Composition for maintaining or improving glucose metabolism function, method for maintaining or improving glucose metabolism function

Abstract

To provide a novel composition that has the effect of maintaining or improving glucose metabolism function. [Solution] A composition for maintaining or improving glucose metabolism function, containing a hexanoic acid compound as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a composition for maintaining or improving sugar metabolism function and a method for maintaining or improving sugar metabolism function.

Background Art

[0002] Currently, it is estimated that more than one billion people worldwide are obese, and obesity has become one of the major public health problems. Obesity has been reported to be associated with diseases such as type 2 diabetes, cardiovascular diseases, and cancer, and the demand for the development of functional foods having anti-obesity properties is increasing. As one of the active ingredients of such functional foods, for example, fatty acids have attracted attention. Fatty acids are classified into three groups according to the length of the carbon chain: short-chain fatty acids (SCFA: generally, the number of carbon atoms in the carbon chain is less than 6), medium-chain fatty acids (MCFA: generally, the number of carbon atoms in the carbon chain is 6 to 12), and long-chain fatty acids (LCFA: generally, the number of carbon atoms in the carbon chain is 12 or more). SCFA in the living body mainly originates from the fermentation of indigestible polysaccharides by microorganisms in the digestive organs (stomach, intestine), and MCFA and LCFA mainly originate from the fat in the ingested diet. SCFA is mainly composed of acetic acid (C2:0), propionic acid (C3:0), and butyric acid (C4:0) (here, in the notation shown by "(x:y)", x indicates the number of carbon atoms and y indicates the number of double bonds, respectively). These anti-obesity properties have been studied conventionally. For example, it has been reported that butyric acid prevents obesity and insulin resistance (decrease in insulin sensitivity) induced by a high-fat diet.

[0003] Hexanoic acid (C6:0) is a fatty acid with six carbon atoms in its carbon chain and is generally classified as a medium-chain fatty acid (MCFA), although it is sometimes classified as a short-chain fatty acid (SCFA). Regarding such hexanoic acid, for example, Akpa MM et al., Lipids., 2010, 45:997-1009 (Non-patent Literature 1) describes that hexanoic acid inhibits the expression and activity of insulin and T3-induced fatty acid synthase in human liver cancer HepG2 cell lines. Also, Fei Wu et al., British Journal of Nutrition, 2022, 128, 75-83 (Non-patent Literature 2) describes that hexanoic acid intake reduces the risk of overweight and obesity. Furthermore, the inventors have reported that hexanoic acid, like butyric acid, suppresses weight gain and fat accumulation caused by the intake of a high-fat diet (Ikuo Kimura, "Fatty Acid Receptors and Molecular Nutritional Signals: Effects of Milk Fat Intake on Growth and Metabolic Function," Summary of Research for Fiscal Year 2023, 2024, Japan Food Research Association, pp. 80-83; Non-Patent Literature 3).

[0004] However, the effects of hexanoic acid on the body's metabolism, including the anti-obesity properties mentioned above, have remained largely unknown. Furthermore, while obesity and glucose metabolism are closely related, as mentioned above, and it is known that obesity can progress to type 2 diabetes, the relationship between fatty acids and glucose metabolism has also not yet been elucidated. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Akpa MM et al.,Lipids.,2010,45:997-1009 [Non-Patent Document 2] Fei Wu et al.,British Journal of Nutrition,2022,128,75-83 [Non-Patent Document 3] Ikuo Kimura, "Fatty Acid Receptors and Molecular Nutritional Signaling: Effects of Milk Fat Intake on Growth and Metabolic Function," Summary of Research for FY2023, 2024, Japan Food Research Association, pp. 80-83. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] This invention has been made in view of the problems of the prior art described above, and aims to provide a novel composition having an effect of maintaining or improving glucose metabolic function, and a method for maintaining or improving glucose metabolic function. [Means for solving the problem]

[0007] To achieve the above objective, the inventors diligently researched the effects of hexanoic acid on metabolism, a substance whose effects on metabolism had been largely unknown until now. As a result, they found that hexanoic acid has an effect of maintaining or improving glucose metabolism function, and that hyperglycemia can be suppressed by hexanoic acid intake, for example, by significantly suppressing hyperglycemia induced by excessive lipid intake (e.g., intake of a high-fat diet) or diet (e.g., intake of glucose). Furthermore, the inventors found that one reason for this effect of maintaining or improving glucose metabolism function is that hexanoic acid has an effect of improving insulin sensitivity. As described above, hexanoic acid, like butyric acid, a short-chain fatty acid (SCFA), has been reported to have anti-obesity properties. However, surprisingly, although butyric acid has been reported to have an effect of improving insulin resistance, the effect of maintaining or improving glucose metabolism function, which the inventors newly discovered in this study, has not been confirmed in hexanoic acid. It has become clear that this effect is a newly discovered attribute of hexanoic acid, distinct from that of butyric acid. Through these studies, the inventors discovered that by having subjects ingest a composition containing hexanoic acid compounds as an active ingredient, their glucose metabolism function can be maintained or improved, leading to the completion of the present invention. The embodiments of the present invention obtained from these findings are as follows. [1] A composition for maintaining or improving glucose metabolism function, containing a hexanoic acid compound as an active ingredient. [2] The composition according to [1], wherein the hexanoic acid compound is at least one selected from the group consisting of hexanoic acid, a salt of hexanoic acid, a hexanoic acid ester, and a hexanoic acid glyceride containing at least one hexanoic acid as a constituent fatty acid. [3] The composition according to [1] or [2] for suppressing hyperglycemia. [4] The composition according to [3], wherein the hyperglycemia is postprandial hyperglycemia. [5] The composition according to [3], wherein the hyperglycemia is fasting hyperglycemia. [6] The composition according to any one of [3] to [5], wherein the hyperglycemia is due to obesity. [7] The composition according to any one of [3] to [6], wherein the hyperglycemia is caused by excessive intake of lipids. [8] A composition according to any one of [1] to [7] for improving insulin sensitivity. [9] A composition according to any one of items [1] to [8], for consumption before or during a meal.

