invention can be preferably taken by a patient in a state in which the production of the above-mentioned adipokine is enhanced, or in a state in which the production of the adipokine that induces insulin resistance is enhanced.

The food and drink of the present invention is preferably sold in the form of a food and drink labeled with a label for improving insulin resistance, for example, a food and drink labeled as "food and drink labeled for improving insulin resistance containing a compound having an insulin resistance improving effect", a food and drink labeled for improving insulin resistance containing a plant extract "," food and drink described for improving insulin resistance containing an aloe vera extract ", or the like. Since the compound of the present invention or a composition containing the compound of the present invention has an insulin resistance-improving action, a marker for improving insulin resistance is considered to have a meaning of enhancing insulin sensitivity. Therefore, the food and drink of the present invention may be indicated as "for insulin sensitivity enhancement". That is, the above-mentioned marker for improvement of insulin resistance may be the above-mentioned "marker for insulin sensitivity hyperactivity".

The words used for the above indication are not limited to the words "for improving insulin resistance" or "for enhancing insulin sensitivity", and other words are included in the scope of the present invention as long as they show the effect of enhancing insulin sensitivity, preventing insulin resistance, or improving insulin resistance. The above words may also be indications based on various uses, such as identification of the effect of improving insulin resistance or insulin sensitivity enhancement by a person in need thereof. For example, the indication may be "suitable for people who tend to have insulin resistance", "reduction in risk factors (risks) for lifestyle-related diseases, removal of effects", or the like.

The above-mentioned "label" means all actions to be performed by the consumer to understand the above-mentioned application, and any label may be used as long as it can be associated with and classified into the above-mentioned application, and any label is suitable for the present invention regardless of the purpose of the label, the content of the label, the object of the label, the medium, and the like. However, it is preferable to use a representation that the user can directly recognize the above-described use. Specifically, the actions of the above-mentioned use may be described in the present invention on a commodity or a package of the commodity relating to a food or drink; a act of assigning and delivering an article in which the use is described in a commodity or a commodity package, and displaying and importing the article for the assignment or delivery; and an act of describing the above-mentioned use in an advertisement, a price list, or a contract document relating to a product, showing or issuing the use, or describing the use in information containing the above-mentioned use, and providing the use by an electromagnetic method (such as the internet). On the other hand, the label is preferably a label recognized by administration or the like (for example, a label recognized by various systems specified by administration and in a manner recognized as described above), and is particularly preferably a label on a promotional material, other documents, or the like at a sales site such as a package, a container, a catalog, a manual, or a POP.

For example, there are markers in the form of health foods, functional foods, enteral nutritional foods, special-purpose foods, nutritional functional foods, quasi-drugs, and the like, and also markers recognized by the japan ministry of health and labor, for example, specific health foods, and markers recognized by a similar system. Examples of the latter are: specific health food labeling, conditional specific health food labeling, labeling showing an effect on the structure or function of the body, labeling for reducing the risk of a disease, and the like, and more specifically, typical examples thereof include labeling for specific health food (in particular, labeling for health use) specified by health promotion law enforcement rules (heisheng labour province 86 of japan, 30 d.4/2003) and labeling similar thereto.

The present invention will be described in further detail with reference to the following examples, but the present invention is not limited to the following examples.

First, a preparation example is given in which the compound or composition of the present invention can be prepared from a plant belonging to the family Liliaceae.

[ preparation example 1]

Hereinafter, a preparation example of 3-O-. beta. -D-glucopyranosyl-4-methylergost-7-en-3-ol from Aloe barbadensis will be given as a preparation example of a plant of the Liliaceae family.

3-O- β -D-glucopyranosyl-4-methylergost-7-en-3-ol is extracted from Aloe barbadensis as follows and purified.

100kg of mesophyll (transparent gel fraction) of Aloe barbadensis Miller was made into liquid, and 100L of ethyl acetate/butanol mixture (3: 1) was added thereto and stirred. After standing overnight, the ethyl acetate/butanol mixture was separated from the aqueous layer to recover the ethyl acetate/butanol mixture. The ethyl acetate/butanol mixture was concentrated under reduced pressure to obtain an ethyl acetate/butanol mixture extract with a mass of 13.5 g. The above-mentioned aqueous layer and ethyl acetate/butanol mixed solution extract were used to evaluate the insulin resistance improving effect by the insulin tolerance test described in example 3 described later, and since this effect was confirmed in the ethyl acetate/butanol mixed solution extract, it was attempted to separate and purify the components of the extract.

