WO2018139624A1 - Composition pour favoriser la sécrétion d'insuline - Google Patents

Composition pour favoriser la sécrétion d'insuline Download PDF

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WO2018139624A1
WO2018139624A1 PCT/JP2018/002614 JP2018002614W WO2018139624A1 WO 2018139624 A1 WO2018139624 A1 WO 2018139624A1 JP 2018002614 W JP2018002614 W JP 2018002614W WO 2018139624 A1 WO2018139624 A1 WO 2018139624A1
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leu
ile
whey protein
protein
val
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PCT/JP2018/002614
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English (en)
Japanese (ja)
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祥子 高井
恭祐 中山
三本木　千秋
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株式会社明治
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a composition for promoting insulin secretion.
  • Japan is now one of the “diabetic powers”. According to the 2012 Ministry of Health, Labor and Welfare's “National Health and Nutrition Survey” (2013), there are about 20.5 million people with diabetes and their reserves in Japan. It is estimated. In Japan, about 95% of diabetics are those who develop type 2 diabetes, and the main causes of the onset are said to be related to disturbances in lifestyle such as overeating, lack of exercise, obesity and stress.
  • the basic treatment of type 2 diabetes is to control blood sugar levels by diet and exercise therapy. If the therapeutic effect is not sufficient even with these therapies, it is necessary to use a combination of pharmacotherapy such as hypoglycemic drugs and insulin preparations. Since such pharmacotherapy for diabetes needs to be carried out continuously for a long period of time, there is no concern about side effects even if taken for a long period of time, and development of a highly safe drug is expected.
  • pharmacotherapy such as hypoglycemic drugs and insulin preparations. Since such pharmacotherapy for diabetes needs to be carried out continuously for a long period of time, there is no concern about side effects even if taken for a long period of time, and development of a highly safe drug is expected.
  • Examples of such a drug include a composition used for promoting storage of glycogen containing milk whey protein as an active ingredient (Patent Document 1), and a composition containing peptide as an active ingredient that promotes storage of glycogen (patent) Reference 2) has been reported so far.
  • the inventors of the present invention have made extensive studies focusing on foods and pharmaceuticals that regulate the action of insulin from the viewpoint of enhancing diabetes prevention and treatment methods. As a result, it was found that a whey protein hydrolyzate containing a dipeptide has an insulin secretion promoting action. The present invention is based on this finding.
  • An object of the present invention is to provide a novel composition for promoting insulin secretion and an insulin secretagogue.
  • a composition for promoting insulin secretion and an insulin secretagogue comprising a whey protein hydrolyzate as an active ingredient, wherein the whey protein hydrolyzate contains a dipeptide, wherein the dipeptide is Ile-Leu, Leu- One selected from the group consisting of Ala, Ala-Leu, Val-Leu, Lys-Ile, Leu-Leu, Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile and Leu-Ile
  • two or more kinds of compositions for promoting insulin secretion and insulin secretagogues hereinafter sometimes referred to as “the composition and agent of the present invention”).
  • the dipeptide is (1) Ile-Leu, (2) Group consisting of Leu-Ala, Ala-Leu, Val-Leu, Lys-Ile, Leu-Leu, Ile-Asn, Leu-Glu, Leu-Val, and Ile-Val, Ile-Ile and Leu-Ile
  • the composition and the agent according to the above [1] comprising at least one dipeptide selected from the group consisting of: [3] The composition and agent according to [1] or [2] above, which increase the blood insulin concentration after a meal. [4] The composition and preparation according to any one of [1] to [3] above, wherein the composition is ingested or administered before eating.
  • composition and preparation according to any one of [1] to [4] above, wherein the composition is ingested or administered to a type 2 diabetic patient or a diabetic reserve army.
  • a method for promoting insulin secretion comprising ingesting or administering an effective amount of whey protein hydrolyzate to mammals including humans, wherein the whey protein hydrolyzate contains a dipeptide,
  • the dipeptides are Ile-Leu, Leu-Ala, Ala-Leu, Val-Leu, Lys-Ile, Leu-Leu, Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile and Leu-.
  • a method for promoting insulin secretion which is one or more selected from the group consisting of Ile.
  • whey protein hydrolyzate for the manufacture of an insulin secretagogue, for the promotion of insulin secretion, or as an insulin secretagogue, wherein the whey protein hydrolyzate contains a dipeptide
  • the dipeptide is selected from the group consisting of Ile-Leu, Leu-Ala, Ala-Leu, Val-Leu, Lys-Ile, Leu-Leu, Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile and Leu.
  • -Use of one or more selected from the group consisting of Ile.
  • a whey protein hydrolyzate for use in promoting insulin secretion the whey protein hydrolyzate containing a dipeptide, wherein the dipeptide is Ile-Leu, Leu-Ala, Ala-Leu, Val-Leu, Hydrolysis of whey protein that is one or more selected from the group consisting of Lys-Ile, Leu-Leu, Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile and Leu-Ile object.
  • a composition for promoting insulin secretion and an insulin secretagogue comprising a whey protein hydrolyzate as an active ingredient. Since the whey protein hydrolyzate contained in the composition and the preparation of the present invention uses milk protein which has been used as a raw material for food for many years, the composition and the preparation of the present invention are used for a long time. Even if it is continuously taken, there is no concern about side effects, which is advantageous in terms of high safety. Moreover, whey protein is usually discharged after the curdling process of raw milk in the process of producing natural cheese, and is discarded to become industrial waste. Since the whey protein hydrolyzate contained as an active ingredient in the composition and the agent of the present invention can be used as a raw material by reusing whey as industrial waste, the present invention is also provided in terms of environment and economy. Is very advantageous.