[10] A composition according to any one of items [1] to [9] for consumption by an obese person.

[11] A composition according to any one of items [1] to

[10] for intake by subjects with a high fat energy ratio.

[12] A method for maintaining or improving glucose metabolism function, comprising the step of administering a composition containing a hexanoic acid compound as an active ingredient to a subject.

[13] Use of hexanoic acid compounds for maintaining or improving glucose metabolism function.

[14] Use of hexanoic acid compounds for the manufacture of compositions for maintaining or improving glucose metabolic function. [Effect of the Invention]

[0008] According to the present invention, it is possible to provide a novel composition as a composition having an action of maintaining or improving glucose metabolism function, and a method of maintaining or improving glucose metabolism function. Since the composition of the present invention can be provided as a food or drink composition, it is easy to ingest orally and is also easy to become accustomed to. Furthermore, since the composition of the present invention has an action of maintaining or improving glucose metabolism function, it is also useful as a functional food or the like for preventing hyperglycemia-related diseases such as type 2 diabetes. [Brief Description of the Drawings]

[0009] <用 [Figure 1A] <Test Example 1>, a graph showing the average value of hexanoic acid concentration (Hexanoic acid (nmol / g)) in the liver in the group fed CE-2, a standard diet (ND; Comparative Example), the group fed a high-fat diet (HFD; Comparative Example), the group fed a high-fat diet containing butyric acid (HFD_C4; Comparative Example), and the group fed a high-fat diet containing hexanoic acid (HFD_C6; Example). [Figure 1B] <Test Example 1>, a graph showing the average body weight (Body weight (g)) at 7 to 11 weeks of age in the group fed CE-2, a standard diet (ND; Comparative Example), the group fed a high-fat diet (HFD; Comparative Example), the group fed a high-fat diet containing butyric acid (HFD_C4; Comparative Example), and the group fed a high-fat diet containing hexanoic acid (HFD_C6; Example). [Figure 1C] <Test Example 1>, a graph showing the average daily food intake (Food intake (g / day)) in the group fed a high-fat diet (HFD; Comparative Example), the group fed a high-fat diet containing butyric acid (HFD_C4; Comparative Example), and the group fed a high-fat diet containing hexanoic acid (HFD_C6; Example). [Figure 2A]A graph showing the average values of blood glucose levels (Blood glucose (mg / dL)) in the group fed the standard diet CE-2 (ND; Comparative Example), the group fed a high-fat diet (HFD; Comparative Example), the group fed a high-fat diet containing butyric acid (HFD_C4; Comparative Example), and the group fed a high-fat diet containing hexanoic acid (HFD_C6; Example) in <Test Example 1>. [Figure 2B] A graph showing the average values of blood insulin levels (Insulin (pg / mL)) in the group fed the standard diet CE-2 (ND; Comparative Example), the group fed a high-fat diet (HFD; Comparative Example), the group fed a high-fat diet containing butyric acid (HFD_C4; Comparative Example), and the group fed a high-fat diet containing hexanoic acid (HFD_C6; Example) in <Test Example 1>. [Figure 3] In the (1) GTT (glucose tolerance test) of <Test Example 2>, graphs (a) showing the average values of blood glucose levels (Blood glucose (mg / dL)) at 0, 15, 30, 60, 90, or 120 minutes after glucose administration and graph (b) showing the area under the blood glucose-time curve (AUC (103 mg / dL·min)) in the mouse group fed hexanoic acid by oral administration (Hexanoic acid; Example) and the control group (Ctrl; Comparative Example). [Figure 4] In the (2) ITT (insulin tolerance test) of <Test Example 2>, graphs (a) showing the average values of blood glucose levels (Blood glucose (mg / dL)) at 0, 15, 30, 60, 90, or 120 minutes after insulin administration and graph (b) showing the area under the blood glucose-time curve (AUC (103 mg / dL·min)) in the mouse group fed hexanoic acid by oral administration (Hexanoic acid; Example) and the control group (Ctrl; Comparative Example).