First, the above-mentioned extracts were investigated by thin layer chromatography (Merck, silica gel 60F254 and RP-18F2543), and as a result, a separation method using normal phase silica gel column chromatography using a chloroform/methanol mixture was considered to be suitable. Therefore, 400g of silica gel 60 (manufactured by Merck corporation) was packed, 13g of the extract was dissolved in 1ml of a chloroform/methanol mixed solution (1: 1), the resulting solution was passed through a column, and adsorbed on the column, and then elution was performed by a stepwise gradient method (chloroform: methanol at respective mixing ratios of 100: 1, 25: 1, 10: 1, 5: 1 and 1: 1) in which the methanol concentration was increased in steps using the chloroform/methanol mixed solution, and the eluates were fractionated at the respective mixing ratios of the above-mentioned mixed solutions. The yields of the crude purified product after removal of the solvents for the respective components were 1.44g, 3.0g, 1.17g, 1.28g and 2.27g, respectively. Of these fractions, the presence of the active ingredient in the fraction eluted with chloroform/methanol at 5: 1 (crude purified product a) was confirmed by the above evaluation of the insulin resistance-improving effect.

In order to further separate and purify the active ingredient from the above-mentioned crude purified product A, the crude purified product A was investigated using thin layer chromatography (manufactured by Merck Co., Ltd., silica gel 60F254 and RP-18F2543), and as a result, a separation method using reverse phase gel column chromatography using methanol was suitable. Thus, the crude purified product A was dissolved in 1ml of a chloroform/methanol mixture (1: 1), 180g of COSMOSIL140 (prepared by Nacalai Tesque Co.) was packed and adsorbed on the column, and then eluted with 600ml of 85% methanol solution, 600ml of 95% methanol solution and 100ml of 100% methanol in this order. 3-O-beta-D-glucopyranosyl-4-methylergost-7-en-3-ol is isolated by concentration in the 95% methanol eluate fraction and the mass after removal of the solvent is 370 mg. This will be referred to as compound 1 hereinafter.

The study of compound 1 by thin layer chromatography revealed a Rf value very close to that of β -sitosterol glucoside, and it was therefore predicted that the aglycon moiety was bound with a single molecular sugar to form a glycoside. In order to further examine the sugar composition of compound 1, compound 1 was methanolyzed, and then measured as a TMS derivative using GC-MS. As a result, when the TMS derivative of the sugar moiety of compound 1 was measured, it was found that the retention times of the main peaks were 14.28 minutes, 14.61 minutes, and 16.34 minutes, and almost coincided with those of the main peaks of 14.27 minutes, 14.60 minutes, and 16.33 minutes of the standard glucose (manufactured by Nacalai Tesque). Furthermore, no peak corresponding to the main peak of galactose as a standard (manufactured by Kishida chemical Co., Ltd.) and xylose as a standard (manufactured by Kishida chemical Co., Ltd.) was observed. Therefore, the kind of the sugar contained in compound 1 was identified as glucose.

From the above results, it is estimated that: compound 1 is a glycoside having one molecule of glucose bound to the aglycone moiety. But using compound 1¹³C-NMR(125MHz、CDCl₃) Since the presence of impurities was confirmed as a result of the measurement, further purification was necessary to confirm the structure. Therefore, compound 1 was subjected to methanolysis, followed by acetylation, followed by confirmation of the structure of the aglycon part and the binding site of the aglycon part to the sugar. The method is given below.

50mg of Compound 1 was dissolved in 50ml of methanol containing 5% hydrochloric acid, and then heated under reflux for 6 hours to effect methanolysis, which was dried to give about 30mg of a residue. The residue was purified by silica gel column chromatography (hexane: chloroform/9: 1) to give 10mg of Compound 2. To 5mg of this compound 2 were added two drops each of acetic anhydride and pyridine, and the mixture was heated at 70 ℃ for 30 minutes to effect acetylation, and then the solvent in the reaction mixture was distilled off to obtain a compound 3. Subjecting the compound 3 to GC-MS and¹³C-NMR(125MHz，CDCl₃) And (6) carrying out analysis.

GC-MS and¹³C-NMR(125MHz，CDCl₃) The measurement conditions and results of (2) are as follows. The 3-acetoxy-4-methylergost-7-ene used as standard material was prepared as follows: extracting and purifying from Aloe, and passing through¹³The structure was confirmed by C-NMR, followed by acetylation.

