JP2023175938A - Glucose metabolism improving composition - Google Patents

Abstract

To provide a human glucose metabolism improving composition containing lactic acid bacteria of Lactobacillus.SOLUTION: A composition comprising lactic acid bacteria of Lactobacillus is fed to a person, to improve the glucose metabolism of the person.SELECTED DRAWING: None

Description

Application for application of Article 30, Paragraph 2 of the Patent Act has been filed.On August 23, 2018, the website address <https://www. sciencedirect. com/science/article/abs/pii/S0899900718309298? Published on via%3Dihub>

Application for application of Article 30, Paragraph 2 of the Patent Act Published in the publication "Nutrition", Vol. 58, pp. 175-180, published in February 2019

Application for application of Article 30, Paragraph 2 of the Patent Act Presented at the public seminar “Promoting Healthy Longevity through Food Using Human Intervention Tests” held in Chiyoda-ku, Tokyo on November 22, 2018

The present invention relates to a composition for improving glucose metabolism in humans.

The increase in the number of patients with obesity and lifestyle-related diseases such as diabetes, which combine with obesity to cause metabolic syndrome, has become a major problem throughout the world, as it leads to a deterioration in people's health standards and an increase in medical costs. Moderate exercise and a well-balanced diet are important for preventing metabolic syndrome, but it is also known that ingesting foods and drinks containing functional ingredients that are effective in preventing metabolic syndrome (non-patent Reference 1). Today, there are various products containing food materials that have the function of preventing and improving metabolic syndrome, but most of them only act as symptomatic treatments, such as promoting fat burning or suppressing fat absorption, and do not improve the metabolism of sugars and lipids. It is difficult to say that it will normalize the metabolic syndrome and fundamentally improve metabolic syndrome.

By the way, chronic inflammation of adipose tissue is known to be one of the causes of a decline in sugar and lipid metabolic functions. Specifically, the increase in inflammatory cytokines such as monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) leads to the influx of macrophages into adipose tissue. It is known that infiltration is enhanced and the production of hormones necessary for normal metabolism of sugars and lipids is reduced (Non-Patent Documents 2 and 3).

It has been known that certain lactic acid bacteria improve sugar and lipid metabolism in mice (Patent Document 1, Non-Patent Documents 4 and 5).

However, from the perspective of health promotion, there is still a need for methods to effectively improve sugar metabolism in humans. Furthermore, suppressing inflammation in patients with lifestyle-related diseases is an important issue.

International Publication No. 2012/014971

Kaoru Egawa et al. Verification of the body fat reducing effect and safety of green tea drinks containing quercetin glycosides (enzyme-treated isoquercitrin) in obese people Jpn Pharmacol Ther (Pharmacology and Treatment) 40:495-03, 2012 Xu H et al. “Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance” J Clin Invest, 112:1821-1830, 2003 Weisberg SP et al. “CCR2 modulates inflammatory and metabolic effects of high-fat feeding” J Clin Invest, 116:115-124, 2006 T. Toshimitsu et al. “Identification of Lactobacillus plantarum strain that meliorates chronic inflammation and metabolic disorders in obese and type 2 diabetic mice” J Dairy Sci, 99:933-946, 2016 Tohru Sakai et al. “Lactobacillus plantarum OLL2712 regulates glucose metabolism in C57BL/6 mice fed a high-fat diet” J Nutr Sci Vitaminol, 59, 144-147, 2013

One object of the present invention is to provide a composition for effectively improving glucose metabolism in humans.

As a result of extensive studies, the present inventors have discovered that lactic acid bacteria belonging to the genus Lactobacillus have the activity of significantly reducing specific inflammatory cytokines in humans, and have found that they can improve sugar metabolism in humans. I found it. The present invention is based on these findings.

According to the present invention, the following inventions are provided.
[1] A composition for improving human sugar metabolism containing lactic acid bacteria belonging to the genus Lactobacillus.
[2] A human anti-inflammatory composition containing lactic acid bacteria belonging to the genus Lactobacillus.
[3] The lactic acid bacteria contain at least one inflammatory cytokine selected from monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) in human blood. The composition according to [1] or [2], which is a lactic acid bacterium having an activity of reducing the amount of.
[4] The composition according to any one of [1] to [3], wherein the lactic acid bacterium is Lactobacillus plantarum.
[5] The composition according to any one of [1] to [4], wherein the lactic acid bacteria contain dead lactic acid bacteria. [6] The composition according to any one of [1] to [5], wherein the lactic acid bacteria contain heat-treated killed bacteria. [7] The composition according to any one of [1] to [6], wherein the composition is a food composition.
[8] The composition according to any one of [1] to [6], wherein the composition is a pharmaceutical composition.
[9] The composition according to any one of [1] to [8], wherein the lactic acid bacterium has a 16S rRNA gene that has 90% or more homology with the base sequence represented by SEQ ID NO: 1.
[10] The composition according to any one of [1] to [9], wherein the lactic acid bacterium is Lactobacillus plantarum OLL2712 strain deposited under accession number FERM BP-11262.