  • FIG. 1 is a diagram showing the effect of whey protein hydrolyzate on blood insulin concentration after glucose loading.
  • the whey protein hydrolyzate (hereinafter sometimes referred to as “the whey protein hydrolyzate of the present invention”), which is an active ingredient of the composition and the agent of the present invention, is also called whey peptide, and is a raw material for whey protein.
  • the whey protein used in the present invention may be a whey protein that has been separated or purified, and is a raw material, food or drink that already contains whey protein and casein protein in a specific protein ratio (for example, a milk protein mixture, etc.) ) Can also be used.
  • the separated and purified whey proteins include, for example, whey stock solutions (sweet whey, acid whey, etc.), concentrates thereof, dried products (whey powder etc.), frozen products thereof, and reduced solutions thereof. Can be used. Furthermore, desalted whey, whey protein concentrate (WPC), whey protein purified product (WPI), ⁇ -lactalbumin ( ⁇ -La), ⁇ -lactoglobulin ( ⁇ -Lg), immunoglobulin, lactoferrin, etc., and These reducing solutions can be used.
  • WPC whey protein concentrate
  • WPI whey protein purified product
  • ⁇ -La ⁇ -lactalbumin
  • ⁇ -Lg ⁇ -lactoglobulin
  • immunoglobulin lactoferrin, etc.
  • raw materials and foods and drinks containing whey protein include raw milk, pasteurized milk (such as milk), skim milk, component-adjusted milk, processed milk, and dairy products (concentrated milk, powdered milk, condensed milk, fermented milk (yogurt) Etc.), lactic acid bacteria beverages, processed cheeses, ice creams, creams) and milk protein concentrates (MPC) and their concentrates, their dried products, their frozen products, and the like.
  • the raw material and food / beverage products containing the said whey protein may acquire and use a commercial item, and may prepare and use them themselves.
  • the whey protein hydrolyzate of the present invention can be prepared by hydrolyzing the whey protein as described above once or more.
  • the whey protein may be hydrolyzed at least partially during the separation and purification steps, and after such partial hydrolysis, further hydrolysis may be performed.
  • the whey protein hydrolyzate of the present invention can be prepared by hydrolyzing the whey protein by a known method, but can be preferably prepared by hydrolysis with a proteolytic enzyme.
  • the protein hydrolase is not particularly limited as long as the insulin secretion promoting effect of the present invention can be obtained, and the type and reaction conditions can be arbitrarily set with reference to the description in Patent Document 2 and the like.
  • proteolytic enzymes derived from microorganisms belonging to the genus Bacillus or Aspergillus papain derived from papaya, bromelain derived from pineapple, actinidine derived from kiwi, pancreatin, trypsin
  • proteolytic enzymes derived from animals such as chymotrypsin can be used alone or in combination.
  • a commercial item can be used for these proteolytic enzymes.
  • proteolytic enzymes include, for example, protease M Amano (Amanoenzyme), protease N Amano (Amanoenzyme), protease P Amano (Amanoenzyme), protease A Amano (Amanoenzyme), trypsin (Novo) ), Pepsin (Wako Pure Chemical Industries), Umamizyme (Amanoenzyme), and Flavorzyme (Novo), but are not limited thereto.
  • the proteolytic enzyme used to hydrolyze whey protein is selected from the group consisting of Bacillus derived proteolytic enzyme, Aspergillus derived proteolytic enzyme, trypsin, pepsin and flavorzyme. Or one or more.
  • the whey protein hydrolyzate of the present invention is characterized by containing a specific dipeptide.
  • a hydrolase used for hydrolyzing the whey protein By appropriately selecting a hydrolase used for hydrolyzing the whey protein, the hydrolyzate containing the desired dipeptide is abundant.
  • a decomposition product can be obtained.
  • Ile-Leu is obtained by hydrolyzing whey protein
  • whey protein when whey protein is hydrolyzed to obtain Val-Leu, Lys-Ile, Ile-Ile, Leu-Ile, Ile-Asn, Leu-Ala, Leu-Glu and Ile-Val, they are derived from the genus Aspergillus. It is preferable to use a protease.
  • a protease When obtaining Ala-Leu and Asp-Leu, it is preferable to react with a protease derived from Bacillus after reacting with trypsin to obtain Gly-Leu, Leu-Leu and Leu-Val. In some cases, it is preferable to react with a protease derived from the genus Aspergillus after the reaction with pepsin.
  • the reaction temperature is preferably 20 to 80 ° C., more preferably 25 to 75 ° C., and still more preferably 30 It is ⁇ 70 ° C., more preferably 35 to 65 ° C., further preferably 40 to 60 ° C., particularly preferably 45 to 55 ° C.
  • a reaction temperature of 20 ° C. or higher is preferable because whey protein can be efficiently hydrolyzed by a proteolytic enzyme.
  • the reaction temperature is 80 ° C. or lower, inactivation due to denaturation of the proteolytic enzyme is suppressed, which is preferable.
  • the reaction temperature is one step or two in consideration of the optimum temperature of the protein hydrolase used. It is possible to set the reaction temperature above the stage. When two or more reaction temperatures are set, the order is arbitrary.
  • the reaction time is preferably 2 to 48 hours, more preferably 2 to 36 hours, still more preferably 2 -24 hours, more preferably 2-18 hours, more preferably 2-14 hours, more preferably 4-12 hours, still more preferably 6-10 hours, particularly preferably 7-9 hours.
  • a reaction time of 2 hours or longer is preferable because much whey protein can be hydrolyzed by a proteolytic enzyme.
  • a reaction time of 48 hours or less is preferable because the whey protein can be efficiently hydrolyzed.
