US20120189611A1 - Dipeptidyl peptidase-4 inhibitor - Google Patents
Dipeptidyl peptidase-4 inhibitor Download PDFInfo
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- US20120189611A1 US20120189611A1 US13/388,913 US201013388913A US2012189611A1 US 20120189611 A1 US20120189611 A1 US 20120189611A1 US 201013388913 A US201013388913 A US 201013388913A US 2012189611 A1 US2012189611 A1 US 2012189611A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/06—Preparation of peptides or proteins produced by the hydrolysis of a peptide bond, e.g. hydrolysate products
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/14—Dipeptidyl-peptidases and tripeptidyl-peptidases (3.4.14)
- C12Y304/14005—Dipeptidyl-peptidase IV (3.4.14.5)
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Definitions
- the present invention relates to a dipeptidyl peptidase-4 inhibitor, and a production method thereof.
- the present invention also relates to an agent for preventing and/or ameliorating diabetes which contains the dipeptidyl peptidase-4 inhibitor.
- DPP-4 Dipeptidyl peptidase-4
- DPP-4 is a type of serine protease that recognizes the second proline or alanine from the N-terminal of a peptide and severs it from the peptide.
- DPP-4 is widely distributed in mammalian tissues, and is known to be present in the kidneys, liver, intestinal epithelium, placenta and plasma in particular. Although the role of DPP-4 in mammals is not completely clear, it is thought to play an important role in processes such as the metabolism of neuropeptides, activation of T cells, adhesion of cancer cells to endothelial cells, and cellular invasion of HIV.
- DPP-4 is known to include peptides associated with nutrition, metabolism, the immune system and sensation of pain.
- DPP-4 is attracting attention as an enzyme that deactivates glucagon-like peptide-1 (hereinafter referred to as GLP-1), which functions to enhance glucose-dependent insulin secretion, and gastric inhibitory polypeptide or glucose-dependent insulinotropic peptide (Non-Patent Document 1).
- GLP-1 In addition to the glucose-dependent secretion of insulin from pancreatic ⁇ cells, examples of other physiological effects of GLP-1 include glucagon secretion inhibitory effect, pancreatic ⁇ tell protective and proliferative effects, inhibition of gastric emptying, and activation of glycogen synthase in the liver. Moreover, GLP-1 also causes a reduction in food intake by acting on the satiety center of the hypothalamus in the central nervous system (Non-Patent Document 2).
- the physiological activity of GLP-1 is also known to be enhanced by inhibiting degradation of GLP-1, for example, through inhibition of DPP-4 activity.
- a compound having DPP-4 inhibitory effect is expected to demonstrate any effect on glucose intolerance, postprandial hyperglycemia, fasting hyperglycemia and accompanying obesity and diabetes complications, and other symptoms observed in type 1 diabetes, type 2 diabetes and the like.
- it is also expected to demonstrate an effect that assists the supply of energy to muscles during exercise because of its ability to promote insulin secretion to promote the uptake of sugar into muscles.
- DPP-4 is also involved in the metabolism of neuropeptides such as neuropeptide Y, endomorphin-1, endomorphin-2 and substance P.
- a compound that inhibits DPP-4 can be expected to serve as a therapeutic for schizophrenia, depression, anxiety, epilepsy or a stress-related disease, or an analgesic by inhibiting the degradation of these physiologically active peptides.
- DPP-4 is also known, to be involved in processes such as the metabolism of various cytokines and chemokines, activation of immunocompetent T cells, adhesion of cancer cells to endothelium, and proliferation of blood cells
- a compound that inhibits DPP-4 is thought to be useful for preventing and/or ameliorating, through these effects, not only diabetes but also diseases such as rheumatoid arthritis, autoimmune diseases, allergic diseases such as asthma and food allergies, cancers, cancer metastasis, HIV infection, anemia and thrombocytopenia.
- DPP-4 inhibitors 1, 2, 3 and 4 Many compounds obtained by chemical synthesis have been reported to be DPP-4 inhibitors. Several of these have already been used practically as diabetes therapeutics. On the other hand, there are known DPP-4 inhibitors derived from natural products, such as a gelatin-derived peptide (Patent Document 5), a milk casein-derived peptide (Patent Document 6), a hydrolyzable tannin (Patent Document 7), and extracts of paprika and other plants (Patent Document 8). In addition, a product obtained by hydrolyzing a protein using a known method has also been reported to be able to be used for the, prevention and/or treatment of symptoms mediated by DPP-4 (Patent Document 9).