According to the present invention, in humans, specific inflammatory cytokines associated with chronic inflammation of adipose tissue and abnormalities in sugar metabolism can be significantly reduced, and as a result, sugar metabolism can be improved.

Specific description of the invention

Composition for improving sugar metabolism According to one embodiment of the present invention, there is provided a composition for improving sugar metabolism in humans, which contains lactic acid bacteria belonging to the genus Lactobacillus (hereinafter also referred to as "lactic acid bacteria"). .

According to one embodiment, the lactic acid bacteria belonging to the genus Lactobacillus contained in the composition of the present invention reduce the amount of at least one inflammatory cytokine selected from MCP-1 and IL-6 in the blood in humans. Preferably, it is a lactic acid bacterium that has a reducing activity. The lactic acid bacteria preferably have an activity of selectively reducing the blood level of at least one of these inflammatory cytokines, and more preferably have the activity of selectively reducing the blood level of both of these inflammatory cytokines. It is an active lactic acid bacterium. Furthermore, since MCP-1 and IL-6 are known to cause inflammation in adipose tissue and cause abnormal sugar and lipid metabolism, the amount of MCP-1 and/or IL-6 in the blood By using lactic acid bacteria that have the activity of reducing sugar metabolism, in addition to improving sugar metabolism, it is also possible to suppress inflammation, especially in adipose tissue, and improve lipid metabolism.

As used herein, "reducing" with respect to inflammatory cytokines means that the blood level of each inflammatory cytokine in the stimulated subject is statistically significantly ( In other words, it means a decrease (beyond the margin of error). Furthermore, "selectively reducing" MCP-1 and IL-6 means that stimulation with lactic acid bacteria or a composition containing lactic acid bacteria does not significantly reduce other inflammatory cytokines in the stimulated subject. In contrast, it means that MCP-1 and/or IL-6 are significantly reduced. The statistical analysis can be performed using statistical analysis methods known to those skilled in the art, such as repeated measures one-way analysis of variance and paired t-test with Bonferroni correction. Furthermore, "activity to reduce the amount of MCP-1 and IL-6 in the blood" means the ability to significantly reduce the amount of MCP-1 and IL-6 in the blood, respectively. The presence or absence of the activity of reducing the amount of MCP-1 and IL-6 in the blood is specifically determined by the method described in the Examples.

The composition for improving sugar metabolism of the present invention is effective for improving sugar metabolism in both humans with normal sugar metabolism and people with abnormal sugar metabolism, but can be particularly effective in humans with abnormal sugar metabolism. . Furthermore, the composition for improving sugar metabolism of the present invention can exhibit the effect of improving sugar metabolism regardless of the amount of MCP-1 and IL-6 in the blood of the subject to whom it is applied. In other words, it showed an effect on improving glucose metabolism in both subjects with low levels of MCP-1 and IL-6 in the blood (low inflammation) and subjects with high levels of MCP-1 and IL-6 in the blood (high inflammation). However, it can have a particularly remarkable effect on improving glucose metabolism in subjects with high inflammation. It is preferable to apply the composition of the present invention to humans with high inflammation from the viewpoint of promoting health by simultaneously suppressing inflammation and promoting sugar metabolism. As used herein, "low inflammation" refers to a state in which the blood MCP-1 concentration is less than 5 pg/mL and/or the blood IL-6 concentration is less than 0.5 pg/mL. Furthermore, "high inflammation" refers to a state in which the blood MCP-1 concentration is 5 pg/mL or more and/or the blood IL-6 concentration is 0.5 pg/mL or more.

The lactic acid bacteria contained in the composition of the present invention can be used without particular limitation as long as they belong to the genus Lactobacillus. Preferably, the lactic acid bacteria belonging to the genus Lactobacillus have an activity of reducing the amount of at least one inflammatory cytokine selected from MCP-1 and IL-6 in human blood. Examples of lactic acid bacteria belonging to the genus Lactobacillus include Lactobacillus delbrueckii subsp. burgaricus, Lactobacillus delbrueckii subsp. lactis, and Lactobacillus casei. , Lactobacillus helveticus, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus amylovorus, Lactobacillus gallinarum, Lactobacillus gallinarum. Lactobacillus gasseri, Lactobacillus oris, Lactobacillus rhamnosus, Lactobacillus johnsonii, Lactobacillus fermentum, Lactobacillus brevis ), Lactobacillus plantarum, Lactobacillus pentosus, Lactobacillus paraplantarum, Lactobacillus paracollinoides, Lactobacillus hammesii, etc. can be mentioned. Among these lactic acid bacteria, Lactobacillus plantarum is preferred, and Lactobacillus plantarum OLL2712 strain is more preferred.