  • the reaction time is arbitrarily determined in the above reaction time. Two or more reaction temperatures can be set.
  • the amount of protein hydrolase added when hydrolyzing whey protein with a protein hydrolase is not particularly limited as long as the effect of promoting insulin secretion is exerted. However, it is preferably 0.5 to 10 g, more preferably 0.7 to 5 g, still more preferably 0.8 to 4 g, and particularly preferably 1 to 2 g with respect to 100 g of protein.
  • the reaction pH is preferably near the optimum pH of the protein hydrolase used.
  • a proteolytic enzyme derived from the genus Bacillus and a proteolytic enzyme derived from the genus Aspergillus are used in combination, it is preferably pH 5-9, more preferably pH 5.5-8.5, still more preferably pH 6-8, and particularly preferably Has a pH of 6.5 to 7.5.
  • reaction pH is one step in view of the optimum pH of the protein hydrolase used, or Two or more stages of reaction pH can be set.
  • reaction pH of two or more steps the order is arbitrary.
  • the whey protein hydrolyzate of the present invention can also be used as an indicator that a specific dipeptide is contained as an indicator of degradation.
  • the specific dipeptide here is preferably Ile-Leu, Leu-Ala, Ala-Leu, Val-Leu, Lys-Ile, Leu-Leu, Ile-Asn, Leu-Glu, Leu-Val, Ile. -Val, Ile-Ile and Leu-Ile, comprising at least one dipeptide selected from these groups.
  • Ile is isoleucine
  • Leu is leucine
  • Ala is alanine
  • Val is valine
  • Lys is lysine
  • Asn is asparagine
  • Glu is glutamic acid.
  • the dipeptide can be measured by LC / MS or LC / MSMS, and specifically, can be measured by the method described in Analysis Example 1 described later.
  • the whey protein hydrolyzate of the present invention containing a specific dipeptide can be produced by referring to the examples described in Production Examples 1 to 11 below, in addition to the hydrolysis reaction conditions as described above. it can.
  • the whey protein hydrolyzate of the present invention preferably contains a specific dipeptide that satisfies the following (1) and (2).
  • Ile-Leu is particularly preferably contained in the whey protein hydrolyzate of the present invention
  • Leu-Ala, Ala-Leu, Val-Leu, Lys-Ile, Leu. -At least one dipeptide among Leu, Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile and Leu-Ile is contained in the whey protein hydrolyzate of the present invention. Particularly preferred.
  • the whey protein hydrolyzate of the present invention contains a specific dipeptide that satisfies the following (1 ′) and (2 ′).
  • Ile-Leu is particularly preferably contained in the whey protein hydrolyzate of the present invention, and (2 ′) Ala-Leu, Val-Leu, Lys-Ile, Leu-Leu, It is particularly preferable that at least one dipeptide among Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile and Leu-Ile is contained in the whey protein hydrolyzate of the present invention.
  • the content of the dipeptide described in (1 ′) and (2 ′) per whey hydrolyzate can be set as follows, for example.
  • Ile-Val 0.5 mg / g hydrolyzate or more (preferably 0.7 to 4 mg / g hydrolyzate, more preferably 0.9 to 1.1 mg / g hydrolyzate)
  • Leu-Val 0.4 mg / g hydrolyzate or more (preferably 0.6 to 3 mg / g hydrolyzate, more preferably 0.8 to 1.0 mg / g hydrolyzate)
  • Val-Leu 2.0 mg / g hydrolyzate or more (preferably 3.0 to 20 mg / g hydrolyzate, more preferably 5.0 to 7.0 mg / g hydrolyzate)
  • Ile-Ile 0.2 mg / g hydrolyzate or more (preferably 0.3 to 2 mg / g hydrolyzate, more preferably 0.4 to 0.6 mg / g hydrolyzate)
  • Leu-Ile
  • the content is preferably the protein content of the whey protein hydrolyzate (before hydrolysis).
  • the protein content of whey protein) is 0.5 mg or more per gram, more preferably 0.5 to 10 mg per gram of protein content, still more preferably 0.5 to 8 mg per gram of protein content, and still more preferably 0.5 per gram of protein content. -6 mg, particularly preferably 0.5-4 mg per gram of protein content. If the dipeptide Ile-Leu content is 0.5 mg or more per gram of protein content of the whey protein hydrolyzate, the insulin secretion-promoting effect of the present invention is more exhibited, which is preferable. Moreover, if the content of the dipeptide Ile-Leu is 10 mg or less per gram of protein content of the whey protein hydrolyzate, the whey protein hydrolyzate of the present invention can be efficiently prepared, which is preferable.
  • protein content means the total amount of amino acids contained in various proteins.
  • the protein content may be measured and calculated by a conventional method such as Kjeldahl method or Raleigh method. Actually, in the case of the Kjeldahl method, it can be calculated by measuring nitrogen contained in various proteins and multiplying the value by a nitrogen-protein conversion factor (usually 6.25).
  • a nitrogen-protein conversion factor usually 6.25.
  • the content thereof is preferably the protein content of whey protein hydrolyzate (before hydrolysis).
  • the protein content of whey protein) is 0.5 mg or more per gram, more preferably 0.5 to 10 mg per gram of protein content, still more preferably 0.5 to 8 mg per gram of protein content, and still more preferably 0.5 per gram of protein content. -6 mg, particularly preferably 0.5-4 mg per gram of protein content.
  • the content of the dipeptide Leu-Ala is 0.5 mg or more per gram of protein content of the whey protein hydrolyzate, the insulin secretion promoting effect of the present invention is more exhibited, which is preferable.