Mode for Carrying Out the Invention

[0010] Hereinafter, the present invention will be described in detail according to its preferred embodiments, but the present invention is not limited to such preferred embodiments.

[0011] The present invention provides a composition (hereinafter referred to as "the composition of the present invention" in some cases) for maintaining or improving glucose metabolic function, comprising a hexanoic acid compound as an active ingredient.

[0012] In this invention, "glucose metabolism" refers to the system in which cells take up glucose from the blood to lower blood glucose levels. This glucose metabolism is mainly promoted by insulin secreted from the pancreas when the blood glucose concentration rises. The glucose taken up by cells is either stored in the cells as glycogen or used for ATP production through glycolysis. In other words, in this invention, "glucose metabolic function" refers to the function of maintaining the blood glucose concentration and also includes the function of maintaining the responsiveness of cells to insulin, i.e., insulin sensitivity.

[0013] In the present invention, "in vivo" refers to the inside of a subject to be given the composition of the present invention. Preferably, the subject is a human or a non-human animal, more specifically, a human or a non-human mammal (primates such as humans, monkeys, gorillas, baboons, and chimpanzees; domestic animals such as horses, cattle, buffalo, sheep, goats, pigs, camels, and deer; pet animals such as dogs and cats, etc.), and preferably a human.

[0014] In the present invention, "maintenance of glucose metabolic function" means that the glucose metabolic function is in a normal state, which can be confirmed, for example, by maintaining blood glucose levels within the normal range. Furthermore, in the present invention, "improvement of glucose metabolic function" means that the glucose metabolic function improves from a reduced state to the normal state or a state close to it, which can be confirmed, for example, by suppressing hyperglycemia, that is, by decreasing blood glucose levels from hyperglycemia, or by gradualizing the rapid rise in blood glucose levels to hyperglycemia during the 0-3 hours after a meal, preferably by decreasing blood glucose levels from hyperglycemia to within the normal range, or by not experiencing a rise in blood glucose levels to hyperglycemia during the 0-3 hours after a meal.

[0015] In this invention, "blood glucose level" refers to the glucose concentration in the blood, and is expressed as the glucose concentration in the plasma. Furthermore, "hyperglycemia" refers to a blood glucose level that is higher than the reference value, and the reference value is, for example, 100 mg / dL for adults before a meal (fasting blood glucose level); and 140 mg / dL for adults 2 hours after a meal (however, this depends on the content of the meal). Hereinafter, in this invention, when we refer to "hyperglycemia," the blood glucose level that is considered hyperglycemia includes so-called "slightly above normal blood glucose levels" and "borderline blood glucose levels," that is, the state of hyperglycemia also includes a pre-disease state (a state that is not a disease state such as diabetes and does not require treatment).

[0016] In humans (preferably adults), the criteria for distinguishing between "normal range" and "hyperglycemia" blood glucose levels according to the present invention are, more specifically, fasting blood glucose levels, for example, the following criteria: Fasting blood glucose level less than 70-100 mg / dL: Normal range (normal type) Fasting blood glucose level between 100 mg / dL and 110 mg / dL: Hyperglycemia (slightly elevated normal) Fasting blood glucose level of 110 mg / dL or higher but less than 126 mg / dL: Hyperglycemia (borderline) Fasting blood glucose level of 126 mg / dL or higher: Hyperglycemia (diabetic type) These include: Furthermore, regarding the blood glucose level two hours after glucose loading in the "Glucose Tolerance Test (OGTT)" as described in the "Diabetes Treatment Guidelines 2024," Japan Diabetes Society, for example, the following criteria apply: Blood glucose level less than 140 mg / dL 2 hours after load: Normal range (normal type) Blood glucose level 2 hours after load: 140 mg / dL or higher but less than 200 mg / dL: Hyperglycemia (borderline) Blood glucose level 200 mg / dL or higher 2 hours after load: Hyperglycemia (diabetic type) These include: Furthermore, the HbA1c value, which indicates the percentage of glycated hemoglobin relative to total hemoglobin, can be used, for example, based on the following criteria: HbA1c between 4.6% and less than 6.0%: Normal range (normal type) HbA1c between 6.0% and 6.5%: Hyperglycemia (borderline) HbA1c 6.5% or higher: Hyperglycemia (diabetic type) These are some examples. These criteria may be applied individually or in combination of two or more.

[0017] Specific forms of hyperglycemia include, for example, chronic hyperglycemia such as fasting hyperglycemia, and postprandial hyperglycemia (for example, hyperglycemia at 2 hours after the aforementioned load). The main causes of hyperglycemia include, for example, excessive energy intake, excessive lipid intake; obesity (a condition in which more fat than normal is accumulated in the body, and is not a disease); juvenile diabetes, gestational diabetes, type 1 diabetes, type 2 diabetes; stress; medications; and aging, and the main causes are a decrease in insulin secretion and decreased insulin sensitivity due to these factors.