Lactobacillus plantarum OLL2712 strain was deposited at the Patent Organism Depositary Center, National Institute of Advanced Industrial Science and Technology (AIST, Japan) on July 2, 2010 (Central 6, Higashi 1-1-1, Tsukuba City, Ibaraki Prefecture, Japan). It has been transferred to the International Deposit and given accession number FERM BP-11262. Furthermore, as stated in Budapest Notification No. 282 (http://www.wipo.int/treaties/en/notifications/budapest/treaty_budapest_282.html), the National Institute of Technology and Evaluation (IPOD, NITE) Due to the succession of the patent microorganism deposit service from the National Institute of Advanced Industrial Science and Technology's Patent Organism Depositary (IPOD, AIST), Lactobacillus plantarum OLL2712 strain is currently transferred to the National Institute of Technology and Evaluation (IPOD, NITE), an independent administrative agency. ) (Room 120, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture) under accession number FERM BP-11262.

As the lactic acid bacteria contained in the composition of the present invention, a strain substantially equivalent to the deposited strain described above can also be used. A substantially equivalent strain is, for example, a strain of lactic acid bacteria belonging to the genus Lactobacillus mentioned above, whose 16S rRNA gene base sequence is the same as the 16S rRNA gene base sequence (SEQ ID NO: 1) of the deposited strain. It refers to a strain that has a homology of 90% or more, preferably 98% or more, more preferably 99% or more, and preferably has the same mycological properties as the above-mentioned strain. A strain having the same mycological properties as the deposited strain preferably has the activity of reducing the amount of at least one inflammatory cytokine selected from MCP-1 and IL-6 in human blood. These strains have similar activity. Furthermore, the lactic acid bacteria contained in the composition of the present invention may be bred from the deposited strain or a strain substantially equivalent thereto by mutation treatment, genetic recombination, selection of natural mutant strains, etc., as long as the effects of the present invention are achieved. It may be a bacterial strain that has been

Examples of the lactic acid bacteria contained in the composition of the present invention include not only lactic acid bacteria cells themselves but also cultures containing lactic acid bacteria cells. Both live and dead lactic acid bacteria cells can be used, but dead cells are preferable, and dead cells obtained by heating live cells are more preferable. treated dead bacterial cells). That is, the lactic acid bacteria contained in the composition of the present invention preferably include killed bacteria, more preferably heat-treated killed bacteria. Furthermore, the passage number of lactic acid bacteria is not particularly limited as long as the effects of the present invention can be achieved, but is, for example, 1 to 30, preferably 5 to 15, more preferably 11 to 13.

The conditions for culturing lactic acid bacteria are not particularly limited as long as the effects of the present invention can be achieved, and may be conditions under which lactic acid bacteria are normally cultured. For example, as a culture medium, whey powder, whey protein concentrate is dissolved in sterile water, digested with protease A, yeast extract, fish extract and _MnSO4 are added, and various nutrients (vitamins, minerals, fatty acids A medium obtained by adding ester), adjusting the pH to 6.7 with NaOH, and sterilizing it by autoclaving can be used. Furthermore, the pH during culturing can be 4.8 to 6.8. K ₂ CO ₃ can be used to adjust the pH. The temperature during culturing can be 29-40°C.

Heat treatment The heat treatment for obtaining killed microbial cells is not particularly limited as long as the effects of the present invention are achieved, and the heat treatment is performed under conditions normally used to sterilize lactic acid bacteria.

In addition to the above-mentioned heat treatment, lactic acid bacteria that have been subjected to treatments such as concentration, dilution, freezing, drying, and pulverization can also be used.

As the lactic acid bacteria contained in the composition of the present invention, those prepared by the above-mentioned culture or various treatments may be used, or commercially available compositions containing lactic acid bacteria may be used.

In the composition of the present invention, the number of lactic acid bacteria per mass of the composition is not particularly limited as long as the effects of the present invention are achieved, but preferably 10 ⁶ to 10 ¹⁴ /g, more preferably 10 ⁷ to 1 ×10 ¹³ pieces/g, even more preferably 10 ⁸ to 10 ¹² pieces/g, particularly preferably 10 ⁸ to 10 ¹⁰ pieces/g. Further, in the composition of the present invention, the dry mass of bacterial cells per mass of solid content in the composition is preferably 0.01 to 100% by mass, more preferably 1 to 80% by mass, and even more preferably 10 to 100% by mass. It is 40% by mass.