  • the content of the dipeptide Leu-Ala is 10 mg or less per gram of protein content of the whey protein hydrolyzate, the whey protein hydrolyzate of the present invention can be efficiently prepared, which is preferable.
  • the content is preferably the protein content of whey protein hydrolyzate (before hydrolysis).
  • the protein content of whey protein) is 0.2 mg or more per gram, more preferably 0.2 to 10 mg per gram of protein content, still more preferably 0.2 to 8 mg per gram of protein content, still more preferably 0.2 per gram of protein content. -6 mg, particularly preferably 0.2-5 mg per gram of protein content. If the content of the dipeptide Ala-Leu is 0.2 mg or more per gram of protein content of the whey protein hydrolyzate, the insulin secretion promoting effect of the present invention is more exhibited, which is preferable. Moreover, if the content of the dipeptide Ala-Leu is 10 mg or less per gram of protein content of the whey protein hydrolyzate, the whey protein hydrolyzate of the present invention can be efficiently prepared, which is preferable.
  • the content thereof is preferably the protein content of whey protein hydrolyzate (before hydrolysis).
  • the protein content of whey protein is 1 mg or more per gram, more preferably 1 to 15 mg per gram of protein content, more preferably 1 to 12 mg per gram of protein content, still more preferably 1 to 10 mg per gram of protein content, particularly preferably the protein content 1-8 mg per gram. If the content of the dipeptide Val-Leu is 1 mg or more per gram of protein content of the whey protein hydrolyzate, the insulin secretion promoting effect of the present invention is more exhibited, which is preferable. Moreover, if the content of dipeptide Val-Leu is 15 mg or less per gram of protein content of the whey protein hydrolyzate, the whey protein hydrolyzate of the present invention can be efficiently prepared, which is preferable.
  • the content is preferably the protein content of the whey protein hydrolyzate (before hydrolysis).
  • the protein content of whey protein) is 0.2 mg or more per gram, more preferably 0.2 to 15 mg per gram of protein content, still more preferably 0.2 to 12 mg per gram of protein content, still more preferably 0.2 per gram of protein content. ⁇ 10 mg, particularly preferably 0.2 to 8 mg / g protein content.
  • the content of the dipeptide Lys-Ile is 0.2 mg or more per gram of protein content of the whey protein hydrolyzate, the insulin secretion promoting effect of the present invention is more exhibited, which is preferable. Further, if the content of the dipeptide Lys-Ile is 15 mg or less per gram of protein content of the whey protein hydrolyzate, the whey protein hydrolyzate of the present invention can be efficiently prepared, which is preferable.
  • the content is preferably the protein content of the whey protein hydrolyzate (before hydrolysis).
  • the protein content of whey protein) is 0.2 mg or more per gram, more preferably 0.2 to 25 mg per gram of protein content, still more preferably 0.2 to 20 mg per gram of protein content, still more preferably 0.2 per gram of protein content. ⁇ 18 mg, particularly preferably 0.2 to 16 mg / g protein content.
  • the dipeptide Leu-Leu content is 0.2 mg or more per gram of protein content of the whey protein hydrolyzate, the insulin secretion promoting effect of the present invention is more exhibited, which is preferable. Moreover, if the content of the dipeptide Leu-Leu is 25 mg or less per gram of protein content of the whey protein hydrolyzate, the whey protein hydrolyzate of the present invention can be efficiently prepared, which is preferable.
  • the content is preferably the protein content of the whey protein hydrolyzate (before hydrolysis).
  • the protein content of whey protein) is 1 mg or more per gram, more preferably 1 to 10 mg per gram of protein content, more preferably 1 to 8 mg per gram of protein content, more preferably 1 to 6 mg per gram of protein content, particularly preferably the protein content 1 to 5 mg per gram. If the content of the dipeptide Ile-Asn is 1 mg or more per gram of protein content of the whey protein hydrolyzate, the insulin secretion promoting effect of the present invention is more exhibited, which is preferable. Moreover, if the content of the dipeptide Ile-Asn is 10 mg or less per gram of protein content of the whey protein hydrolyzate, the whey protein hydrolyzate of the present invention can be efficiently prepared, which is preferable.
  • the content thereof is preferably the protein content of whey protein hydrolyzate (before hydrolysis).
  • the protein content of whey protein) is 0.5 mg or more per gram, more preferably 0.5 to 12 mg per gram of protein content, still more preferably 0.5 to 10 mg per gram of protein content, more preferably 0.5 per gram of protein content. ⁇ 8 mg, particularly preferably 0.5 to 6 mg per g protein content. If the content of the dipeptide Leu-Glu is 0.5 mg or more per gram of protein content of the whey protein hydrolyzate, the insulin secretion promoting effect of the present invention is more exhibited, which is preferable. Moreover, if the content of the dipeptide Leu-Glu is 12 mg or less per gram of protein content of the whey protein hydrolyzate, the whey protein hydrolyzate of the present invention can be efficiently prepared, which is preferable.
  • the whey protein hydrolyzate of the present invention is in a liquid state immediately after preparation, in order to enhance its storage stability, it is cryopreserved, dried (spray-dried, freeze-dried), concentrated, and heat-sterilized (plate-type heat-sterilized, tube -Type heat sterilization, batch-type heat sterilization, current heat sterilization, microwave heat sterilization, indirect heat sterilization such as retort heating, direct heat sterilization such as steam injection and steam infusion), non-heat sterilization (light irradiation sterilization, radiation Irradiation sterilization, high voltage pulse sterilization).
  • the form dried (spray drying, freeze-drying) is preferable from the ease of handling.
  • the composition of the present invention containing a whey protein hydrolyzate can increase the blood insulin concentration after glucose load compared to the control group. Therefore, the whey protein hydrolyzate can be used as an active ingredient of a composition for promoting insulin secretion and an insulin secretagogue, and can be used particularly for increasing blood insulin concentration after a meal.