[¹³C-NMR spectrum (delta value)In CDCl₃Middle)]

C-1：36.8，C-2：27.3，C-3：78.7，C-4：37.0，C-5：46.9，C-6：26.8，C-7：117.4，C-8：139.4，C-9：49.7，C-10：34.9，C-11：21.6，C-12：39.7，C-13：43.6，C-14：55.1，C-15：23.1，C-16：28.2，C-17：56.3，C-18：12.0，C-19：14.2，C-20：36.5，C-21：19.0，C-22：33.9， C-23：30.6，C-24：39.1，C-25：32.6，C-26：20.4，C-27：18.4，C-28：15.6，C-29：15.3

[GC-MS]

The device comprises the following steps: GC-17A/GCMS5050A (Shimadzu)

And (3) GC column: NEUTRA BOND-5(GL science)

Column temperature: 100 ℃ (2 min) → (10 ℃/min) → 300 ℃ (28 min)

Injection temperature: 250 deg.C

Carrier gas: he (1.3 ml/min)

Interface temperature: 300 deg.C

MS mode: EI (El)

Ionization energy: 70eV

[ results ]

Standard substance: 3-acetoxy-4-methylergost-7-ene: tR [ min ]]＝39.4；m/z456[M]⁺，441[M-CH₃]⁺，396[M-AcOH]⁺，381[M-CH₃-AcOH]⁺

Compound 3: tR [ min ]]＝39.2；m/z456[M]⁺，441[M-CH₃]⁺，396[M-AcOH]⁺，381[M-CH₃-AcOH]⁺

The results of NMR measurements showed: the compound 3 has a literature value consistent with that of 3-acetoxy-4-methylergost-7-ene (oil chemistry, vol. 36, No. 5, pp. 301-319, 1987). This result indicates that Compound 2 is 4-methylergosta-7-en-3-ol. The molecular weight of Compound 1 was 576 as determined using FAB-MS. When compound 2 (aglycone moiety) was dehydrocondensed with glucose, the molecular weight of the resulting compound was 414 (compound 2) +180 (glucose) -18 (water) ═ 576, which was consistent with the molecular weight of compound 1. The above results show that: the structure of the compound 1 is 3-O-beta-D-glucopyranosyl-4-methylergost-7-en-3-ol.

Molecular formula, molecular weight, chemical formula are given below, respectively.

(Compound 1)

The molecular formula is as follows: c₃₅H₆₀O₆

Molecular weight: 576

The chemical formula is as follows: the following chemical formula (1)

(Compound 2)

The molecular formula is as follows: c₂₉H₅₀O

Molecular weight: 414

The chemical formula is as follows: the following chemical formula (2)

(Compound 3)

The molecular formula is as follows: c₃₁H₅₂O₂

Molecular weight: 456

The chemical formula is as follows: the following chemical formula (3)

[ preparation example 2]

The mesophyll (transparent gel fraction) of aloe vera was heat-dried and pulverized, and 60ml of 60%, 80% or 100% ethanol was added to 0.3g of the dried aloe vera powder, followed by heat-refluxing at 60 ℃ for 1 hour. The extract was centrifuged at 1500rpm for 20 minutes, and the supernatant was concentrated under reduced pressure to completely remove ethanol to obtain a crude extract. The dry mass of the crude extracts obtained by extraction with 60%, 80% and 100% ethanol was 65mg, 42mg and 18mg, respectively. Confirmation by thin layer chromatography: these crude extracts contain 3-O-beta-D-glucopyranosyl-4-methylergost-7-en-3-ol.

[ preparation example 3]

The mesophyll (transparent gel fraction) of aloe vera was heat-dried and pulverized, and 60ml of water was added to 0.3g of the dried aloe vera powder, followed by heating reflux at 95 ℃ for 5 hours. The extract was centrifuged at 1500rpm for 20 minutes and the supernatant was freeze-dried to give 75mg of crude extract. Confirmation by thin layer chromatography: these crude extracts contain 3-O-beta-D-glucopyranosyl-4-methylergost-7-en-3-ol.

[ preparation example 4]

The mesophyll (transparent gel fraction) of aloe vera was dried by heating and pulverized, 90L of chloroform/methanol mixture (2: 1) was added to 21kg of dried aloe vera powder, followed by overnight soaking at room temperature, followed by filtration, and 90L of chloroform/methanol mixture (2: 1) was added again to the filtration residue, and the same procedure was carried out for 4 times in total. The 350L filtrate obtained was concentrated at 28 ℃ to give 784g of crude extract. To 780g of the crude extract, 2L of chloroform/methanol mixture (2: 1) was added, and after stirring for 1 hour, filtration was carried out to recover the chloroform/methanol mixture layer (A). To the filtered residue were added 2.5L of water and 2L of ethyl acetate in this order, and after stirring for 1 hour, the ethyl acetate layer (B) was recovered, and to the remaining aqueous layer was added 5L of chloroform again, and after stirring for 1 hour, the chloroform layer (C) was recovered.