- Patent Document 1 JP 2005-500321 T
- Patent Document 2 JP 2004-535455 T
- Patent Document 3 JP 2004-536115 T
- Patent Document 4 JP 2000-327689 A
- Patent Document 5 WO 2008/066070
- Patent Document 6 JP 2007-39424 A
- Patent Document 7 JP 2008-280291 A
- Patent Document 8 JP 2007-277163 A
- Patent Document 9 JP 2008-500304 T
- Non-Patent Document 1 Journal of Pharmacological Sciences, 125, 379-384 (2005)
- Non-Patent Document 2 Expert Opin. Investig. Drugs, 1091-1102 (2004)
- the present invention aims to provide a DPP-4 inhibitor that is produced using a natural product that has been eaten, as a raw material and that is suitable for oral applications not only in terms of DPP-4 inhibitory activity but also from the viewpoints of flavor and absorbability, and a composition (such as a food or beverage, functional food, pharmaceutical, enteral nutrient or animal feed) for the prevention and/or amelioration of diabetes which contains the DPP-4 inhibitor.
- a composition such as a food or beverage, functional food, pharmaceutical, enteral nutrient or animal feed
- the inventors of the present invention have found that a product obtained by breaking a peptide bond of a protein present in a specific type of bean through hydrolysis with a microorganism or a proteolytic enzyme derived from the microorganism has a DPP-4 inhibitory effect, and that the product is superior in terms of flavor as well, thereby leading to completion of the present invention.
- the present invention relates to a DPP-4 inhibitor, obtained by treating an azuki bean or a kidney bean with a microorganism or a proteolytic enzyme produced by the microorganism.
- the microorganism is preferably one or more types selected from the group consisting of koji molds, lactic acid bacteria, and natto bacteria
- the proteolytic enzyme is preferably one or more enzymes derived from one or more types of microorganisms selected from the group consisting of koji molds, lactic acid bacteria, and natto bacteria.
- the present invention also relates to a DPP-4 inhibitor, obtained by treating a soybean with a koji mold or a proteolytic enzyme derived from the koji mold.
- the present invention also relates to a method of producing a DPP-4 inhibitor, which comprises treating an azuki bean or a kidney bean with a microorganism or a proteolytic enzyme produced by the microorganism.
- a DPP-4 inhibitor having superior DPP-4 inhibitory activity and a food or beverage, functional food, pharmaceutical, animal feed or the like containing the DPP-4 inhibitor as an active ingredient, are provided by treating a specific type of bean that has been eaten, with a microorganism that has also been commonly used in food or an enzyme derived from the microorganism.
- the DPP-4 inhibitor of the present invention is not only superior in terms of safety in consideration of the above, but is also suitable for oral ingestion in particular from the viewpoints of flavor and absorbability.
- the DPP-4 inhibitor of the present invention is useful as an active ingredient of a composition for the prevention and/or amelioration of diabetes.
- the DPP-4 inhibitor of the present invention is obtained by treating an azuki bean or a kidney bean with a microorganism or a proteolytic enzyme produced by the microorganism.
- the present invention is also directed to a method of producing a DPP-4 inhibitor, which comprises treating an azuki bean or a kidney bean with a microorganism or a proteolytic enzyme produced by the microorganism.
- a product that has been fragmented (reduced in molecular weight) by hydrolysis of a peptide bond of a protein in the above bean is thought to be involved as the active ingredient of the DPP-4 inhibitor.
- a DPP-4 inhibitor containing as an active ingredient a protein hydrolysate derived from an azuki bean or a kidney bean is also included in the scope of the present invention.
- microorganism used to treat an azuki bean or a kidney bean a microorganism that produces a proteolytic enzyme is preferred, and from the viewpoint of safety, a microorganism used in food production is preferred.
- a microorganism used in food production is preferred.
- Specific examples of such microorganisms include koji molds, lactic acid bacteria, and natto bacteria. Among these, koji molds are particularly preferred.