[0018] In addition, the aforementioned "excessive intake of lipids" refers, for example, to a high proportion of energy intake from fat (fat energy ratio) as described in the ["Dietary Reference Intakes for Japanese (2020 Edition)", Ministry of Health, Labour and Welfare], or more specifically, to an upper limit (30% or more) of the target amount for the aforementioned fat energy ratio (20% or more but less than 30% for people aged 1 year or older).

[0019] The aforementioned "obesity" refers, for example, to the international standard indicator BMI (Body Mass Index = weight (kg) ÷ height (m)) in adults. 2 This includes a waist circumference of 25 or higher, and a condition in which there is excessive accumulation of fat in the adipose tissue (for example, in Japan, waist circumference ≥ 85 cm (men), waist circumference ≥ 90 cm (women)).

[0020] The composition of the present invention is for maintaining or improving the glucose metabolic function, more specifically, for suppressing hyperglycemia, i.e., for suppressing fasting hyperglycemia and / or postprandial hyperglycemia. Furthermore, the composition of the present invention is preferable for administration to subjects who are obese or have a high fat energy ratio, which are causes of hyperglycemia, for administration to subjects who are concerned about their postprandial blood glucose levels (based on their own judgment), or for suppressing hyperglycemia due to obesity or hyperglycemia due to excessive lipid intake. Moreover, in the present invention, one of the reasons for the effect of maintaining or improving the glucose metabolic function is that the hexanoic acid compound according to the present invention improves insulin sensitivity; therefore, the composition of the present invention is also preferable as a composition for improving insulin sensitivity. Furthermore, the compositions of the present invention can be used for purposes such as preventing or improving diseases associated with hyperglycemia (e.g., type 2 diabetes, heart disease, diabetic retinopathy, diabetic nephropathy, Alzheimer's disease, vascular dementia), or alleviating or improving symptoms associated with the said diseases; maintaining a healthy blood glucose level; lowering blood glucose levels in individuals with elevated blood glucose levels; slowing (or moderating) the rise in blood glucose levels after meals; and reducing the risk of hyperglycemia.

[0021] The active ingredient contained in the composition of the present invention is a hexanoic acid compound. The inventors have newly discovered that the hexanoic acid compound has the effect of maintaining or improving the above-mentioned glucose metabolism function.

[0022] Examples of the "hexanoic acid compound" according to the present invention include at least one selected from the group consisting of hexanoic acid, a salt of hexanoic acid, a hexanoic acid ester, and a hexanoic acid glyceride containing at least one hexanoic acid as a constituent fatty acid.

[0023] In this invention, "hexanoic acid" refers to the chemical formula C6H 12 Represented as O2, it is a straight-chain, saturated fatty acid with 6 carbon atoms in its carbon chain. Generally, its molecular weight is 116.13 and its density is 0.93 g / cm³. 3 Hexanoic acid has a melting point of -3°C and a boiling point of 205°C, and exists as a colorless liquid at room temperature. Hexanoic acid is also known as "caproic acid."

[0024] The "salt" of hexanoic acid according to the present invention is not particularly limited as long as it is a food or pharmaceutically acceptable salt, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and inorganic salts such as hydrochloride salts and sulfate salts.

[0025] Examples of the "hexanoic acid ester" according to the present invention include esters of hexanoic acid and alcohol, such as ethyl hexanoate, which is an ester of hexanoic acid and ethanol.

[0026] In the present invention, "hexanoic acid glyceride" refers to an ester in which at least one of the three hydroxyl groups of glycerol is esterified with the carboxyl group of hexanoic acid (i.e., 1 to 3 molecules of fatty acids containing hexanoic acid are esterified to 1 molecule of glycerol). In the present invention, among the above hexanoic acid esters, the ester of hexanoic acid and glycerol is separately referred to as "hexanoic acid glyceride". Furthermore, in the present invention, "constituent fatty acid" means a fatty acid esterified to the glycerol, that is, the fatty acid from which the fatty acid residue in the glyceride originates, or a fatty acid released by hydrolysis of the glyceride.

[0027] The glyceride may be a monoglyceride with one constituent fatty acid molecule, a diglyceride with two constituent fatty acid molecules, or a triglyceride with three constituent fatty acid molecules, but a triglyceride is preferred. Furthermore, if the glyceride contains fatty acids other than hexanoic acid, the fatty acids other than hexanoic acid are not particularly limited, but are preferably linear (linear fatty acids) and / or saturated (saturated fatty acids), and more preferably one or two selected from short-chain fatty acids or medium-chain fatty acids having 4 to 12 carbon atoms in their carbon chains.

[0028] Furthermore, the "hexanoic acid glyceride" according to the present invention preferably has a stereochemical configuration in which the constituent fatty acids are bonded in the order of 1st, 3rd, and 2nd positions, more preferably at positions 1 and 3, and even more preferably at all positions, when the hydroxyl group bonded to the carbon atom (position 2) of glycerol is placed to the left in the Fischer projection formula, with the top position being 1st and the bottom position being 3rd, and more preferably at positions 1 and 3, and it is even more preferable that all three constituent fatty acids are hexanoic acid.

