JP5260033B2 - Postprandial GIP and / or postprandial insulin secretion inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for suppressing postbrandial GIP and/or postbrandial insulin secretion and having an effect for suppressing the secretion of hormones such as insulin and GIP. <P>SOLUTION: The agent for suppressing postbrandial GIP and/or postbrandial insulin secretion contains cellulose fiber, wherein the cellulose fiber has an average fiber diameter of &le;200 nm and a carboxy group content of the cellulose constituting the cellulose fiber of 0.1-2 mmol/g. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a postprandial GIP and / or a postprandial insulin secretion inhibitor capable of suppressing the secretion of insulin, GIP and the like by meals.

  Gastric inhibitory polypeptide (GIP) is a gastrointestinal hormone that enhances glucose-dependent insulin secretion, and it is known that secretion is enhanced by lipids in the diet during feeding. Moreover, since GIP is known to have gastric acid secretion inhibitory action and gastric motility inhibitory action (Non-Patent Documents 1 to 3), a substance that inhibits GIP secretion is effective in promoting digestion and improving stomach leaning. It is considered useful. As a result of research so far, 3-bromo-5-methyl-2-phenylpyrazolo [1,5-a] pyrimidin-7-ol (BMPP) is known as a substance that inhibits the function of GIP. Gua gum etc. are known as what suppresses the secretion of (patent document 1, nonpatent literatures 4-9). However, the former substance has not been confirmed to have an inhibitory effect on GIP function in vivo, and the latter substance has a problem that the effect of suppressing GIP secretion upon intake of lipids has not been studied. However, it is not necessarily sufficient in terms of the above.

  After the meal, when blood sugar rises, insulin is secreted from pancreatic β cells of the pancreas, sugar uptake into fat and muscle is promoted, fat synthesis in fat tissue and muscle is promoted, and decomposition and combustion are suppressed.

  However, when hyperglycemia occurs and insulin secretion continues, insulin sensitivity decreases in the target organs of insulin, skeletal muscle, liver, and adipose tissue (insulin resistance), and more insulin is secreted from the pancreas. Will come to be.

  When such insulin secretion is repeated, the pancreas is eventually exhausted and insulin secretion from the pancreatic β cells decreases, but the insulin resistance of each target organ remains increased. Thus, it is known that if the insulin action mechanism does not function well, eventually, the constitution tends to cause diabetes.

  On the other hand, if the secretion of GIP increases, in addition to causing indigestion and stomach sag, it may also be a factor that promotes insulin secretion.

Currently, refined cellulose produced by mechanically applying shearing force to cellulose fibers is used as a food improver (stabilizer), cosmetic material (gel / dispersed stabilizer), filter agent, and binder. Although it is sold, the secretory effect of these postprandial hormones such as GIP and insulin is not known.
International Publication No. 01/87341 Pamphlet JCBrown et al., Canadian J Physiol Pharmacol 47: 113-114, 1969 JM Falko et al., J Clin Endocrinol Metab 41 (2): 260-265, 1975 Toshiji Oda et al., Gastrointestinal function and pathology, 1981, Chugai Medical, P205-216 Gagenby SJ et al., Diabet Med. 1996 Apr; 13 (4): 358-64 Ellis PR et al., Br J Nutr. 1995 Oct; 74 (4): 539-56 Simoes Nunes C et al., Reprod Nutr Dev. 1992; 32 (1): 11-20 Morgan LM et al., Br J Nutr. 1990 Jul; 64 (1): 103-10 Requejo F et al., Diabet Med. 1990 Jul; 7 (6): 515-20 Morgan et al., Br J Nutr. 1985 May; 53 (3): 467-75

  This invention makes it a subject to provide the postprandial GIP and / or postprandial insulin secretion inhibitor which can suppress hormone secretion, such as insulin and GIP by a meal.

  The invention of claim 1 is a postprandial GIP and / or postprandial insulin secretion inhibitor containing cellulose fiber as means for solving the problem, wherein the cellulose fiber has an average fiber diameter of 200 nm or less and is prepared under the following conditions: Provided is a postprandial GIP and / or postprandial insulin secretion inhibitor having a light transmittance of 5% or more.

(Preparation and observation method)
After adding 10 g of cellulose fibers to a beaker containing 990 g of ion-exchanged water (25 ° C.), the mixture is stirred for 10 seconds with a juicer mixer, and the transmittance at an optical path length of 1 cm and a wavelength of 600 nm is measured with an absorptiometer. .