The recovered organic solvent extracts of A, B and C were mixed, concentrated at 23 ℃, and then added to a silica gel column [ glass column: 52mm × 350mm, filler: IR-63/210-W (manufactured by Daiso Co., Ltd.). Then, the eluate was monitored by thin layer chromatography, and while sequentially introducing 10L of a hexane/chloroform mixture (1: 1), 10L of chloroform, 20L of a chloroform/methanol mixture (10: 1), and 20L of a chloroform/methanol mixture (5: 1), fraction 1 (about 1L, fraction 2 (about 1.5L), fraction 3 (about 1.5L), and fraction 4 (about 1.5L) were recovered in this order.

Wherein it was confirmed by thin layer chromatography that fraction 3 contained the target glycoside, and then the solvent was removed to obtain 131.6g of a crude extract. 130g of this crude extract was added again to a silica gel column [ glass column: 70mm × 500mm, filler: SP-60-40/60 (manufactured by Daiso Kabushiki Kaisha)]In the elution solvent, 10L of chloroform/methanol mixture (30: 1), 50L of chloroform/methanol mixture (20: 1), 10L of chloroform/methanol mixture (10: 1), and 10L of chloroform/methanol mixture (1: 1) were used, respectively, under the following conditions: 10kgfcm^-2Flow rate: the elution was performed sequentially at 40 ml/min. The eluate is fractionated by 100ml each by a fraction collector to give fractions 1 to 8.

The recovered fraction was confirmed by thin layer chromatography, and as a result, the target glycoside and impurities were present in fraction 7, and thus concentrated and added again to a silica gel column [ glass column: 70mm × 500mm, filler: SP-60-40/60 (manufactured by Daiso Kabushiki Kaisha)]In (1), 10L of chloroform/methanol mixture (20: 1) and 10L of chloroform/methanol mixture (10: 1) were used as eluting solvents, respectively, under the following pressure: 10kgfcm^-2Flow rate: the elution was performed sequentially at 40 ml/min. As a result, 25.3g of the target glycoside 3-O-. beta. -D-glucopyranosyl-4-methylergost-7-en-3-ol contained in the eluted fraction of a chloroform/methanol mixture (10: 1) was prepared.

Example 1

Example 1 is an evaluation of the change in the amount of Free Fatty Acids (FFA) in serum by the insulin resistance improving agent of the present invention using zdf (zucker diabetes mellitus) rats, an obese Diabetic model animal showing insulin resistance.

(1) Preparation of the samples

3-O-. beta. -D-glucopyranosyl-4-methylergost-7-en-3-ol prepared in the above preparation example 1 was dissolved in DMSO, and then prepared with distilled water to a concentration of 15. mu.g/ml to serve as a test sample. The final concentration of DMSO was adjusted to 0.2% at this time. A solution containing no test sample was used as a negative sample.

(2) Test method

Male ZDF rats (purchased from Charles River Laboratories, USA) of 6 weeks of age were prepared for one month with high fat Diet (manufactured by Research Diet company) and then divided into 6 per group. The rats in each group were given 1ml (37.5. mu.g/kg body weight) per 400g body weight using a feeding tube (sonde) once a day, and either the test sample or the negative sample was continuously administered orally. On the 45 th day after the start of administration of the sample, blood was collected by fasting, and the amount of free fatty acids in serum was measured by NEFA C-test wako (manufactured by Wako pure chemical industries, Ltd.).

(3) Results (blood free fatty acid concentration)

Table 1 shows the free fatty acid concentration in the serum of rats at 45 days from the start of administration. In the test sample administration group, the free fatty acid value in serum was significantly reduced by about 53% as compared with the negative sample administration group. In addition, no pathologically visible side effects were observed at all during the administration period. The p-values in the table represent the significant probability of Tukey-Kramer's detection.

[ Table 1]

In the table, "-" indicates a statistically significant effect of inhibiting the production of free fatty acids.

Example 2

Example 2 is an evaluation of the effect of the insulin resistance-improving agent of the present invention on the production amounts of TNF-. alpha.and MCP-1 in respective cells of adipose tissue using ZDF (zucker diabetes Fatty) rat, an obese Diabetic model animal showing insulin resistance.

(1) Preparation of the samples

The same test sample and negative sample as those prepared in example 1 above were used as the sample of example 2.