- proteolytic enzyme used to treat an azuki bean or a kidney bean is a microorganism-derived proteolytic enzyme capable of hydrolyzing a peptide bond
- a proteolytic enzyme derived from a koji mold, a lactic acid bacterium, or a natto bacterium is preferred, and a proteolytic enzyme derived from a koji mold is more preferred.
- a product obtained by treating a soybean with a koji mold or a proteolytic enzyme derived from the koji mold can also be used as the DPP-4 inhibitor in the present invention.
- koji mold used in the present invention or the koji mold from which an enzyme used in the present invention is derived, provided it is related to the production of food in Japan or overseas and is safe.
- examples thereof include, for example, ones used in the production of soy sauce, miso (fermented soybean paste), or alcohol.
- Specific examples of such koji molds include molds of the genus Aspergillus such as Aspergillus oryzae, Aspergillus sojae, Aspergillus kawachii, Aspergillus awamori, Aspergillus tamari and Aspergillus glaucus, as well as red koji molds.
- koji molds used to produce soy sauce are preferably used because of their high protease activity, Aspergillus oryzae and Aspergillus sojae are more preferably used, and Aspergillus oryzae is particularly preferably used.
- so-called “koji (rice malt)” or “koji starter,” in which a koji mold as mentioned above is grown on a bean, rice, wheat, barley, bran, or the like, may also be used.
- lactic acid bacterium used in the present invention or the lactic acid bacterium from which an enzyme used in the present invention is derived, provided it is a bacterium that produces lactic acid by metabolism.
- bacterium that produces lactic acid by metabolism.
- Specific examples thereof include bacteria of the genera Lactobacillus, Bifidobacterium, Enterococcus, Lactococcus, Pediococcus and Leuconostoc.
- examples of the natto bacterium used in the present invention or the natto bacterium from which an enzyme used in the present invention is derived include Bacillus subtilis var. natto.
- proteolytic enzymes include peptidases capable of hydrolyzing a peptide bond of a peptide and proteases capable of hydrolyzing a peptide bond of a protein.
- the proteolytic enzyme used in the present invention may be a single peptidase purified or a single protease purified, or may be a composition containing two or more members selected from the group consisting of peptidases, proteases and the like.
- the proteolytic enzyme may also be a composition that contains another enzyme to an extent that does not impair the activity of the peptidase or protease.
- a commercially available product as described later can be used for the proteolytic enzyme used, or a treated cell product or a partially purified enzyme which is obtained by disrupting or partially purifying a microorganism that produces a proteolytic enzyme may also be used. Moreover, a treated cell product of a recombinant microorganism that produces a proteolytic enzyme or an enzyme derived from the recombinant microorganism may also be used. Production of the recombinant microorganism can be carried out by using an ordinary genetic engineering technique.
- the proteolytic enzyme used in the present invention preferably includes a peptidase.
- X-prolyl dipeptidyl aminopeptidase is an enzyme that specifically releases X-proline dipeptides (where X represents an arbitrary amino acid residue) from the amino terminal, and a proteolytic enzyme having this enzyme activity is thought to more easily reduce the molecular weight of a protein.
- the microorganism or the proteolytic enzyme used in the present invention more preferably has X-prolyl dipeptidyl aminopeptidase activity. It is noted that Aspergillus oryzae has been reported to produce X-prolyl dipeptidyl aminopeptidase (H. Tachi, Phytochemistry, 31(11), 3707-3709 (1992)).
- proteolytic enzyme in the present invention, although there are no particular limitations on the type of commercially available proteolytic enzyme, those which are commercially available as food additives can be suitably used. Examples thereof include Umamizyme G, Protease A “Amano” G, Protease A “Amano” S D, Protease M “Amano” G, and Protease M “Amano” S D (all of which are manufactured by Amano Enzyme Inc.), Sumizyme L P, Sumizyme F P, and Sumizyme L P L (all of which are manufactured by Shin Nihon Chemical Co., Ltd.), Pantidase NP-2 (manufactured by Yakult Pharmaceutical Industry Co., Ltd.) and Orientase ONS (manufactured by HBI Enzyme Inc.).
- proteolytic enzyme can be used in the present invention even if its form has been altered.
- the proteolytic enzyme may be in the form of granules, powder or liquid.