[0029] The hexanoic acid compound according to the present invention may be an extract from a natural product or a chemically synthesized product. Examples of natural products include oils and fats contained in dairy products such as cow's milk, sheep's milk, and goat's milk; and oils and fats collected from plants such as coconuts and palm fruit, from which extracts, crude products, and refined products obtained by appropriately known or similar methods can be used. Furthermore, the hexanoic acid compound can also be obtained from fermentation products of microorganisms in the digestive tracts (stomach, intestines) of ruminants and non-ruminants, specifically from cultures of such microorganisms. Chemically synthesized compounds are not particularly limited and can be synthesized by appropriately known or similar methods. Commercially available products may also be used as appropriate.

[0030] In the composition of the present invention, the content of the hexanoic acid compound can be adjusted as appropriate depending on the form of the composition, the amount ingested, the purpose and method of intake, etc., and therefore cannot be stated in general terms. However, for example, in terms of hexanoic acid, it can be 0.001 to 100% by mass, preferably 0.01 to 99% by mass, relative to the total mass of the composition. For example, if the composition of the present invention is the following oil and fat composition, examples of hexanoic acid content include 1 to 20% by mass, 1 to 15% by mass, 2 to 13% by mass, 5 to 10% by mass, and 2 to 3% by mass, relative to the total mass of the composition. For example, if the composition of the present invention is a food and beverage composition containing the above oil and fat composition, examples of hexanoic acid content include 0.1 to 3% by mass, 0.1 to 1% by mass, 0.2 to 0.5% by mass, and 0.2 to 0.3% by mass.

[0031] The composition of the present invention may further contain, in addition to the hexanoic acid compound, other food or pharmaceutically acceptable components, provided that the effects of the present invention are not inhibited. The other components are not particularly limited, but include, for example, water, lipids other than the hexanoic acid compound, sugars, sugar alcohols, minerals (calcium, magnesium, sodium, potassium, iron, copper, zinc, etc.), vitamins (vitamins A, B1, B2, B6, B12, C, D, E, K, etc.), proteins, peptides, amino acids, organic acids, auxiliaries, other active ingredients other than the hexanoic acid compound, and components other than those mentioned above contained in the following foods and beverages or their raw materials or intermediate products in the manufacturing process, and may contain one or more of these in combination.

[0032] The aforementioned auxiliary agents are not particularly limited, but more specifically, examples include solvents, dispersants, emulsifiers, thickeners, thickening stabilizers, gelling agents, surfactants, buffers, stabilizers, excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspending agents, coating agents, carriers (solid carriers, liquid carriers such as water), pH adjusters, preservatives, sweeteners, flavorings, and coloring agents, and may be one of these or a combination of two or more.

[0033] Furthermore, while there are no particular limitations on other active ingredients besides the hexanoic acid compound, more specifically, examples include dietary fiber (such as indigestible dextrin), fruits, vegetables and their processed products, animal and plant herbal extracts, and naturally derived polymers (such as collagen, hyaluronic acid, and chondroitin). It may be one of these or a combination of two or more.

[0034] If the composition of the present invention contains the above-mentioned other components, the amount of such other components is not particularly limited and can be appropriately adjusted depending on the form of the composition, the amount ingested, the purpose and method of intake, etc.

[0035] The composition of the present invention may be taken orally or parenterally, but orally is preferred. It may also be taken before, during, or after meals, but before or during meals is preferred. The composition of the present invention can be a composition that depends on the purpose, target, method, and amount of intake. For example, it is preferable to take it orally as a food or beverage composition or a feed composition to the target, but it may also be administered orally or parenterally to the target as a pharmaceutical composition or a quasi-drug composition.

[0036] In the present invention, the form of the food and beverage composition is not particularly limited and can take the following forms: solid form such as a bar, liquid form such as a beverage or liquid diet, paste form, semi-liquid form, gel form (jelly form), gel-like oil (semi-solid oil), powder form, etc. Furthermore, the food and beverage composition can be administered to patients, the elderly, infants, etc., as a liquid diet, powdered liquid diet, nutritional paste, oral nutritional supplement, beverage, gel-like food, etc.

[0037] Examples of the aforementioned food and beverage compositions are not particularly limited, but include, for example, beverages (tea, carbonated drinks, cocoa, coffee, lactic acid bacteria drinks, soy milk drinks, fruit and vegetable juice drinks, soft drinks, nutritional drinks, alcoholic beverages, etc.), processed foods (chocolate, gum, gummies, jelly, baked goods (bread, cakes, cookies, biscuits, etc.), candy, etc.), prepared foods (curry, stew, soup, fried rice, Chinese rice bowl, etc.), dairy products (prepared milk powder (powdered milk, etc.), processed milk, milk drinks, fermented milk, yogurt, ice cream, cheese, cream, butter, margarine, condensed milk, etc.), seasonings (sauces, soups, dressings, mayonnaise, mayonnaise-type seasonings, cream, etc.), supplements, edible oils, etc. Among these, the composition of the present invention is preferably an oil and fat composition such as butter, margarine, mayonnaise, chocolate, or edible oil.