(2) Test method

Male ZDF rats (purchased from Charles River Laboratories, USA) of 6 weeks of age were prepared for one month with high fat Diet (manufactured by Research Diet company) and then divided into 6 per group. The rats in each group were administered 1ml per 400g body weight (37.5. mu.g/kg body weight) using a feeding tube once a day, and either the test sample or the negative sample was continuously administered orally. On the 45 th day after the start of sample administration, 1.5ml of D-MEM/F12 medium containing 0.5% bovine serum albumin was added to 1g of peritestis fat collected under fasting, and the mixture was cultured at 37 ℃. After 1 hour of the culture, the culture supernatant was collected, and the concentrations of TNF-. alpha.and MCP-1 in the supernatant were measured by ELISA method (Biosource).

(3) Results (TNF-. alpha., MCP-1 production amount)

Table 2 shows the amount of TNF-. alpha.produced from adipose tissue. Table 3 also shows the amount of MCP-1 produced. From the above results, it was found that the group to which the test sample was administered exhibited a significant effect of inhibiting the production of both TNF-. alpha.and MCP-1, as compared with the group to which the negative sample was administered. The results of this example show that administration of the insulin resistance-improving agent of the present invention has an effect of preventing deterioration of insulin resistance by reducing the production of adipocyte cytokines that initiate insulin resistance in adipose tissues in which insulin resistance deteriorates. The p-values in the table represent the significant probability of Tukey-Kramer's detection.

[ Table 2]

In the table, "-" indicates a statistically significant effect of inhibiting TNF- α production.

[ Table 3]

In the table, "+" indicates a statistically significant effect of inhibiting the production of MCP-1.

Example 3

In this example, an insulin tolerance test was conducted using an obese Diabetic model animal zdf (zucker diabetes fatty) showing insulin resistance to confirm the insulin sensitivity potentiating effect of the insulin resistance improving agent of the present invention.

(1) Preparation of the samples

The same test sample and negative sample as those prepared in example 1 or 2 above were used as the sample of example 3.

(2) Test method

Male ZDF rats (purchased from Charles River Laboratories, USA) of 6 weeks of age were prepared for one month with high fat Diet (manufactured by Research Diet company) and then divided into 6 per group. The rats in each group were administered 1ml per 400g body weight (37.5. mu.g/kg body weight) using a feeding tube once a day, and either the test sample or the negative sample was continuously administered orally. The 35 th day after the start of the administration of the test sample, an insulin tolerance test was performed. In the insulin tolerance test in this example, after the rats were fasted for 4 hours, human insulin (manufactured by EliLily) was administered intraperitoneally at a dose of 10U/kg body weight, and the change in blood glucose level with time was measured from the start of insulin administration to 60 minutes.

(3) Results (insulin tolerance test)

The results of this example are shown in FIG. 1. Fig. 1 shows the results of an insulin tolerance test. As is clear from fig. 1, the blood glucose levels in the group to which the test sample was administered were lower than those in the group to which the negative sample was administered at any time between 15 minutes and 60 minutes after the start of insulin administration. The results of this example show that administration of the insulin resistance-improving agent of the present invention can increase insulin sensitivity.

Industrial applicability

The present invention can provide a safe insulin resistance-improving agent which can enhance insulin sensitivity without side effects, and a functional food or drink such as a specific health food containing the insulin resistance-improving agent, and has the effect of improving or preventing lifestyle-related diseases such as hypertension, diabetes, hyperlipidemia, and arteriosclerosis, which are caused by low insulin sensitivity, and reducing the risk of such diseases and complications.

Claims (4)

1. Use of a compound represented by the following chemical formula (1) for the preparation of a medicament for improving insulin resistance:

2. use of an ethyl acetate/butanol 3: 1 mixed liquor extract or a chloroform/methanol 2: 1 mixed liquor extract of aloe vera mesophyll, or an ethyl acetate/butanol 3: 1 mixed liquor extract fraction or a chloroform/methanol 2: 1 mixed liquor extract fraction of aloe vera mesophyll for the preparation of a medicament for improving insulin resistance, wherein the medicament contains a compound represented by the following formula (1) in a dry mass of at least 0.001% by mass:

3. use of a compound represented by the following chemical formula (1) for preparing a food or drink for improving insulin resistance:

4. use of an ethyl acetate/butanol 3: 1 mixed liquor extract or a chloroform/methanol 2: 1 mixed liquor extract of aloe vera mesophyll, or an ethyl acetate/butanol 3: 1 mixed liquor extract fractionation fraction or a chloroform/methanol 2: 1 mixed liquor extract fractionation fraction of aloe vera mesophyll for the preparation of a food and drink for improving insulin resistance, wherein the food and drink contains at least 0.0001% by mass in dry matter of a compound represented by the following formula (1):