- the proteolytic enzyme can be used in the present invention provided it is able to hydrolyze a protein.
- Umamizyme G is more suitably used because of its strong X-prolyl dipeptidyl aminopeptidase activity.
- the azuki bean refers to Vigna angularis
- the soybean refers to Glycine max
- the kidney bean refers to Phaseolus vulgaris
- examples of the kidney bean include cultivars such as tora beans, otebo beans, uzura beans (pinto beans) and ofuku beans.
- non-GMO soybeans since there is a lack of adequate data pertaining to safety and allergenicity when proteins of genetically modified soybeans (GMO soybeans) are hydrolyzed by microorganisms or proteases derived from the microorganisms, a non-genetically modified (non-GMO) soybean is preferably used.
- non-GMO soybeans can be more suitably used than GMO soybeans from the viewpoints of DPP-4 inhibitory activity and flavor.
- beans usable in the present invention may be used as is for the raw material, or alternatively compositions produced by using beans as raw materials, such as natto (fermented soybeans), soy sauce, soy milk, bean jam and other similar products, and foods consisting of residues that remain following the production of other foods from beans, such as okara (soybean curd residue) and defatted soybeans, may be used as raw materials.
- natto Fermented soybeans
- soy sauce soy milk
- bean jam and other similar products and foods consisting of residues that remain following the production of other foods from beans, such as okara (soybean curd residue) and defatted soybeans
- the above-mentioned beans can be used as is as raw materials for producing the DPP-4 inhibitor of the present invention, they may also undergo pretreatment such as drying, crushing, grinding, heating, pressurizing, defatting, acid treatment, alkali treatment, pressing or extraction. In addition, two or more types of these pretreatments may be carried out in combination. Moreover, the above-mentioned bean materials can be used as raw materials for producing the DPP-4 inhibitor of the present invention after separating protein or a fraction containing a large amount of protein therefrom.
- a method may be employed in which a bean material is pretreated in the manner described above as necessary, a microorganism is allowed to grow on the surface of the bean material, and water is added to the grown microorganism for further reaction, whereby a peptide bond of a protein present in the bean is broken by hydrolysis.
- other examples thereof include a method in which a microorganism is grown in a bean material or treated bean material suspended and/or dissolved in a liquid such as water, and a method in which a microorganism is grown in a liquid processed bean product.
- a method may be employed in which a bean material is pretreated in the manner described above as necessary, and a proteolytic enzyme is sprinkled on the surface of the bean material, or the proteolytic enzyme is allowed to act on the bean material or treated bean material suspended and/or dissolved in a liquid such as water, whereby a peptide bond of a protein present in the bean is broken by hydrolysis, as well as a method in which a proteolytic enzyme is added to a liquid processed bean product.
- the product treated with a microorganism or a proteolytic enzyme obtained according to the method described above can be used as is as a DPP-4 inhibitor, it may also be subjected to deodorization, decolorization or the like within a range that does not cause a loss of DPP-4 inhibitory activity.
- fractionation using a method such as extraction, precipitation, filtration, ultrafiltration or column chromatography, or a combination thereof may be carried out in order to concentrate the component having DPP-4 inhibitory activity.
- the DPP-4 activity can be measured by, for example, adding glycyl-L-proline 4-methylcoumaryl-7-amide as substrate to human DPP-4 enzyme and incubating the mixture, followed by assaying the amount of 7-amino-4-methylcoumarin formed using a spectrofluorometer.
- a comparison is made in the assay between the DPP-4 activities in the case in which a specimen to be evaluated for DPP-4 inhibitory activity is present (sample) and the case in which it is not present (vehicle control), and a sample that significantly lowers DPP-4 activity with respect to the DPP-4 activity of the vehicle control is evaluated as “having DPP-4 inhibitory activity.”
- the DPP-4 activity of a sample for the DPP-4 inhibitor of the present invention based on a value of 100% for the DPP-4 activity of a vehicle control is preferably 70% or less, more preferably 60% or less and particularly preferably 50% or less.
- the DPP-4 inhibitor of the present invention may also have ⁇ -glucosidase inhibitory activity in addition to DPP-4 inhibitory activity.