[0038] The aforementioned food and beverage composition can be produced, for example, by blending the hexanoic acid compound according to the present invention with an existing food or beverage, or its raw materials or intermediate products in the manufacturing process. In this case, the hexanoic acid compound blended may be in the form of a formulation listed in the following pharmaceutical and quasi-pharmaceutical compositions.

[0039] Furthermore, in the present invention, the food and beverage composition may be, for example, general foods, health foods, functional foods, health functional foods (e.g., foods for specified health uses, foods with nutritional function, nutritional supplements, foods with functional claims, etc.), foods for special dietary uses (e.g., foods for infants, foods for pregnant and lactating women, foods for sick people, etc.), medical foods (foods prescribed under the supervision of a physician as defined by the U.S. Food and Drug Administration (FDA) and the Orphan Drug Act), therapeutic foods (foods that serve a therapeutic purpose and are prepared based on menus created by a dietitian or the like in accordance with a diet prescription from a physician), or therapeutic diets.

[0040] Furthermore, the food and beverage composition may display the effects and efficacy brought about by the hexanoic acid compound according to the present invention in the product (for example, suppression of hyperglycemia, prevention of postprandial hyperglycemia, improvement of insulin sensitivity, and prevention or improvement of diseases for which these are effective, or alleviation or improvement of symptoms related to said diseases). More specifically, for example, the product may display "Helps maintain a healthy blood glucose level," "Lowers blood glucose levels in people with elevated blood glucose levels," "Slows down the rise in blood glucose levels after meals," "Moderates the rise in blood glucose levels after meals," "For maintaining normal blood glucose levels," "For reducing the risk of hyperglycemia," "Suppresses the rise in blood glucose levels after meals," "For people with elevated blood glucose levels," "Suppresses the rise in blood glucose levels after meals," "Reduces the risk of diabetes," "Reduces the risk of hyperglycemia due to obesity," etc. In addition, other displays may be made as long as they express the effects resulting from the maintenance or improvement of glucose metabolism function, suppression of hyperglycemia, suppression of postprandial hyperglycemia, suppression of fasting hyperglycemia, suppression of hyperglycemia due to obesity, suppression of hyperglycemia due to excessive lipid intake, and improvement of insulin sensitivity.

[0041] When the composition of the present invention is a feed composition, this includes any modifications made to the above-mentioned food and beverage composition depending on the form, amount ingested, purpose of ingestion, target, method, etc.

[0042] Furthermore, when the composition of the present invention is a pharmaceutical composition or a quasi-drug composition, these can be, for example, in the form of a formulation, and the form is not particularly limited, but examples include solid preparations such as tablets, pills, granules, powders, and capsules; liquid preparations such as general liquids, suspensions, emulsions, and syrups; jelly preparations; injectable and intravenous preparations; enteral and nasogastric preparations; and suppositories. The formulation can be manufactured, for example, by adding one or more of the aforementioned auxiliary agents, and optionally one or more other components other than the aforementioned auxiliary agents, to the hexanoic acid compound according to the present invention by known methods or similar methods.

[0043] The composition of the present invention is preferably packaged (preferably sealed) in a packaging container from the time of manufacture until consumption. The packaging container is not particularly limited, but examples include wrapping paper, packaging bags, soft bags, tubes, chia packs, paper containers, cans, bottles, and capsules.

[0044] The composition of the present invention contains the hexanoic acid compound as an active ingredient, and when ingested by the subject, maintains or improves the glucose metabolic function in the subject, more specifically, maintains blood glucose levels within the normal range, lowers blood glucose levels from hyperglycemia, or moderates the rapid rise to postprandial hyperglycemia. Therefore, the present invention also provides a method for maintaining or improving glucose metabolic function, comprising the step of ingesting a composition containing the hexanoic acid compound as an active ingredient; the use of the hexanoic acid compound for maintaining or improving glucose metabolic function; and the use of the hexanoic acid compound for producing a composition for maintaining or improving glucose metabolic function.

[0045] The subjects and methods of intake, including their preferred embodiments, are as described above. The subjects are those whose purpose is to maintain or improve the glucose metabolism function described above. Preferably, such subjects are those in a pre-disease state (not diseased, not requiring treatment) where the composition of the present invention is a non-therapeutic composition such as the food and beverage composition. Examples of preferred subjects include obese subjects and subjects with a high fat energy ratio. However, the subjects are not excluded from those suffering from diseases caused by abnormal glucose metabolism function (e.g., type 2 diabetes, heart disease, diabetic retinopathy, diabetic nephropathy, Alzheimer's disease, vascular dementia). Furthermore, if the subject is a person suffering from a disease caused by abnormal glucose metabolism function and whose purpose is to alleviate or improve their symptoms, or to prevent the onset of such disease, the composition of the present invention may be administered to the subject as the pharmaceutical composition or quasi-drug composition, etc.