The composition of the present invention may contain components other than lactic acid bacteria, as long as they do not impede the effects of the present invention. Ingredients other than lactic acid bacteria include, for example, culture medium components, additives suitable for oral tube ingestion, solvents such as water, carbohydrates, proteins, lipids, vitamins, minerals, trace metals essential to living organisms (manganese sulfate, zinc sulfate, , magnesium chloride, potassium carbonate, etc.), fragrances, food hygiene or pharmaceutically acceptable carriers, food additives, etc.

Examples of carbohydrates include saccharides, processed starches (dextrin, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like.

Examples of proteins include whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, α-casein, β-casein, κ-casein, β-lacto Animal and vegetable proteins such as globulin, α-lactalbumin, lactoferrin, soybean protein, egg protein, and meat protein, their hydrolysates, butter, milk minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipids, Examples include various milk-derived components such as lactose.

Examples of lipids include lard, fish oil, etc., animal fats and oils such as their fractionated oils, hydrogenated oils, and transesterified oils, palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, and their fractionated oils. Examples include vegetable oils and fats such as hydrogenated oils and transesterified oils.

Examples of vitamins include vitamin A, carotenes, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, and choline. , folic acid, etc.

Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, and selenium.

The composition of the present invention contains, in addition to lactic acid bacteria belonging to the genus Lactobacillus, pharmaceutically acceptable carriers and/or additives, food hygiene acceptable carriers and/or additives, etc. It can be manufactured by Therefore, according to another aspect of the present invention, there is provided a method for producing a composition for improving sugar metabolism, which comprises the step of incorporating lactic acid bacteria belonging to the genus Lactobacillus.

According to one embodiment of the present invention, the composition for improving sugar metabolism of the present invention can be provided as a food composition. The food composition of the present invention is useful for suppressing increases in blood sugar levels, promoting decreases in blood sugar levels, maintaining normal blood sugar levels, suppressing increases in blood insulin levels, promoting decreases in blood insulin levels, and normal insulin levels. or for the prevention and/or treatment of diabetes, obesity, metabolic syndrome, and dyslipidemia.

The food composition of the present invention may be in any form as long as it can contain lactic acid bacteria, such as a solution, suspension, emulsion, powder, paste, semi-solid molded product, or solid molded product. It may be in any form that can be taken orally or through a tube. Specific foods include, for example, milk, milk drinks, soft drinks, fermented milk, lactic acid bacteria drinks, milk drinks, yogurt, cheese, ice cream, ice cream, chocolate, tablets, gummies, candies, bread, Examples include biscuits, crackers, pizza crusts, powdered milk, liquid milk, liquid foods, foods for the sick, nutritional foods, frozen foods, processed foods, seasonings, and other commercially available foods.

The food composition of the present invention can be made into a food or drink labeled with uses such as improving glucose metabolism, suppressing MCP-1 production, suppressing IL-6 production, and suppressing inflammation. Foods and beverages include ``improving glucose metabolism'', ``suppressing the rise in blood sugar levels'', ``lowering blood sugar levels'', ``maintaining normal blood sugar levels'', ``suppressing the rise in blood insulin levels'', and ``normal "Maintaining insulin levels", "Reducing HbA1c", "Improving insulin resistance", "Preventing diabetes, obesity, and metabolic syndrome", "Helping the action of the hormone (insulin) that lowers blood sugar levels" , "For suppressing MCP-1 production," "For suppressing IL-6 production," "For suppressing inflammation," "For anti-inflammatory use," etc. In addition, expressions other than these can be used in the same manner as long as they express the effects caused by suppressing MCP-1 production and/or IL-6 production.

In this specification, "display" refers to all acts to inform consumers of the above-mentioned uses, and if the display is such that they can remind or infer the above-mentioned uses, the purpose of the display and the purpose of the display Regardless of the content, displayed object, medium, etc., all fall under the "display" of the present invention. However, it is preferable to use expressions that allow the consumer to directly recognize the use.

The display is preferably a display permitted by the government (for example, a display that has been approved based on various systems established by the government and is performed in a manner based on such approval). Examples include labeling as a health food, functional food, food with functional claims, enteral nutrition food, food for special use, food for the sick, food with nutrient function claims, quasi-drugs, etc. Examples include labeling approved by the Ministry of Labor, such as food for specified health uses, and labeling approved under similar systems. Examples of the latter include labeling as a food for specified health uses, labeling as a food for specified health uses with conditions, labeling that it affects the structure or function of the body, labeling that reduces disease risk, etc. More specifically, the labeling as a food for specified health uses (especially the labeling of health uses) stipulated in the Health Promotion Law Enforcement Regulations (Ordinance No. 86 of the Ministry of Health, Labor and Welfare of Japan, April 30, 2003), and Examples of similar displays can be given.