- This ⁇ -glucosidase activity can be measured by, for example, adding sucrose as substrate to yeast-derived ⁇ -glucosidase and incubating the mixture, followed by assaying the amount of glucose formed with a commercially available glucose assay kit.
- a comparison is made in the assay between the ⁇ -glucosidase activities in the case in which a specimen to be evaluated for ⁇ -glucosidase inhibitory activity is present (sample) and the case in which it is not present (vehicle control), and a sample that significantly lowers ⁇ -glucosidase activity with respect to the ⁇ -glucosidase activity of the vehicle control is evaluated as “having ⁇ -glucosidase inhibitory activity.”
- the DPP-4 inhibitor of the present invention preferably also has ⁇ -glucosidase inhibitory activity such that the ⁇ -glucosidase activity of a sample based on a value of 100% for the ⁇ -glucosidase activity of a vehicle control is 90% or less and more preferably 80% or less.
- the DPP-4 inhibitor of the present invention which is obtained by treating an azuki bean or a kidney bean with a microorganism or a proteolytic enzyme produced by the microorganism
- the DPP-4 inhibitor of the present invention which is obtained by treating a soybean with a koji mold or a proteolytic enzyme derived from the koji mold
- a DPP-4 inhibitor can be produced that has a superior flavor.
- the DPP-4 inhibitor of the present invention can be particularly favorably used for a composition for oral ingestion for which having a superior flavor is preferred.
- the composition for oral ingestion herein refers to a composition orally ingested by humans, livestock, pets or the like, and specific examples thereof include foods and beverages, pharmaceuticals, animal feeds and the like.
- the DPP-4 inhibitor of the present invention may be used as a composition for oral ingestion as described above, or may be used as a composition that is administered directly into the gastrointestinal tract and absorbed therefrom in the manner of an enteral nutrient.
- it may be used as is as a food or beverage, pharmaceutical, animal feed or the like, it may also be used in the form of a composition containing it in applications such as foods and beverages, pharmaceuticals and animal feeds.
- the DPP-4 inhibitor of the present invention in applications described above there are no particular limitations on the form thereof, and for example, it may be used as a food or beverage in the form of a general food or a supplement such as a functional food (e.g.
- food with health claims (food for specified health uses, food with nutrient function claims), health food, nutritional supplement, sports supplement).
- it may be used as a pharmaceutical in the form of a prescription pharmaceutical, an easily acquired drug or quasi drug such as an OTC drug, or a cosmetic or the like.
- the DPP-4 inhibitor of the present invention may be ingested directly or may be ingested in the form of a composition in which it is mixed with a known additive (e.g. carrier, adjuvant) by molding into an easily taken form such as a capsule, tablet or granule.
- a known additive e.g. carrier, adjuvant
- it may also be used after adding and combining with any vitamin such as vitamin A, C, D or E for the purpose of nutritional enrichment.
- it may also be compounded with another functional food or the like.
- examples include known functional foods having metabolic regulatory effects such as blood sugar lowering effect, lipid lowering effect or anti-obesity effect, blood pressure lowering effect, osteoporosis preventive and/or ameliorative effect, or the like.
- the DPP-4 inhibitor of the present invention may be used in general foods by mixing with food or beverage materials, examples of which include confections such as chewing gum, chocolate, candy, jelly, cookies or crackers; frozen confections such as ice cream or ice candy; beverages such as tea, soft drinks, nutritional drinks or beauty drinks; noodles such as udon noodles, Chinese noodles, spaghetti or instant noodles; fish jelly products such as kamaboko (boiled fish paste), chikuwa (tube-shaped fish cakes) or happen (ground fish cakes); condiments such as salad dressing, mayonnaise or sauce; and oils and fats such as margarine, butter or salad oil; as well as bread, ham, soup, pre-cooked foods and frozen foods.
- confections such as chewing gum, chocolate, candy, jelly, cookies or crackers
- frozen confections such as ice cream or ice candy
- beverages such as tea, soft drinks, nutritional drinks or beauty drinks
- noodles such as udon noodles, Chinese noodles, spaghetti or instant noodles
- fish jelly products such as kamaboko (boiled fish paste), chiku
- DPP-4 inhibitor of the present invention as a pharmaceutical, there are no particular limitations on the form thereof, and examples include capsules, tablets, granules, injections, suppositories and patches.