  • insulin secretion promotion means to increase the insulin concentration in blood as compared with the control group.
  • the composition and agent of the present invention can increase the insulin concentration in blood after glucose loading, it is taken by those who need to increase the amount of insulin secretion (especially type 2 diabetic patients and diabetic reserves). Or can be administered. Among patients with type 2 diabetes, those with insulin secretion deficiency have a decreased amount of insulin secretion. Therefore, it can be said that the composition and the preparation of the present invention can particularly exert their effects.
  • the blood insulin concentration can be measured according to a chemiluminescent enzyme immunoassay (CLEIA).
  • a method for promoting insulin secretion comprising ingesting or administering an effective amount of a whey protein hydrolyzate to a human or non-human animal (or a mammal including a human) Is provided.
  • the insulin secretion promoting method of the present invention can be carried out according to the description of the composition and the preparation of the present invention.
  • the said whey protein hydrolyzate can be implemented according to the description content about the whey protein hydrolyzate of this invention.
  • non-therapeutic means that it does not include an act of operating, treating or diagnosing a human (ie, a medical act on a human). Specifically, a doctor or a person who has received instructions from a doctor It means not including methods for performing surgery, treatment or diagnosis on humans.
  • the whey protein hydrolyzate of the present invention can be added with other food raw materials and / or food additive raw materials as long as the insulin secretion promoting effect can be exhibited.
  • sweeteners sucgars, liquid saccharides, fructose, maltose, trisaccharide, etc.), sugar alcohols (erythritol, etc.), high-sensitivity sweeteners ( Stevia, aspartame, sucralose, acesulfame potassium), acidulant, thickening polysaccharide, flavor, fruit juice, emulsifier, vegetable juice and the like can be added.
  • composition and agent of the present invention can be used.
  • composition and agent of the present invention can be in the form of a powder in a container for the purpose of providing on the market.
  • a well-known thing can be used for a container, such as paper, a bag, a box, a can, and a bottle.
  • the capacity of the container is not particularly limited, and for example, 1 to 5000 g, 2 to 4000 g, 3 to 3000 g, 4 to 2000 g, 4 to 1000 g, 4 to 500 g, 4 to 250 g, 4 to 200 g, 4 to 100 g, 4 to 100 g, 50 g, 4-30 g.
  • a family size for example, 300 to 5000 g, 300 to 4000 g, 300 to 3000 g, 300 to 2000 g, 300 to 1500 g, 300 to 1400 g, 300 to 1300 g, 300 to 1200 g, 300 to 1100 g.
  • personal size 1 to 500 g, 2 to 250 g, 3 to 200 g, 4 to 100 g, 4 to 50 g, 4 to 40 g, 4 to 30 g, 5 to 30 g, 10 to 30 g, 15 to 30 g.
  • composition and preparation of the present invention can be in the form of a beverage in a container (a beverage in which powder is dispersed and dissolved) for the purpose of providing on the market.
  • a container such as a paper container, a soft bag, a PET bottle, a can, and a bottle.
  • the capacity of the container is not particularly limited, and is, for example, 1 to 5000 g, 2 to 4000 g, 3 to 3000 g, 4 to 2000 g, 5 to 1000 g, 6 to 800 g, 7 to 1300 g, 80 to 1200 g, 90 to 1100 g.
  • a family size for example, 300 to 5000 g, 300 to 4000 g, 300 to 3000 g, 300 to 2000 g, 300 to 1500 g, 300 to 1400 g, 300 to 1300 g, 300 to 1200 g, 300 to 1100 g
  • it is 10 to 500 g, 20 to 500 g, 30 to 500 g, 40 to 500 g, 50 to 500 g, 60 to 500 g, 70 to 500 g, 80 to 500 g, 90 to 500 g.
  • the whey protein hydrolyzate has a protein content of 0.05 g / kg body weight (preferably 0.1 g / kg / (kg body weight) may be ingested (administered), preferably 0.05 to 5.0 g / kg body weight, more preferably 0.05 to 1.0 g / kg body weight, still more preferably 0.00. It can be ingested (administered) so as to be 1 to 5.0 g / kg body weight, particularly preferably 0.1 to 1.0 g / kg body weight.
  • the typical weight of the subject is estimated to be about 60 kg.
  • one meal means one time of a state requiring insulin secretion promotion.
  • a single meal is not taken at a time (at a time), but several times. May be taken separately.
  • the time when the composition and the preparation of the present invention are ingested (administered) to a subject in need of insulin secretion is promoted before normal food intake (before consumption) from the viewpoint of promoting insulin secretion after normal food intake.
  • normal food intake Preferably 15 to 240 minutes before normal food intake, more preferably 30 to 180 minutes before normal food intake, and more preferably 45 to 135 minutes before food intake. it can.
  • the timing of ingesting (administering) the composition and the preparation of the present invention to a subject in need of insulin secretion promotion is not limited to the above, and the composition and the preparation of the present invention are combined with ingesting a normal food. You may ingest, mix in normal food, ingest normal food after ingestion, or ingest between regular meals.
  • the method of ingesting (administering) the composition and the preparation of the present invention to a subject in need of insulin secretion promotion is appropriately selected according to the subject and application from oral ingestion (oral administration), enteral administration, gastric fistula and the like. Although it can be selected, it is preferably taken orally.
  • the composition and the agent of the present invention may be provided in a unit package form per serving, and the whey protein hydrolyzate is contained in the unit.