  The invention of claim 2 is a postprandial GIP and / or postprandial insulin secretion inhibitor containing cellulose fibers as a means for solving the problem, and has an average fiber diameter of 200 nm or less and contains a carboxyl group of cellulose constituting the cellulose fibers. Provided is a postprandial GIP and / or postprandial insulin secretion inhibitor whose amount is 0.1-2 mmol / g.

  Invention of Claim 3 is the postprandial GIP and / or postprandial of Claim 1 or 2 whose average aspect-ratio (average fiber length / average fiber diameter) of the said cellulose is 10-5,000 as a solution of a subject. An insulin secretion inhibitor is provided.

  The invention of claim 4 is as claimed in any one of claims 1 to 4, wherein the postprandial GIP and / or postprandial insulin secretion inhibitor is in the form of tablets, granules, powders or liquids as means for solving the problems. A postprandial GIP and / or postprandial insulin secretion inhibitor is provided.

  By ingesting postprandial GIP and / or postprandial insulin secretion inhibitor containing the cellulose fiber of the present invention, secretion of hormones such as insulin and GIP can be suppressed, which is effective in preventing obesity.

<Cellulose fiber>
First, the cellulose fiber contained in the postprandial GIP and / or postprandial insulin secretion inhibitor of the present invention will be described.

  Cellulose fibers have an average fiber diameter of 200 nm or less, preferably 1 to 200 nm, more preferably 1 to 100 nm, and still more preferably 1 to 50 nm. An average fiber diameter is calculated | required by the measuring method as described in an Example.

  The carboxyl group content of cellulose constituting the cellulose fiber is preferably 0.1 to 2 mmol / g, more preferably 0.4 to 2 mmol / g, and still more preferably 0.6 to 1.8 mmol / g. Carboxyl group content is calculated | required by the measuring method as described in an Example.

  The cellulose fibers preferably have an average aspect ratio (average fiber length / average fiber diameter) of 10 to 5,000, more preferably 10 to 2,000, still more preferably 10 to 1,000, and even more preferably 10. ~ 500. An average fiber diameter and an average fiber length are calculated | required by the measuring method as described in an Example.

  Since cellulose fibers are very fine compared to known cellulose fibers, the adjustment liquid prepared under the following conditions is not an aqueous solution but is transparent by visual observation, and the measurement of the light transmittance described above. When measured by the method, it shows a light transmittance of 5% or more. For example, in the case of a known biocellulose or cellulose prepared by mechanical shearing (for example, trade name Selish FD-200L manufactured by Daicel Chemical Industries, Ltd.), when a suspension is prepared under the same conditions, It becomes a cloudy liquid and has a light transmittance of 0%.

  The light transmittance of the cellulose fiber of the present invention can be adjusted by adjusting its production method, but is preferably 30% or more, more preferably 50% or more, still more preferably 60% or more, particularly The light transmittance is preferably 70% or more.

  The cellulose fiber of the present invention is also characterized by high crystallinity, and the crystallinity is preferably 10% to 95%, particularly preferably 70% to 90%.

(Preparation and observation method)
After adding 10 g of cellulose fibers to a beaker containing 990 g of ion-exchanged water (25 ° C.), the mixture is stirred with a juicer mixer stirrer, and the transmittance at an optical path length of 1 cm and a wavelength of 600 nm is measured with an absorptiometer.

  The method for producing the cellulose fiber used in the present invention is not particularly limited, and can be produced by appropriately selecting or combining mechanical methods, chemical methods, biochemical methods, and the like. Hereinafter, an example of the manufacturing method will be described.

  First, about 10 to 1000 times the amount (mass basis) of water is added to the raw natural fiber (absolute dry basis), and processed with a mixer or the like to form a slurry. Here, the absolute dry standard is to calculate the absolute dry pulp amount based on the moisture content of the oxidized pulp naturally dried in an environment of 20 ° C. and 50% RH measured with a halogen moisture meter.

The natural fibers as a raw material, for example, can be used wood pulp, non-wood pulp, cotton, play cellulose, bacterial cellulose, and the like.

  Next, the slurry is oxidized using 2,2,6,6, -tetramethyl-1-piperidine-N-oxyl (TEMPO) as a catalyst.

  The amount of TEMPO used is in a range of about 0.1 to 10% by mass with respect to the natural fiber (absolute dry standard) used as a raw material.