According to another aspect of the present invention, the composition for improving sugar metabolism of the present invention can be provided as a pharmaceutical composition. The pharmaceutical composition of the present invention is useful for suppressing increases in blood sugar levels, promoting decreases in blood sugar levels, maintaining normal blood sugar levels, suppressing increases in blood insulin levels, promoting decreases in blood insulin levels, and normal insulin levels. It may be used for the maintenance of diabetes, anti-inflammation, or the prevention and/or treatment of diabetes, obesity, metabolic syndrome, and dyslipidemia. The pharmaceutical composition of the present invention can be manufactured according to the usual manufacturing procedure for the food, except for containing lactic acid bacteria. Here, the pharmaceutical composition refers to the composition of the present invention prepared as an oral or parenteral preparation according to a conventional method. For formulation, acceptable additives may be used in combination. Acceptable additives for formulation include, for example, excipients, stabilizers, preservatives, wetting agents, emulsifiers, lubricants, sweeteners, colorants, flavors, buffers, antioxidants, pH Conditioners and the like can be mentioned. When the pharmaceutical composition is an oral preparation, solid preparations such as tablets, powders, fine granules, granules, capsules, pills, sustained-release preparations, and liquid preparations such as solutions, suspensions, and emulsions can be used. It can take a form. Furthermore, when the pharmaceutical composition is a parenteral preparation, it can take the form of an injection, a suppository, or the like. In addition, from the viewpoint of ease of ingestion (administration) to a subject, the pharmaceutical composition is preferably an oral preparation.

According to another aspect of the present invention, there is provided a composition for reducing MCP-1 and/or IL-6 in humans, which contains lactic acid bacteria belonging to the genus Lactobacillus.

The intake amount of the composition of the present invention is not particularly limited as long as the effects of the present invention are achieved, and can be adjusted as appropriate depending on the age, health condition, body weight, etc. of the person taking the composition. Typically 0.01-10000 mg/kg body weight per day, preferably 0.1-1000 mg/kg body weight, more preferably 0.5-300 mg/kg body weight, even more preferably 1-100 mg/kg. It's weight. In addition, the bacterial cell dry mass of lactic acid bacteria is preferably 0.001 to 1000 mg/kg body weight, more preferably 0.01 to 100 mg/kg body weight, more preferably 0.05 to 30 mg/kg body weight, and even more preferably 0. .1-10 mg/kg body weight. Further, the number of lactic acid bacteria is preferably 1×10 ⁴ to 1×10 ¹² /kg body weight, more preferably 10 ⁵ to 10 ¹¹ /kg body weight, even more preferably 10 ⁶ to 10 ¹⁰ /kg body weight, Particularly preferred is 10 ⁶ to 10 ⁸ pieces/kg body weight.

In order to better exhibit its effects, the composition of the present invention is preferably ingested (administered) continuously over a long period of time, and specifically, it is preferable to be ingested (administered) continuously for three days or more. Preferably, it is more preferable to take (administer) continuously for one week or more. Examples of the intake (administration) period include 1 to 6 weeks, 1 to 12 weeks, 2 to 10 weeks, 4 to 10 weeks, 4 to 12 weeks, and the like. As used herein, "continuously" means continuing to take a determined amount of the composition of the present invention every day.

According to another aspect of the present invention, there is provided a method for improving sugar metabolism in a human, which comprises causing the human to ingest an effective amount of lactic acid bacteria belonging to the genus Lactobacillus. Further, according to a preferred embodiment of the present invention, the above method is a method for ameliorating inflammation in humans.

According to one embodiment of the present invention, "improving glucose metabolism" includes improving abnormalities in glucose metabolism, activating or promoting low glucose metabolism, maintaining normal glucose metabolism or preventing its decline, and the like. The cause of abnormality or decline in sugar metabolism is not particularly limited, but lifestyle habits are a typical cause. The sugar metabolism improving effect of the composition of the present invention includes, for example, the effect of suppressing an increase in blood sugar level, the effect of reducing blood sugar level, the effect of maintaining normal blood sugar level, and the effect of suppressing increase in blood insulin level. , the effect of reducing the amount of insulin in the blood, the effect of maintaining the normal amount of insulin in the blood, etc. Note that in this specification, "improvement" not only includes the meaning of "treatment" to stop, alleviate, or delay the progression or aggravation of an abnormality or disease by medical treatment, but also includes the meaning of "treatment" that halts, alleviates, or delays the progression or aggravation of an abnormality or disease. , including stopping, mitigating or delaying by non-medical procedures. Furthermore, "improvement" also includes the meaning of "prevention," which involves preparing in advance for the expected deterioration of an abnormality or disease and preventing the occurrence or recurrence of the abnormality or disease through non-medical or medical actions. .