  • the food intake is preferably adjusted to 3 g or more (preferably 6 g or more) in terms of total protein content, and the food intake is preferably adjusted to 300 g or less (preferably 60 g or less) in terms of total protein content.
  • the content of the whey protein hydrolyzate of the present invention per unit package is, for example, from 3 to 300 g, preferably from 3 to 60, more preferably from 6 to 300 g, even more preferably, as a single meal intake in terms of total protein content. Can be 6-60 g.
  • ⁇ consisting of a unit packaging form per meal '' is a form in which the intake amount per meal is determined in advance, for example, as a food and drink that can be taken orally in a specific amount, not only general foods, It means forms such as beverages (drinks, etc.), health supplements, health functional foods, and supplements.
  • unit packaging form per meal for example, in the case of liquid beverages, gel-like, paste-like, paste-like jelly, powder-like, granule-like, capsule-like, block-like solid foods, etc.
  • a specific amount (dose) can be defined in packaging containers such as cans, glass bottles (such as bottles), plastic containers (such as plastic bottles), packs, pouches, film containers, paper boxes, etc., or intake per serving (usage, dose) ) Is displayed on a packaging container, a homepage, etc., and the form which can prescribe
  • regulate specific quantity is mentioned. Since the composition and the agent of the present invention use whey protein hydrolyzate as an active ingredient, it is less gelled by heating than whey protein, and therefore has suitable physical properties in the production process of beverages, jellies and the like. Can be maintained.
  • composition and the preparation of the present invention are in any form such as a bite-sized block or a mini-can drink that can be consumed with a single drink in order to achieve the effects of the present invention even with a small amount.
  • ingestion and swallowing are easy, and convenience for children and the elderly can be improved.
  • the whey protein hydrolyzate is at least Ile-Leu, Leu-Ala, Ala-Leu, Val-Leu, Lys-Ile, Those including Leu-Leu, Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile and Leu-Ile are provided.
  • the whey protein hydrolyzate is at least Ile-Leu, Leu-Ala, Val-Leu, Lys-Ile, Leu-Leu as a dipeptide.
  • Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile and Leu-Ile are provided.
  • the whey protein hydrolyzate is at least Ile-Val, Leu-Val, Val-Leu, Ile-Ile, Leu-Ile as a dipeptide. , Ile-Leu and Leu-Leu are provided.
  • the whey protein hydrolyzate is at least Ile-Val, Leu-Val, Val-Leu, Ile-Ile, Leu-Ile as a dipeptide.
  • Ile-Val 0.5 mg / g hydrolyzate or more (preferably 0.7 to 4 mg / g hydrolyzate, more preferably 0.9 to 1.1 mg / g hydrolyzate)
  • Leu-Val 0.4 mg / g hydrolyzate or more (preferably 0.6 to 3 mg / g hydrolyzate, more preferably 0.8 to 1.0 mg / g hydrolyzate)
  • Val-Leu 2.0 mg / g hydrolyzate or more (preferably 3.0 to 20 mg / g hydrolyzate, more preferably 5.0 to 7.0 mg / g hydrolyzate)
  • Ile-Ile 0.2 mg / g hydrolyzate or more (preferably 0.3 to 2 mg / g hydrolyzate, more preferably 0.4 to 0.6 mg / g hydrolyzate)
  • Leu-Ile 0.02 mg / / / g hydrolyzate
  • composition of the present invention can be provided in the form of a composition in which a plurality of components are blended.
  • the form of the composition of the present invention is not particularly limited as long as it has an insulin secretion promoting effect.
  • it is solid (powder, granule, capsule, block, etc.), liquid, gel, glue
  • the shape may be in the form of a paste or paste, preferably in the form of a powder.
  • Compositions include food compositions and pharmaceutical compositions.
  • the composition and the preparation of the present invention are Even if taken continuously over a long period of time, there is no concern about side effects and the safety is high. Therefore, when the composition and agent of the present invention are used in combination with a drug such as an existing insulin secretagogue, the dose of the existing drug can be reduced, and the side effects of the existing drug can be reduced or eliminated. This is advantageous.
  • the other drugs and the composition and agent of the present invention can be prepared separately, but the other drug and the composition and agent of the present invention are combined in the same composition. Also good.
  • a food for promoting insulin secretion containing a whey protein hydrolyzate as an active ingredient.
  • the form of the food is not particularly limited as long as it is a form that can be taken orally, such as a solution, suspension, emulsion, powder, or solid molded product.
  • soft drink, fruit juice drink, vegetable drink, soy milk drink, coffee drink, tea Beverages such as beverages, powdered beverages, concentrated beverages, alcoholic beverages
  • flour products such as bread, pasta, noodles, cake mixes, bread crumbs
  • milk drinks, yogurts, lactic acid bacteria drinks, ice creams, creams How dairy products; agricultural canning, jam, marmalade such, processed agricultural products such as serial; such as frozen food, and the like.
  • the food or drink is a dairy product, more preferably
  • Food / drinks include health foods, functional foods, dietary supplements, functional labeling foods, foods for specified health use, foods for the sick, infant formulas, milk powders for pregnant or lactating women, or insulin secretion promoting products.
  • foods and beverages with a label indicating that they are used are included.
  • the food of the present invention may be marked with an effect of promoting insulin secretion.
  • the food of the present invention may be displayed, for example, with some or all of the following displays. ⁇ Food that suppresses the increase in blood sugar level ⁇ Food suitable for those concerned about blood sugar level ⁇ Food that moderates the increase in blood sugar level
  • a whey protein hydrolyzate for the production of an insulin secretagogue or for the promotion of insulin secretion, and a whey protein hydrolyzate as an insulin secretagogue Use of is provided.
  • the use of the present invention can be carried out in accordance with the description of the composition and agent of the present invention.