- other pharmaceutically acceptable preparation materials can be appropriately added, examples of which include excipients, disintegrating agents, lubricants, binders, antioxidants, colorants, dispersing agents, absorption promoters, dissolution promoters and stabilizers.
- the DPP-4 inhibitor of the present invention may be compounded with another pharmaceutical such as an anti-diabetic drug, anti-obesity drug or anti-osteoporosis drug.
- anti-diabetic drugs or anti-obesity drugs include sulfonylurea drugs, biguanide drugs, ⁇ -glucosidase inhibitors, insulin preparations, insulin secretion promoters, insulin sensitizers, PPAR agonists (such as PPAR ⁇ agonists, PPAR ⁇ agonists or PPAR ⁇ + ⁇ agonists), ⁇ 3 adrenergic receptor agonists, aldose reductase inhibitors, DPP-4 inhibitors, AMP kinase activators, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1) inhibitors, lipase inhibitors and appetite suppressants.
- anti-diabetic drugs or anti-obesity drugs include sulfonylurea drugs
- ⁇ -glucosidase is an enzyme that degrades disaccharides such as maltose or sucrose into monosaccharides in the intestine. Since inhibiting ⁇ -glucosidase makes it possible to inhibit absorption of polysaccharides and disaccharides and thereby significantly inhibit postprandial hyperglycemia, it is known to be effective in preventing or ameliorating diabetes.
- ⁇ -glucosidase inhibitors are not recognized to demonstrate effects against increases in blood sugar levels attributable to glucose intake.
- ⁇ -glucosidase inhibitors also have limitations on the manner in which they are taken, such as being unable to demonstrate their effects unless ingested immediately before eating.
- the DPP-4 inhibitor of the present invention not only has an effect against increases in blood sugar levels attributable to glucose intake, but also offers the considerable advantage of not being subjected to limitations on the timing for administration. Moreover, the DPP-4 inhibitor of the present invention can be expected to demonstrate a more potent blood sugar lowering effect since it more preferably has both DPP-4 inhibitory activity and ⁇ -glucosidase inhibitory activity as previously described.
- a composition containing the DPP-4 inhibitor of the present invention can be used as a composition for the prevention and/or amelioration of diabetes.
- the DPP-4 inhibitor of the present invention can also be used as a blood sugar elevation inhibitor, hypoglycemic agent, insulin secretion promoter, active GLP-1 content-increasing agent, glucagon secretion inhibitor, pancreatic ⁇ cell regeneration promoter and/or agent promoting sugar uptake by muscle.
- the present invention is also directed to a method for the prevention and/or amelioration of diabetes, which comprises administrating to a subject the above-mentioned DPP-4 inhibitor.
- the present invention is also directed to a method for inhibiting an increase in blood sugar level, which comprises administration of the above-mentioned DPP-4 inhibitor to a subject.
- the scope of the prevention of diabetes includes reducing the risk of onset of diabetes.
- preferred examples of the subject in the above cases include diabetes patients and persons at risk for diabetes (persons having blood sugar levels at the high end of the normal range and persons having been indicated as being at high risk for diabetes on the basis of genetic factors or lifestyle), the subject may also be a healthy individual.
- the DPP-4 inhibitory activity was evaluated by measuring the DPP-4 activity using a commercially available assay kit (DPP-4 Drug Discovery Kit, Biomol) in accordance with the instructions provided with the kit and then comparing measured values.
- DPP-4 Drug Discovery Kit Biomol
- the following provides a brief description of the measurement method.
- Amounts of 50 ⁇ L (for blank), 35 ⁇ L (for control), and 25 ⁇ L (for sample), of buffer (50 mM Tris, pH 7.5) were placed in the respective wells of a white 96-well half area plate provided with the kit.
- buffer 50 mM Tris, pH 7.5
- an enzyme solution human DPP-4 enzyme
- glycyl-L-proline 4-methylcoumaryl-7-amide serving as a DPP-4 substrate was added to all of the wells (total liquid volume in each well: 100 ⁇ L) followed by allowing the enzyme reaction to proceed by incubating at 37° C.