Furthermore, the human being to be inoculated with lactic acid bacteria is preferably a person with high inflammation. Further, in this specification, the blood MCP-1 concentration in a person with high inflammation is usually 5 pg/mL or more, preferably 10 pg/mL or more, and more preferably 15 pg/mL. There is no particular upper limit to the blood MCP-1 concentration in people with high inflammation, but it is preferably 1000 pg/mL or less, more preferably 500 pg/mL or less. These upper limit values and lower limit values can be combined. Further, the blood IL-6 concentration in people with high inflammation is usually 0.5 pg/mL or more, preferably 1.0 pg/mL, and more preferably 1.5 pg/mL or more. There is no particular upper limit to the blood IL-6 concentration in people with high inflammation, but it is preferably 100 pg/mL or less, more preferably 50 pg/mL or less. These upper limit values and lower limit values can be combined.

In the method for improving sugar metabolism, the dosage and administration period of the lactic acid bacteria are not particularly limited as long as the effects of the present invention are achieved, and may be adjusted as appropriate depending on the age, health condition, body weight, etc. of the subject. can. Typically, in the method of the present invention, the dose and period of administration of the lactic acid bacteria are the same as those of the lactic acid bacteria in the composition of the present invention.

According to another aspect of the present invention, the method includes ingesting an effective amount of a composition containing lactic acid bacteria belonging to the genus Lactobacillus to treat diseases and/or disorders caused by abnormalities in sugar metabolism in the human. Methods of treatment and/or prevention are provided.

Diseases and disorders caused by abnormalities in sugar metabolism include, but are not particularly limited to, diabetes, obesity, metabolic syndrome, and the like.

According to another aspect of the present invention, there is provided the use of lactic acid bacteria belonging to the genus Lactobacillus for improving sugar metabolism.

According to another aspect of the present invention, there is provided the use of lactic acid bacteria belonging to the genus Lactobacillus for producing a composition for improving sugar metabolism.

The present invention will be specifically explained based on the following examples, but the present invention is not limited to these examples.

Example 1: Confirmation of the sugar metabolism improving effect of a composition containing lactic acid bacteria (1) Selection of subjects (screening)
Based on the following selection criteria A and exclusion criteria B, subjects were selected for a test to confirm the effect of improving glucose metabolism.
A: Selection criteria - Those who have received a sufficient explanation of the purpose and content of this study, who have the capacity to consent, and who have fully understood the subject, volunteered voluntarily, and consented to participation in writing - Those who are between the ages of 35 and 65 Healthy men and women ・Subject B whose fasting blood glucose level is 105 mg/dL or more and less than 130 mg/dL at the time of screening test: Exclusion criteria ・Persons undergoing drug treatment or outpatient treatment ・Severe medical history that may affect test results -Those who have a history of consuming yogurt or lactic acid bacteria drinks at least twice a week in the 3 months before the screening test. -In the 3 months before the screening test, those who have had the habit of consuming yogurt or lactic acid bacteria beverages at least twice a week. Persons who have taken or ingested foreign products, health foods, or foods for specified health uses on a daily basis. Persons who drink alcohol frequently (persons who drink an average of more than 60 g of pure alcohol per day)
・Those who have participated in another clinical trial within one month before obtaining consent to participate in this study, or those who plan to participate in another clinical trial after obtaining consent to participate in this study. Persons judged to be unsuitable as subjects

Thirty subjects (22 males, 8 females) were selected from 221 volunteers based on the above criteria. The age of the subjects was 52.5±8.1 years (male: 51.9±8.7 years, female: 54.3±6.3 years).

(2) Preparation of composition The composition of the present invention (colorless and transparent grapefruit-flavored soft drink) is obtained by mixing each raw material (acidulant, sweetener, stabilizer, fruit juice, fragrance, lactic acid bacteria, water). , approximately 100 mL was bottled (hereinafter also referred to as "test composition"). The amount of lactic acid bacteria (heat-treated lactic acid bacteria Lactobacillus plantarum strain OLL2712 (accession number: FERM BP-11262) in the test composition was approximately ¹⁰ cells/100 mL. After concentrating the body to the above concentration, the suspension was suspended in ion-exchanged water and heated at 95°C for 3 minutes.