[0046] The amount of the composition of the present invention to be taken (or, in the case of a pharmaceutical composition or quasi-drug composition, the dosage) can be appropriately determined on a case-by-case basis, taking into consideration the form of the composition, the purpose and method of intake, the species, age, weight, sex, medical history of the target, and the method of intake. Therefore, although not particularly limited, for example, the amount of intake for a human (preferably an adult) food and beverage composition is preferably 0.1 to 25 g per day, more preferably 0.15 to 10 g, and even more preferably 0.2 to 5 g or 0.2 to 2 g per day in terms of hexanoic acid. The above intake amount may be taken in multiple doses per day. [Examples]

[0047] The present invention will be described more specifically below based on examples and comparative examples, but the present invention is not limited to the following examples.

[0048] In the following, unless otherwise specified, "%" indicates mass / volume (w / v) percent (g / 100mL). Furthermore, all results are shown as standard error (SEM) (mean ± SEM). Statistical analysis was performed using GraphPad Prism (GraphPad Software), and the Shapiro-Wilk test was used to test for normality. Statistical significance between two groups was evaluated using Student's t-test, and statistical significance between multiple groups was evaluated using the Tukey-Kramer test or Dunn's test after one-way ANOVA, depending on normality. A p<0.05 value was considered statistically significant. Values ​​with p<0.05 are indicated by "*", p<0.01 by "**", p<0.001 by "***", and values ​​that were not statistically significant are indicated by "ns". Furthermore, all animal experiments were conducted appropriately in accordance with the guidelines established by the Kyoto University Animal Experiment Committee (application permit number Lif-K24002), and efforts were made to minimize suffering to the experimental animals.

[0049] <Test Example 1> (1) High-fat diet challenge test Male mice (C57BL / 6J strain) were purchased from SLC Japan and reared at 24°C, 50% humidity, and under 12-hour light / dark cycles. Six-week-old male mice were acclimatized for one week with the standard diet CE-2 (manufactured by CLEA Japan), and then randomly divided into four groups (n=10 each). Each group underwent a loading test, being fed either CE-2 (ND; comparative example), a high-fat diet (HFD: 60% of calories from lipids; comparative example), a high-fat diet containing 5% sodium butyrate (HFD_C4; comparative example), or a high-fat diet containing 5% sodium hexanoate (HFD_C6; example) for four weeks. The composition of each diet, HFD, HFD_C4, and HFD_C6, is shown in Table 1 below.

[0050] [Table 1]

[0051] During the 4-week stress test, body weight (g) was measured once a week and the average value was calculated (n=10). The results (average body weight at each age (start of stress test: 7 weeks old to 4 weeks after: 11 weeks old)) are shown in Figure 1B. The amount of each food consumed was calculated as the average daily food intake (g / day) under ad libitum feeding conditions (n=5). The results are shown in Figure 1C.

[0052] (2) Determination of hexanoic acid in the liver After a 4-week loading test, liver samples were collected under deep anesthesia with isoflurane. The collected liver samples were homogenized in a methanol solution containing an internal standard (C19:0), and lipids were extracted by mixing with chloroform and water. After centrifugation (2000 × g, 10 min, 17°C), the supernatant was collected and dried to nitrogen. After redissolution in a chloroform:methanol solution (1:3 (v / v)), hexanoic acid was detected using a liquid chromatograph-mass spectrometer (Waters Xevo TQD mass spectrometer; Waters). The hexanoic acid concentration in the liver (Hexanoic acid (nmol / g)) was quantified using a calibration curve, and the average values ​​were calculated (n=10). The detection was performed using a 10 mM ammonium formate aqueous solution with a methanol gradient as the solvent, and separation was performed using an ACQUITY UPLC BEH C18 column (2.1 × 150 mm, 1.7 μm; Waters). The results are shown in Figure 1A.

[0053] (3) Measurement of blood glucose levels and blood insulin levels After a 4-week stress test, blood was collected from the inferior vena cava using a heparinized syringe, and plasma samples were obtained by centrifugation (7000 × g, 5 min, 4°C). Blood glucose levels (mg / dL) were measured in the obtained plasma samples using One Touch Ultra Test Strips (LifeScan), and the average values ​​were calculated (n=10). The results are shown in Figure 2A.

[0054] Furthermore, the obtained plasma samples were analyzed using an insulin enzyme-binding immunosorbent assay (ELISA) kit (RTU) (Shibayagi Corporation) to measure blood insulin levels (Insulin (pg / mL)) according to the kit's instructions, and the average values ​​were calculated (n=10). The results are shown in Figure 2B.

[0055] As shown in Figure 1A, the intake of a high-fat diet containing hexanoic acid (HFD_C6) significantly increased the hexanoic acid concentration (nmol / g) in the liver, confirming that hexanoic acid is absorbed orally and transported directly to the liver. Furthermore, as shown in Figure 1B, the body weight of mice fed a high-fat diet containing hexanoic acid (HFD_C6) and mice fed a high-fat diet containing butyrate (HFD_C4) was significantly lower compared to mice fed only a high-fat diet (HFD). Although sodium hexanoate and sodium butyrate have tastes and odors, as shown in Figure 1C, there was no difference in the average daily food intake (g / day) across all groups. These results confirm that hexanoic acid, like butyrate, prevents obesity induced by a high-fat diet (HFD) without reducing food intake.