  • the said whey protein hydrolyzate can be implemented according to the description content about the whey protein hydrolyzate of this invention.
  • a whey protein hydrolyzate for use in promoting insulin secretion is provided.
  • Said whey protein hydrolyzate can be implemented according to the description regarding the composition and agent of this invention.
  • the said whey protein hydrolyzate can be implemented according to the description content about the whey protein hydrolyzate of this invention.
  • protein in “mg / g protein” and “g protein / kg body weight” described later means a protein content.
  • protease derived from Bacillus Protease M Amano, Amano Enzyme
  • Aspergillus Protease N Amano, Amano Enzyme
  • the LC / MS / MS conditions are as follows. Analysis condition column: ACQUITY UPLC BEH C18 1.7 ⁇ m, 2.1 ⁇ 50 mm Column Mobile phase: Liquid A: 0.1% trifluoroacetic acid-containing aqueous solution Liquid B: 0.1% trifluoroacetic acid-containing acetonitrile solution
  • Ile-Leu of the whey protein hydrolyzate of Production Example 1 was 3.82 mg / g protein, Ala-Leu was 1.53 mg / g protein, Val-Leu was 4.70 mg / g protein, and Lys-Ile was 4.82 mg. / G protein, Leu-Leu was 1.56 mg / g protein, Ile-Asn was 3.98 mg / g protein, Leu-Ala was 0.75 mg / g protein, Leu-Glu was 4.35 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 2 was measured.
  • Ile-Leu is 2.39 mg / g protein
  • Ala-Leu is 0.64 mg / g protein
  • Val-Leu is 2.35 mg / g protein
  • Lys-Ile is 1.97 mg.
  • Leu-Leu was 0.67 mg / g protein
  • Ile-Asn was 2.73 mg / g protein
  • Leu-Ala was 1.22 mg / g protein
  • Leu-Glu was 1.90 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 3 was measured.
  • Ile-Leu of the whey protein hydrolyzate of Production Example 3 is 3.74 mg / g protein, Ala-Leu is 1.98 mg / g protein, Val-Leu is 2.13 mg / g protein, and Lys-Ile is 1.07 mg. / G protein, Leu-Leu was 8.20 mg / g protein, Ile-Asn was 2.40 mg / g protein, Leu-Ala was 1.77 mg / g protein, Leu-Glu was 1.08 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 4 was measured.
  • Ile-Leu is 3.16 mg / g protein
  • Ala-Leu is 4.77 mg / g protein
  • Val-Leu is 5.33 mg / g protein
  • Lys-Ile is 4.84 mg.
  • G protein Leu-Leu was 1.07 mg / g protein
  • Ile-Asn was 1.65 mg / g protein
  • Leu-Ala was 0.83 mg / g protein
  • Leu-Glu was 4.82 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 5 was measured.
  • Ile-Leu is 3.57 mg / g protein
  • Ala-Leu is 2.04 mg / g protein
  • Val-Leu is 2.60 mg / g protein
  • Lys-Ile is 0.74 mg.
  • G protein Leu-Leu was 4.89 mg / g protein
  • Ile-Asn was 1.61 mg / g protein
  • Leu-Ala was 1.96 mg / g protein
  • Leu-Glu was 0.71 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 6 was measured.
  • Ile-Leu is 1.47 mg / g protein
  • Ala-Leu is 0.75 mg / g protein
  • Val-Leu is 4.92 mg / g protein
  • Lys-Ile is 0.54 mg.
  • Leu-Leu was 2.21 mg / g protein
  • Ile-Asn was 1.59 mg / g protein
  • Leu-Ala was 2.80 mg / g protein
  • Leu-Glu was 0.62 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 7 was measured.
  • Ile-Leu is 2.86 mg / g protein
  • Ala-Leu is 2.28 mg / g protein
  • Val-Leu is 3.90 mg / g protein
  • Lys-Ile is 0.81 mg.
  • Leu-Leu was 13.37 mg / g protein
  • Ile-Asn was 2.82 mg / g protein
  • Leu-Ala was 3.08 mg / g protein
  • Leu-Glu was 0.97 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 8 was measured.
  • Ile-Leu of the whey protein hydrolyzate of Production Example 8 was 0.62 mg / g protein, Ala-Leu was 0.35 mg / g protein, Val-Leu was 1.58 mg / g protein, and Lys-Ile was 1.54 mg.
  • G protein Leu-Leu was 0.20 mg / g protein
  • Ile-Asn was 1.64 mg / g protein
  • Leu-Ala was 1.05 mg / g protein
  • Leu-Glu was 1.40 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 9 was measured.
  • Ile-Leu is 2.78 mg / g protein
  • Ala-Leu is 1.09 mg / g protein
  • Val-Leu is 6.25 mg / g protein
  • Lys-Ile is 6.45 mg.
  • G protein Leu-Leu was 1.85 mg / g protein
  • Ile-Asn was 4.93 mg / g protein
  • Leu-Ala was 3.93 mg / g protein
  • Leu-Glu was 5.87 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 10 was measured.
  • Ile-Leu is 2.17 mg / g protein
  • Ala-Leu is 0.64 mg / g protein
  • Val-Leu is 4.23 mg / g protein
  • Lys-Ile is 2.72 mg.
  • Leu-Leu was 2.22 mg / g protein
  • Ile-Asn was 3.23 mg / g protein
  • Leu-Ala was 2.97 mg / g protein
  • Leu-Glu was 2.48 mg / g protein .
  • the dipeptide content of the whey protein hydrolyzate of Production Example 11 was measured.