(3) Effect on inflammatory cytokines The effect of the composition of the present invention on the blood level of inflammatory cytokines was evaluated according to the following procedure.
First, the test composition was ingested once daily at any time for 12 weeks. Blood was collected at 0 weeks, 4 weeks, 8 weeks, and 12 weeks after the start of intake, and blood concentrations of the following cytokines related to glucose metabolism were measured using serum using the Bio-Plex multiplex system. . In addition, the intake of the test composition was discontinued 12 weeks after the start of intake, and the same measurements were performed 4 weeks after the intake was discontinued.
・Monocyte chemoattractant promoting factor (MCP-1)
・Interleukin-6 (IL-6)
・Interleukin-8 (IL-8)
・Tumor necrosis factor (TNF-α)
・Interleukin-1β (IL-1β)
・Interleukin-17 (IL-17)

Measurements for each inflammatory cytokine at each time point were evaluated by repeated measures one-way analysis of variance and paired t-test with Bonferroni correction. The results are shown in Table 1. Note that the units of all numerical values in the table are pg/mL.

As shown in Table 1, the amounts of MCP-1 and IL-6 in the blood significantly decreased after the start of ingestion of the test composition compared to before the start of ingestion. Specifically, the amount of MCP-1 in the blood significantly decreased compared to before the start of intake at all four, eight, and 12 weeks after the start of intake of the test composition, and the intake of the test composition was stopped. Even after 4 weeks, there was a significant decrease compared to before the start of intake. Furthermore, the amount of IL-6 in the blood significantly decreased 4 weeks after the start of ingestion of the test composition compared to before the start of ingestion. On the other hand, there were no significant changes in the levels of IL-8, TNF-α, IL-1β, and IL-17 in the blood at any of the 4, 8, and 12 weeks after the start of intake. There wasn't. These results showed that the composition of the present invention selectively reduces the amount of specific inflammatory cytokines (MCP-1 and IL-6).

In addition, the blood concentrations of inflammatory cytokines (MCP-1 and IL-6) of all subjects were measured before the start of ingestion of the test composition, and any of the blood concentrations of these inflammatory cytokines was higher than the average value. group (high inflammation group, n = 19 (14 males, 5 females), average concentration of MCP-1: 23.92 ± 7.95 pg/mL, average concentration of IL-6: 2.83 ± 0.56 pg/mL), and both groups below the average value (low inflammation group, n = 11 (male: 8 people, female: 3 people), average concentration of MCP-1: 0.02 ± 0.02 pg / mL, average concentration of IL-6: 0.28±0.18 pg/mL), and the fasting blood glucose (FPG) value and insulin resistance index (HOMA-IR) were measured for each group. Insulin resistance was observed in many of the subjects in the high inflammation group before starting the test composition (HOMA-IR≧2.0). The results for fasting blood glucose (FPG) values and insulin resistance index (HOMA-IR) are shown in Tables 2 and 3, respectively.

As shown in Tables 2 and 3, in both the low-inflammation group and the high-inflammation group, after the start of ingestion of the test composition, the amount of MCP-1 and IL-6 in the blood decreased compared to before the start of ingestion. There was also a tendency to maintain or reduce the In particular, in the high-inflammation group that tends to cause abnormalities in glucose metabolism, the amount of MCP-1 in the blood was significantly reduced 8 and 12 weeks after the start of ingestion of the test composition compared to before the start of ingestion. The amount of IL-6 in the test composition was significantly reduced 8 weeks after the start of intake of the test composition compared to before the start of intake, and after 12 weeks it was reduced, although not significantly, compared to before the start of intake. These results demonstrate that the composition of the present invention can selectively reduce the amount of specific inflammatory cytokines (MCP-1 and IL-6) in humans, particularly in highly inflammatory conditions that tend to cause abnormalities in glucose metabolism. It has been shown that these inflammatory cytokines are selectively reduced particularly in humans. In relation to the above results, it is known that as the fasting blood sugar level approaches the diabetic type from the normal type, the rate of inflammatory status increases, and as the inflammatory status worsens, the rate of hyperinflammatory status accelerates. There is. Therefore, from the results in Tables 2 and 3 showing that the levels of MCP-1 and IL-6 in the blood were maintained by intake of the composition of the present invention in the low inflammation group, it can be seen that the composition of the present invention It is suggested that it can suppress the increase in MCP-1 and IL-6 in humans with a low inflammatory state, thereby suppressing the worsening of the inflammatory state and the abnormalities in glucose metabolism caused thereby.