  During the oxidation treatment, an oxidant such as sodium hypochlorite and a bromide such as sodium bromide are used in combination with TEMPO.

  The amount of the oxidizing agent used is in the range of about 1 to 50% by mass with respect to the natural fiber (absolute dry standard) used as the raw material.

  The amount of bromide used is in the range of about 1 to 30% by mass with respect to the natural fiber (absolute dry basis) used as the raw material.

  The pH is in the range of 9 to 12 from the point of allowing the oxidation reaction to proceed efficiently.

  The temperature (temperature of the slurry) and time for the oxidation treatment are 1 to 50 ° C. and 1 to 300 minutes.

  And the used catalyst etc. are removed by water washing etc., and the intermediate body (cellulose fiber before the below-mentioned refinement | miniaturization process mentioned later) which was dried as needed can be obtained.

  Thereafter, the intermediate is dispersed in a solvent such as water and refined. Refinement treatment is performed by a disaggregator, a beater, a low-pressure homogenizer, a high-pressure homogenizer, a grinder, a cutter mill, a ball mill, a jet mill, a short-axis extruder, a twin-screw extruder, an ultrasonic stirrer, and a domestic juicer mixer. And can be adjusted to length.

  After such refinement treatment, the used catalyst can be removed by washing with water or the like to obtain the cellulose fiber as described above.

<Postprandial GIP and / or postprandial insulin secretion inhibitor containing cellulose fiber>
The postprandial GIP and / or postprandial insulin secretion inhibitor containing the cellulose fiber of the present invention should be in a desired form such as tablet, granule, powder, liquid (suspension), gel, etc., depending on the form of use. Can do.

  In the case of solid form such as tablet, granule, powder, etc., cellulose fiber alone may be used, and excipients, binders, disintegrants, lubricants, colorants, flavoring agents that can be used in foods and pharmaceuticals. , A flavoring agent and the like can be blended and molded using a desired molding machine (tablet press, granule manufacturing machine, spray dryer, etc.).

  When liquid (suspension) is used, water alone may be used, and together with water, other organic solvents that can be used in foods (for example, ethanol), surfactant aqueous solution, acid aqueous solution, base aqueous solution, etc. A mixed solvent may be used. When the gel is formed, a thickener or the like can be added and blended.

  The postprandial GIP and / or postprandial insulin secretion inhibitor of the present invention is desirably taken with or after a meal, and the intake amount as cellulose fiber is preferably about 0.002 to 2 g / kg of body weight.

  The postprandial GIP and / or postprandial insulin secretion inhibitor of the present invention can be administered to humans and animals, and can be ingested in various foods, medicines, pet foods and the like. As food, the concept is a hormone secretion inhibitory effect, and it can be applied to functional foods, foods for the sick, and foods for specified health. Although the form of a drink is not specifically limited, For example, it can mix | blend with all drinks, such as a fruit juice drink, a carbonated drink, a tea-type drink, a milk drink, an alcoholic drink, a soft drink, and it can be used for manufacture. Moreover, it can mix | blend with all food forms, such as jelly-like foodstuffs, various snacks, baked confectionery, cakes, chocolate, gum, candy, a tablet, a capsule, soup, and can be used for manufacture.

  The postprandial GIP and / or postprandial insulin secretion inhibitor of the present invention is orally administered as a pharmaceutical in solid dosage forms such as tablets and powders or liquid dosage forms such as elixirol, syrups and suspensions. When preparing an oral solid preparation, the postprandial GIP and / or postprandial insulin secretion inhibitor of the present invention is mixed with an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a taste masking agent. After adding the agent, flavoring agent, etc., tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. Moreover, when preparing an oral liquid formulation, it can manufacture by a conventional method, adding a flavoring agent, a buffering agent, a stabilizer, etc.

  In addition, the postprandial GIP and / or postprandial insulin secretion inhibitor of the present invention is administered in the form of a nutritional composition such as an enteral nutritional agent in elderly people who are difficult to supplement with an appropriate amount or who are in bed rest. Is done.

(1) Average fiber diameter, average fiber length, and average aspect ratio In an image in which the diameter of cellulose fibers taken by an atomic force microscope (Veeco Dimension 3100 Tapping mode) can be confirmed, 50 or more points are extracted, and the fiber diameter and fiber length The average aspect was calculated.