- the incubation was carried out in a temperature-controllable fluorescence intensity measuring device (Powerscan H T, Dainippon Pharmaceutical Co., Ltd.), and measurements were carried out immediately after the start of incubation and 12 minutes later at an excitation wavelength of 380 nm and a measuring wavelength of 460 nm to measure the amount of 7-amino-4-methylcoumarin formed as a result of the enzyme reaction.
- the DPP-4 activity of a sample was calculated in the manner indicated below based on a value of 100% for the value of DPP-4 activity of the control.
- DPP-4 activity (%) ⁇ ( A ⁇ B )/( C ⁇ D ) ⁇ 100
- A represents a fluorescence intensity of the sample well at 12 minutes after the start of incubation
- B represents a fluorescence intensity of the sample well immediately after the start of incubation
- C represents a fluorescence intensity of the control well at 12 minutes after the start of incubation
- D represents a fluorescence intensity of the control well immediately after the start of incubation.
- each bean was placed in a container equipped with a filter that allows sterile air to pass through, followed by autoclaving at high pressure for 30 minutes at 121° C.
- a wheat-bran koji obtained using a koji mold Aspergillus oryzae KBN616, Bio'c Co., Ltd.
- a koji mold Aspergillus oryzae KBN616, Bio'c Co., Ltd.
- 3 g of a wheat-bran koji obtained using a koji mold was inoculated onto the sterilized raw material in a clean bench for preventing contamination by microorganisms other than the koji mold, followed by fermenting with only the koji mold for 48 hours at 31° C. while supplying sterile air to the container.
- Each of the enzyme-treated beans was then dissolved in water to a concentration of 10 mg/mL or 30 mg/mL to give a sample (concentration on measurement of DPP-4 activity: 1 mg/mL and 3 mg/mL), and the DPP-4 inhibitory activity of each sample was then evaluated according to the method previously described. The results are shown in Table 2.
- the enzyme-treated azuki bean, tora bean and otebo bean prepared in Example 2 and an enzyme-treated defatted soybean prepared using the same method as Example 2 were evaluated for their actual blood sugar lowering effects in the body by using an oral glucose tolerance test.
- C57BL/6J SPF male mice (Clea Japan, Inc.) were used at age 10 weeks for the study animals. Twenty mice were divided into four groups of 5 mice each. In a single experiment, evaluation was carried out on four groups consisting of a control group (administered distilled water), a positive control group (administered sitagliptin) and two sample groups. Two experiments were carried out and a total of four samples were evaluated.
- Distilled water (control group), the sitagliptin suspension (positive control group) or the enzyme-treated bean aqueous solution (sample group) was administered orally at 10 mL/kg of body weight.
- a 40% aqueous glucose solution was administered orally at 5 mL/kg of body weight 30 minutes after administering the distilled water, sitagliptin suspension, or sample.
- Blood samples were collected from the caudal veins of the mice at, 30, 60 and 120 minutes after the oral administration of glucose, followed by measurement of these blood sugar levels in the same manner as that used for measurement of pretest values. The results of measuring blood sugar levels are shown in Table 4.
- proteolytic enzyme-treated products of the defatted soybean, azuki bean, tora bean and otebo bean all significantly inhibited increases in blood sugar levels following glucose loading.
- the effect of inhibiting increases in blood sugar levels was found to be superior for the proteolytic enzyme-treated azuki bean.
- Example 2 Each of the proteolytic enzyme-treated azuki bean prepared in Example 2 and an enzyme-treated defatted soybean prepared using the same method as Example 2 was dissolved in 0.25 M phosphate buffer (pH 6.8) used as assay buffer to a concentration of 16.7 mg/mL to give a sample. Measurement of ⁇ -glucosidase activity was carried out in the manner described below. Specifically, 60 ⁇ L of the sample was added to wells of a 96-well plate while 60 ⁇ L of assay buffer was added to wells for control.
- 0.25 M phosphate buffer pH 6.8
- yeast-derived ⁇ -glucosidase (Oriental Yeast Co., Ltd.) adjusted to a concentration of 1.25 U/mL (10 ⁇ g protein/mL) was added followed by incubating for 10 minutes at 37° C.
- 20 ⁇ L of a 250 mM solution of sucrose in assay buffer was added followed by incubating for 20 minutes at 37° C. (the concentration of each enzyme-treated product during the reaction was 10 mg/mL).