  • Ile-Leu is 1.85 mg / g protein
  • Ala-Leu is 0.66 mg / g protein
  • Val-Leu is 5.19 mg / g protein
  • Lys-Ile is 3.83 mg.
  • G protein Leu-Leu was 1.74 mg / g protein
  • Ile-Asn was 3.70 mg / g protein
  • Leu-Ala was 3.54 mg / g protein
  • Leu-Glu was 3.56 mg / g protein .
  • Test Example 1 a test was conducted on the effect of whey protein hydrolyzate on blood insulin concentration.
  • Screening of subjects For screening of subjects preliminary questionnaires, interviews / physical examinations and blood collection were performed, and subjects were selected and assigned. Specifically, it is a Japanese male who is 40 years old or older and younger than 60 years old and has the following two conditions: (i) fasting blood glucose level is 100 mg / dL or more and less than 126 mg / dL, (ii) hemoglobin A1c (hereinafter, “ HbA1c ”) was 5.6% or more and less than 6.5% (NGSP value), and screening was performed according to the criterion that at least one of them was satisfied, and 6 subjects were selected.
  • HbA1c hemoglobin A1c
  • test method The test was conducted twice, and each test was conducted on another test day (test days 1 and 2) with a gap of 6 days or more.
  • the 6 subjects selected in (1) above were randomly assigned to 2 groups, 3 test groups and 3 control groups.
  • the subjects who were the test group on the test day 1 were used as the control group on the test day 2, and the subjects who were the control group on the test day 1 were used as the test group on the test day 2 to perform the single blind crossover test.
  • the test subject ingested the regular meal 12 hours or more before the test meal or the control meal (hereinafter referred to as “food” in this test example), and received a medical check before the food intake.
  • the test group was fed with a solution prepared by dissolving 18.9 g of whey hydrolyzate in 200 mL of water as a test meal, and the control group was fed with 200 mL of water as a control meal.
  • Blood was collected at the same time as food intake (0 minutes), and after 15 minutes from the time of food intake, 75 g of sugar solution (Traillan (trademark) G solution, manufactured by Awai Pharma Co., Ltd.) was ingested and blood was collected. Blood was collected at the lapse of minutes, 45 minutes, 60 minutes, 75 minutes, 105 minutes, 135 minutes, and 195 minutes. Insulin concentration in blood is based on chemiluminescent enzyme immunoassay (CLEIA), Mika Karasawa et al .: Medical and testing equipment / reagent 29 (5): 479-484 (2006) According to the above, the measurement was performed using Lumipulse pre-insulated insulin (Fujirebio). For the test group and the control group, the average value of the blood insulin concentration of 6 subjects in each group was calculated.
  • CLIA chemiluminescent enzyme immunoassay
  • Test meal Whey protein hydrolyzate obtained by hydrolyzing whey protein with protease was used for the test meal.
  • the hydrolyzate contained about 79% by mass of protein per solid content.
  • the powder of the whey protein hydrolyzate was diluted 1000 times (volume ratio) in a 0.1% aqueous trifluoroacetic acid solution, and the dipeptide content of the hydrolyzate was measured according to the procedure described in Analysis Example 1.
  • Ile-Val, Leu-Val, Val-Leu, Ile-Ile, Leu-Ile, Ile-Leu and Leu-Leu were quantified (unit: mg / g hydrolyzate) as main dipeptides.
  • the dipeptide content of the whey protein hydrolyzate in the test meal was 0.985 mg / g hydrolyzate for Ile-Val, 0.896 mg / g hydrolyzate for Leu-Val, and 6.11 mg for Val-Leu.
  • Ile-Ile is 0.524 mg / g hydrolyzate
  • Leu-Ile is 0.145 mg / g hydrolyzate
  • Ile-Leu is 4.27 mg / g hydrolyzate
  • Leu-Leu is 6 It was 0.55 mg / g hydrolyzate.

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Abstract

L'objet de la présente invention est de fournir une nouvelle composition pour favoriser la sécrétion d'insuline. Selon la présente invention, l'invention concerne une composition pour favoriser la sécrétion d'insuline, ladite composition comprenant un hydrolysat de protéines lactosériques en tant que principe actif, l'hydrolysat de protéines lactosériques contenant un dipeptide et le dipeptide étant au moins un élément choisi dans le groupe constitué par Ile-Leu, Leu-Ala, Ala-Leu, Val-Leu, Lys-Ile, Leu-Leu, Ile-Asn, Leu-Glu, Leu-Val, Ile-Val, Ile-Ile et Leu-Ile.
PCT/JP2018/002614 2017-01-30 2018-01-29 Composition pour favoriser la sécrétion d'insuline WO2018139624A1 (fr)

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WO2007123200A1 (fr) * 2006-04-21 2007-11-01 Meiji Seika Kaisha, Ltd. Composition contenant un peptide comme principe actif
JP2009514780A (ja) * 2003-07-10 2009-04-09 “エス．ウー．カー．”ベタイリグングス・ゲーエムベーハー メタボリックシンドロームの処置のためのホエーパーミエートの使用
JP2009536016A (ja) * 2006-01-20 2009-10-08 インエル ビョルク， アミノ酸を含む食品組成物
JP2013184962A (ja) * 2012-03-09 2013-09-19 Morinaga Milk Ind Co Ltd ジペプチジルペプチダーゼ−ｉｖ阻害剤
JP2016193865A (ja) * 2015-03-31 2016-11-17 キリン株式会社 ミクログリア貪食活性亢進のための組成物及びミクログリア貪食活性亢進作用の予測方法

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JP2013184962A (ja) * 2012-03-09 2013-09-19 Morinaga Milk Ind Co Ltd ジペプチジルペプチダーゼ−ｉｖ阻害剤
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