(2) Carboxyl group content (mmol / g)
Take 0.5g of absolute dry pulp in a 100ml beaker, add ion exchange water to make a total of 55ml, add 5ml of 0.01M sodium chloride solution to make 0.83% mass pulp suspension, and fully disperse the pulp. Stir with a stirrer until Then, 0.1M hydrochloric acid is added to adjust the pH to 2.5 to 3.0, and then using an automatic titrator (AUT-501, manufactured by Toa DK Corporation), a 0.05M sodium hydroxide aqueous solution is waited for 60 seconds. The electrical conductivity and the pH value of the pulp suspension every minute were measured, and the measurement was continued until the pH reached about 11. And the sodium hydroxide titration amount was calculated | required from the obtained electrical conductivity curve, and carboxyl group content was computed.

Production Examples 1 to 3 (Production of cellulose fiber of the present invention)
(1) Raw material Natural fiber: Bleached kraft pulp of conifers (Manufacturer: Fletcher Challenge Canada, trade name “Machenzie”, CSF 650 ml)
TEMPO: Commercial product (Manufacturer: ALDRICH, Free radical, 98%)
Sodium hypochlorite: Commercial product (Manufacturer: Wako Pure Chemical Industries, Ltd. Cl: 5%)
Sodium bromide: Commercial product (manufacturer: Wako Pure Chemical Industries, Ltd.).

(2) Production procedure First, 100 g of bleached kraft pulp fiber of the above coniferous tree was sufficiently stirred with 9900 g of ion-exchanged water, then 1.24% by mass of TEMPO, 28.1% by mass of sodium hypochlorite with respect to 100 g of pulp, Sodium bromide (12.4% by mass) was added in this order, and dropped using 0.5M sodium hydroxide using a pH stud. .

  Next, dripping was stopped at the predetermined oxidation time of each Example shown in Table 1, and oxidized pulp was obtained. The oxidized pulp was sufficiently washed with ion-exchanged water, dehydrated, and naturally dried in an atmosphere at 23 ° C. Thereafter, 10 g of oxidized pulp and 990 g of ion-exchanged water are stirred for 10 minutes with a mixer (trade name, ABSOLUTE (Vita-Mix Blender), manufactured by Osaka Chemical Co., Ltd.), thereby performing fiber refining treatment. A turbid liquid was obtained. The amount of oxidized pulp (the aforementioned solid content concentration) in the obtained cellulose fibers was 01.0% by mass (oxidized pulp 10 g / ion-exchanged water 990 g).

Example The inhibitory effect of insulin and GIP secretion when the cellulose fibers of the present invention obtained in Production Examples 1 to 3 were provided as postprandial GIP and / or postprandial insulin secretion inhibitor was tested.

Test Example 1 Effects of cellulose fiber of the present invention on postprandial blood components (inhibition of blood sugar elevation, blood neutral lipid elevation, blood insulin elevation inhibition, blood GIP elevation inhibition)
1-1 Test sample Production Example 1 was used as the cellulose fiber of the present invention. As a comparative example, refined cellulose (non-TEMPO oxidized product) (Serish FD-200L, manufactured by Daicel Chemical Industries, Ltd., average fiber diameter of 0.1 to 0.01 μm) was used.

1-2 Test animals
Nine-week-old male mice C57BL / 6J Jcl (CLEA Japan) were used. Each group was N = 6-7.

1-3 Preparation and dosage of orally administered sample Glucose (manufactured by Kanto Chemical) and triolein (manufactured by Sigma), lecithin (manufactured by egg) (manufactured by Kanto Chemical) and albumin (derived from bovine serum) (manufactured by Sigma) It was emulsified to prepare an emulsion. To this emulsion, the cellulose fiber of the present invention and a micronized cellulose for comparison (non-TEMPO oxidized product) were added to prepare a sample for oral administration. The oral doses for animals are as shown in the table below.

1-4 経口投与試験（食後血糖、血中中性脂質（血中TG）、血中インスリン、血中GIP測定）
16時間絶食させたマウスをエ−テル麻酔下、眼窩静脈よりヘパリン処理ヘマトクリット毛細管（VITREX製）を用い、初期採血を行った。その後、試験試料を経口ゾンデ針にて経口投与し、10分、30分、1時間、2時間後にエーテル麻酔下、眼窩静脈より採血を行った。

1-4 Oral administration test (postprandial blood glucose, blood neutral lipid (blood TG), blood insulin, blood GIP measurement)
Mice fasted for 16 hours were subjected to initial blood collection using an heparinized hematocrit capillary tube (manufactured by VITREX) from the orbital vein under ether anesthesia. Thereafter, the test sample was orally administered with an oral sonde needle, and blood was collected from the orbital vein under ether anesthesia 10 minutes, 30 minutes, 1 hour and 2 hours later.