[0056] On the other hand, as shown in Figure 2A, in mice fed a high-fat diet (HFD), blood glucose levels (mg / dL) were significantly reduced in mice fed a high-fat diet containing hexanoic acid (HFD_C6), but blood glucose levels did not decrease in mice fed a high-fat diet containing butyrate (HFD_C4). As shown in Figure 2B, blood insulin levels (pg / mL) were reduced in mice fed a high-fat diet containing hexanoic acid (HFD_C6) and in mice fed a high-fat diet containing butyrate (HFD_C4). These results confirm that while butyrate can improve the hyperinsulinemia (high blood insulin concentration) induced by a high-fat diet (HFD), it cannot suppress hyperglycemia. It was confirmed that hexanoic acid, unlike butyrate, can suppress hyperglycemia induced by a high-fat diet (HFD).

[0057] <Test Example 2> (1) GTT (Glucose Tolerance Test) Similar to <Test Example 1>(1) above, 6-week-old male mice were acclimatized to the standard diet CE-2 (manufactured by CLEA Japan) for one week, and then fasted for 16 hours. Next, hexanoic acid dissolved in 0.5% carboxymethylcellulose was administered orally (2.5 g of sodium hexanoate per kg of mouse body weight) (Hexanoic acid (n=3); Example). One hour later, glucose (1 g of glucose per kg of mouse body weight) was administered intraperitoneally to the mice. Blood glucose levels were measured at 0, 15, 30, 60, 90, or 120 minutes after glucose administration, and the average value was calculated, similar to <Test Example 1>(3) above. As a control group (Ctrl (n=4); Comparative Example), 0.5% carboxymethylcellulose was administered orally instead of hexanoic acid. The results are shown in Figure 3(a). Furthermore, by calculating the average of the integral values ​​from time 0 to 120 minutes in the graph of Figure 3(a), the area under the blood glucose-time curve (AUC(10)) can be calculated. 3 The concentration (mg / dL·min) was calculated. The results are shown in Figure 3(b).

[0058] (2) ITT (Insulin Stimulation Test) Similar to <Test Example 1>(1) above, 6-week-old male mice were acclimatized to the standard diet CE-2 (manufactured by CLEA Japan) for one week, and then fasted for 3 hours. Next, hexanoic acid dissolved in 0.5% carboxymethylcellulose was administered orally (2.5 g of sodium hexanoate per kg of mouse body weight) (Hexanoic acid (n=3); Example). One hour later, insulin (0.75 mU / g) was administered intraperitoneally to the mice. Blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 minutes after insulin administration, and the average value was calculated, similar to <Test Example 1>(3) above. As a control group (Ctrl (n=4); Comparative Example), 0.5% carboxymethylcellulose was administered instead of hexanoic acid. The results are shown in Figure 4(a). Furthermore, by calculating the average of the integral values ​​from time 0 to 120 minutes in the graph in Figure 4(a), the area under the blood glucose-time curve (AUC(10)) can be calculated.3 The concentration (mg / dL·min) was calculated. The results are shown in Figure 4(b).

[0059] As shown in Figure 3, oral administration of hexanoic acid significantly suppressed hyperglycemia induced by the glucose tolerance test. Furthermore, as shown in Figure 4, oral administration of hexanoic acid significantly lowered blood glucose levels in the insulin tolerance test and significantly enhanced insulin sensitivity. These results suggest that one reason for the suppression of hyperglycemia under high-fat diet (HFD) intake by hexanoic acid is the improvement in insulin sensitivity. [Industrial applicability]

[0060] As described above, the present invention makes it possible to provide a novel composition having an effect of maintaining or improving glucose metabolism function, and a method for maintaining or improving glucose metabolism function.

Claims

1. A composition for maintaining or improving glucose metabolism function, containing a hexanoic acid compound as an active ingredient.

2. The composition according to claim 1, wherein the hexanoic acid compound is at least one selected from the group consisting of hexanoic acid, a salt of hexanoic acid, a hexanoic acid ester, and a hexanoic acid glyceride containing at least one hexanoic acid as a constituent fatty acid.

3. The composition according to claim 1 for suppressing hyperglycemia.

4. The composition according to claim 3, wherein the hyperglycemia is postprandial hyperglycemia.

5. The composition according to claim 3, wherein the hyperglycemia is fasting hyperglycemia.

6. The composition according to claim 3, wherein the hyperglycemia is due to obesity.

7. The composition according to claim 3, wherein the hyperglycemia is caused by excessive intake of lipids.

8. The composition according to claim 1 for improving insulin sensitivity.

9. The composition according to claim 1, for consumption before or during a meal.

10. The composition according to claim 1, for ingestion by an obese person.

11. The composition according to claim 1, for use in subjects with a high fat energy ratio.

12. A method for maintaining or improving glucose metabolism function, comprising the step of administering a composition containing a hexanoic acid compound as an active ingredient to a subject.

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