- 100 ⁇ L of 2 M Tris-HCl buffer (pH 7.0) was added to stop the reaction.
- reaction liquid in each well was transferred to a separate 96-well plate followed by the addition of 200 ⁇ L of a Glucose CII Test Wako reagent (Wako Pure Chemical Industries, Ltd.) and incubating for 5 minutes at 37° C. Following completion of incubation, the absorbance at 505 nm was measured, and the amount of glucose formed was determined from a calibration curve prepared using glucose standards. Furthermore, the a-glucosidase activity was calculated as indicated below based on a value of 100% for the value of ⁇ -glucosidase activity of the control.
- ⁇ -Glucosidase activity (%) ( A/B ) ⁇ 100
- A represents the amount of glucose of a sample
- B represents the amount of glucose of the control.
- An amount of 6 g of a commercially available azuki bean was crushed with a mill and then autoclaved for 15 minutes at 121° C.
- the sterilized material was divided into two portions, and after placing each portion in a separate container, 30 mL of water and 3 mL of a separately prepared proteolytic enzyme solution (a 1% w/v aqueous solution of Umamizyme G (Amano Enzyme Inc., koji mold-derived protease) or a 1% w/v aqueous solution of Bromelain F (Amano Enzyme Inc., pineapple-derived protease)) were added to each container.
- a separately prepared proteolytic enzyme solution a 1% w/v aqueous solution of Umamizyme G (Amano Enzyme Inc., koji mold-derived protease) or a 1% w/v aqueous solution of Bromelain F (Amano Enzyme Inc., pineapple-derived protea
- a test to assess bitter taste was carried out in the form of a sensory evaluation of the resulting enzyme-treated products by five panelists. Evaluations were carried out by scoring according to the criteria indicated below and calculating the average score of the five panelists.
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KR101771867B1 (ko) | 2013-06-12 | 2017-08-25 | 마루하 니치로 가부시키가이샤 | 디펩티딜 펩티다아제 ⅳ (dppⅳ) 저해 펩티드 화합물, 그것을 함유하는 조성물, 및 그 제조 방법 |
CN104256047B (zh) * | 2014-09-09 | 2017-09-29 | 安徽省农业科学院农产品加工研究所 | 一种豆渣蛋白质的提取方法及其用于制备dpp‑iv抑制肽的方法 |
CN113209295A (zh) * | 2015-02-27 | 2021-08-06 | 财团法人峨山社会福祉财团 | 含有dpp-4抑制剂的用于预防或治疗瓣膜钙化的组合物 |
CN106578961A (zh) * | 2016-12-13 | 2017-04-26 | 黑龙江省农业科学院食品加工研究所 | 一种发酵法制作具有降压降糖功效的红豆肽口服液方法 |
JP2019030229A (ja) * | 2017-08-04 | 2019-02-28 | マルコメ株式会社 | 麹菌、麹菌由来の酵素、血糖値上昇抑制剤、飲食品、医薬組成物、食品添加物、サプリメント及びこれらの製造方法、並びに血糖値上昇抑制方法及び糖取り込み促進方法 |
CN110800858B (zh) * | 2019-11-22 | 2021-06-15 | 中国农业大学 | 一种鲟鱼蛋白肽粉及其制备方法与应用 |
JP7453662B2 (ja) | 2019-12-13 | 2024-03-21 | 国立大学法人鳥取大学 | ジペプチジルペプチダーゼiv阻害活性が高い豆類発酵物およびその製造方法 |
JP2023069271A (ja) * | 2021-11-05 | 2023-05-18 | 住友化学株式会社 | Dpp-4阻害剤およびその製造方法。 |
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JP4795511B2 (ja) * | 2000-07-14 | 2011-10-19 | 日本サプリメント株式会社 | α−グルコシダーゼ阻害剤の製造法 |
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- 2010-08-03 US US13/388,913 patent/US20120189611A1/en not_active Abandoned
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- 2010-08-03 WO PCT/JP2010/004872 patent/WO2011016220A1/ja active Application Filing
- 2010-08-03 EP EP10806220.9A patent/EP2462943A4/en not_active Withdrawn
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US20140142036A1 (en) | 2014-05-22 |
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US9399051B2 (en) | 2016-07-26 |
CN102470166B (zh) | 2014-04-09 |
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