  After blood collection, the blood glucose level was measured immediately using a portion of the blood using a simple blood glucose meter (glucose dehydrogenase / potential difference measurement method, manufactured by Roche Diagnostick). Blood collected with a heparinized hematocrit capillary tube was stored under ice cooling until plasma separation, and then centrifuged at 11000 rpm for 5 minutes to obtain plasma. Insulin, GIP, and neutral lipid (TG) were measured from the obtained plasma.

  The measurement of blood insulin is an insulin measurement kit (manufactured by Morinaga Biochemical Laboratory, ELISA method), and the blood GIP concentration is Rat / Mouse GIP (Total) ELISA kit (manufactured by Linco Research / Millipore co., ELISA method), The blood TG concentration was measured using Triglyceride E-Test Wako (manufactured by Wako Pure Chemical Industries, GPO / DAOS method).

1-5 Results FIGS. 1 to 4 show blood glucose levels, blood TG, blood insulin, and blood GIP time course curves (Δ values from initial values) after oral administration of samples. In addition, about the statistical significant difference between groups, the t test with respect to the control group was performed, and when p value was 0.05 or less by the two-sided test, p value was shown on the graph.

  From the results of FIGS. 1 to 4, the cellulose fiber administration group of the present invention has a maximum postprandial blood glucose level (10 minutes value), a maximum blood TG value (30 to 60 minutes value), and a maximum insulin as compared to the control administration group. The value (10 minutes value) and the maximum GIP value (10 minutes value) were low. On the other hand, the refined cellulose (non-TEMPO oxidized product) administration group did not differ from the control. From these results, it was found that the cellulose fiber of the present invention has postprandial blood glucose elevation inhibition, blood neutral lipid elevation inhibition, insulin secretion inhibition, and GIP secretion inhibition effects.

  On the other hand, the postprandial blood glucose level, blood neutral lipid, blood insulin, and blood GIP values in the micronized cellulose administration group, which is a comparative example, are time course curves that are almost the same as those in the control administration group. (Non-TEMPO oxidized product) was considered to have no postprandial blood glucose increase inhibitory effect, blood neutral lipid increase suppressive effect, blood insulin increase suppressive effect, or blood GIP increase suppressive effect. That is, these actions were considered to be effects obtained only with the cellulose fiber of the present invention.

The figure which shows the time-dependent curve of the blood glucose level after oral administration of a sample. The figure which shows the time curve of blood TG after oral administration of a sample. The figure which shows the time curve of the insulin in blood after sample oral administration. The figure which shows the time curve of the blood GIP after oral administration of a sample.

Claims (4)

Postprandial GIP (Gastric inhibitory polypeptide) and / or postprandial insulin secretion inhibitor containing cellulose fiber, wherein the cellulose fiber is 2,2,6,6-tetramethyl-1-piperidine-N-oxyl (TEMPO) A postprandial GIP and / or postprandial insulin secretion inhibitor, wherein the preparation is prepared by oxidation treatment using an acid, the average fiber diameter is 200 nm or less, and the light transmittance of the adjustment liquid prepared under the following conditions is 5% or more.
(Preparation and observation method)
After addition of cellulose fiber 10g into a beaker containing deionized water 990 g (25 ° C.), after stirring hand 10 seconds juicer mixer, the optical path length 1cm at an absorbance photometer, the transmittance in a wavelength of 600nm measured To do.   Postprandial GIP and / or postprandial insulin secretion inhibitor containing cellulose fiber, wherein the cellulose fiber is oxidized using 2,2,6,6, -tetramethyl-1-piperidine-N-oxyl (TEMPO) A postprandial GIP and / or postprandial insulin secretion inhibitor that is processed and has an average fiber diameter of 200 nm or less and a cellulose carboxyl group content of 0.1 to 2 mmol / g.   The postprandial GIP and / or postprandial insulin secretion inhibitor according to claim 1 or 2, wherein the cellulose has an average aspect ratio (average fiber length / average fiber diameter) of 10 to 5,000.   The postprandial GIP and / or postprandial insulin secretion inhibitor according to any one of claims 1 to 3, wherein the postprandial GIP and / or postprandial insulin secretion inhibitor is in the form of tablets, granules, powders or liquids.

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