(4) Evaluation of sugar metabolism improvement effect The composition of the present invention was evaluated for sugar metabolism improvement effect based on the following index in the same manner as described in (3) above.
・Fasting blood glucose (FPG) value ・Blood glycoalbumin (GA) value ・Blood hemoglobin A1c (HbA1c) value ・Blood insulin level ・Insulin resistance index (HOMA-IR)
・Quantitative insulin sensitivity testing index (QUICKI)

Specifically, the above-mentioned indicators were measured for each blood sample taken from the subjects at Health Science Research Institute, Inc. That is, the FPG value in plasma, the GA value in serum, and the HbA1c value in whole blood were measured by an enzymatic method using an automatic biochemical analyzer. In addition, the insulin level in serum was measured by the CLIA method (chemiluminescence immunoassay) using a fully automated chemiluminescence immunoassay device. Furthermore, HOMA-IR and QUICKI were each calculated based on the following formulas.
HOMA-IR=(Fasting blood insulin concentration (μU/mL))×(Fasting blood glucose level (mg/dl))/405
QUICKI = 1/[log (fasting blood insulin concentration (μU/mL)) + log (fasting blood glucose level (mg/dL))]

Measurements for each index at each time point were evaluated by repeated measures one-way analysis of variance and paired t-test with Bonferroni correction. The results are shown in Table 4.

As shown in Table 4, the fasting blood sugar level and blood glycoalbumin level significantly improved (decreased) 4 and 8 weeks after the start of ingestion of the test composition compared to before the start of ingestion. Furthermore, the values of HOMA-IR and QUICKI, which are indicators of insulin resistance, significantly improved 12 weeks after the start of ingestion of the test composition compared to before the start of ingestion. Regarding the blood HbA1c value, no significant changes were observed at any time points 4 weeks, 8 weeks, and 12 weeks after the start of intake; however, as a result of multiple comparison analysis, 12 weeks after the start of intake. Later, there was a significant improvement (decrease) compared to 4 weeks after the start of intake. Furthermore, since the blood HbA1c value reflects the average blood sugar level from 1 to 2 months before the time of measurement, the results of the blood HbA1c value mentioned above and the results of other indicators are not contradictory. it is conceivable that. These results showed that the composition of the present invention improves sugar metabolism in humans.

In addition, fasting blood glucose (FPG) values and insulin resistance index (HOMA-IR) were measured in each of the low inflammation group and the high inflammation group using the same method as described in (3) above. The results for FPG value and HOMA-IR are shown in Tables 5 and 6, respectively.

As shown in Tables 5 and 6, both the fasting blood glucose level and the HOMA-IR value were maintained or decreased after the start of ingestion of the test composition compared to before the start of ingestion in both the low inflammation group and the high inflammation group. There was a tendency to In particular, in the high inflammation group that tends to cause abnormalities in glucose metabolism, fasting blood sugar levels significantly improved (decreased) 8 and 12 weeks after the start of ingestion of the test composition compared to before the start of ingestion, The HOMA-IR value improved (decreased) 8 weeks after the start of intake of the test composition, although not significantly compared to before the start of intake, and after 12 weeks, significantly improved (decreased) compared to before the start of intake. . These results indicate that the composition of the present invention maintains or improves glucose metabolism in humans, and particularly improves glucose metabolism particularly markedly in humans who are in a state of high inflammation that tends to cause abnormalities in glucose metabolism. It was done.

These results showed that by using the composition of the present invention, it is possible to selectively reduce specific inflammatory cytokines that cause abnormalities in glucose metabolism and improve glucose metabolism in humans.

According to the present invention, it is possible to significantly reduce specific inflammatory cytokines that cause abnormalities in sugar metabolism and improve sugar metabolism in humans.

Claims (10)

A composition for improving human sugar metabolism containing lactic acid bacteria belonging to the genus Lactobacillus. A human anti-inflammatory composition containing lactic acid bacteria belonging to the genus Lactobacillus. The composition according to claim 1 or 2, wherein the lactic acid bacterium is a lactic acid bacterium having an activity of reducing the amount of at least one inflammatory cytokine selected from MCP-1 and IL-6 in human blood. The composition according to any one of claims 1 to 3, wherein the lactic acid bacterium is Lactobacillus plantarum. The composition according to any one of claims 1 to 4, wherein the lactic acid bacteria contain dead lactic acid bacteria. The composition according to any one of claims 1 to 5, wherein the lactic acid bacteria contain heat-treated killed bacteria. Composition according to any one of claims 1 to 6, wherein the composition is a food composition. A composition according to any one of claims 1 to 6, wherein the composition is a pharmaceutical composition. The composition according to any one of claims 1 to 8, wherein the lactic acid bacterium has a 16S rRNA gene having 90% or more homology with the base sequence represented by SEQ ID NO: 1. The composition according to any one of claims 1 to 9, wherein the lactic acid bacterium is Lactobacillus plantarum strain OLL2712, deposited under accession number FERM BP-11262.