WO2012086406A1 - Sécrétagogue de glp-1 - Google Patents

Sécrétagogue de glp-1 Download PDF

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WO2012086406A1
WO2012086406A1 PCT/JP2011/078168 JP2011078168W WO2012086406A1 WO 2012086406 A1 WO2012086406 A1 WO 2012086406A1 JP 2011078168 W JP2011078168 W JP 2011078168W WO 2012086406 A1 WO2012086406 A1 WO 2012086406A1
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Prior art keywords
salt
lysophosphatidylinositol
secretion
glp
lpi
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PCT/JP2011/078168
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English (en)
Japanese (ja)
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良恵 藤井
浩二郎 橋爪
玲 下豊留
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花王株式会社
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Priority to JP2011267765A priority Critical patent/JP2012144518A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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

Definitions

  • the present invention relates to a GLP-1 (glucagon-like peptide-1) secretion promoter.
  • Glucagon-like peptide-1 is a hormone produced from a gene and precursor common to glucagon, which is an endocrine hormone. While glucagon is produced by ⁇ cells in the splenic islets, GLP-1 is produced by endocrine cells (L cells) in the intestine, and is produced from its precursor through processing different from that of glucagon. GLP-1 is a hormone with an incretin (Instine Secretion Insulin) action that plays an important role in glucose metabolism. It is secreted into the blood by ingestion of nutrients and acts on the pancreatic ⁇ cells to promote insulin secretion. , Lower blood sugar levels.
  • GLP-1 also acts on the pancreas to suppress glucagon secretion, thereby reducing glucose release from the liver and lowering blood glucose levels.
  • Other actions of GLP-1 are known to promote proliferation of pancreatic ⁇ cells, suppress gastric excretion and gastric acid secretion, and suppress appetite and food intake (Non-patent Document 1). Therefore, enhancing the effect of GLP-1 is useful for improving lifestyle-related diseases such as obesity and diabetes.
  • GLP-1 replacement therapy and GLP-1 receptor (GLP-1R) agonists has also been promoted.
  • GLP-1 is also known to have an action on the central nervous system. GLP-1's appetite and feeding-suppressing effects are thought to be mediated by GLP-1R present in the central nervous system (Non-patent Document 1). In addition, while learning ability decreases in GLP-1R-deficient mice, memory learning ability improves in mice in which GLP-1R is overexpressed (Non-patent Document 2). In experiments in a culture system, GLP-1 has been observed to promote neurite outgrowth and protect against apoptosis due to nerve injury (Non-patent Document 3). Therefore, GLP-1 is expected as a useful substance for suppressing neurodegeneration and improving neurodegenerative diseases such as dementia and neuropathy associated with diabetes.
  • GLP-1 is considered useful for blood glucose level control in diabetic patients.
  • GLP-1 suppresses glucagon secretion in the pancreas, glucose release from the liver decreases and blood glucose decreases. It has been reported that this action does not antagonize glucagon secretion due to hypoglycemia and does not depend on insulin concentration. It has also been reported that administration of GLP-1 decreased the amount of insulin required to make blood glucose constant in both type 1 and type 2 diabetic patients.
  • GLP-1 can exert an effect on blood glucose level control in the long term by acting on the central nervous system and suppressing appetite. Therefore, GLP-1 may improve the symptoms of patients with diabetes and insulin resistance through these actions.
  • Exenatide and Lilaglutide which are GLP-1 analog preparations, are actually used as antidiabetic drugs and reported to have an effect of improving insulin resistance (Non-patent Document 4).
  • GLP-1 is usually very easily degraded and has a very short half-life in vivo. Therefore, even if GLP-1 is administered from outside the body, it is very difficult to keep the blood concentration constant. Therefore, in order to increase the in vivo GLP-1 concentration over a long period of time, it is desirable to promote endogenous GLP-1 secretion rather than external administration.
  • Lysophosphatidylinositol is a substance obtained by allowing phospholipase A 2 (PLA 2 ) to act on phosphatidylinositol (PI), and together with PI, cell signaling mechanisms such as intracellular calcium It is involved in elevation, calcium release, PLA 2 activation, adenylate cyclase activation, PKC activation, cell proliferation, K channel release, insulin release, and the like.
  • Non-Patent Document 1 brain function improvement, learning ability enhancement, memory enhancement, dementia prevention / treatment
  • Patent Literature 2 interferon production enhancement
  • hyaluronic acid secretion induction hyaluronic acid secretion induction
  • reepithelialization promotion of re-mesothelial Wound treatment by promoting cell formation (patent document 3), collagen production promotion (patent document 4), TRPV2 or TRPV8 activation
  • ligand of GPR55 non-patent document 12
  • RhaA-dependent calcium signal Further, activation of the transcription factor NFAT (Non-Patent Document 13) and K-channel TREK-1 activation (Non-Patent Document 14) are known.
  • Patent Document 15 discloses a blood glucose lowering effect by continuous ingestion of LPI.
  • PTP1B protein tyrosine phosphatase
  • LPI has an effect of suppressing temporary postprandial blood glucose increase due to meals.
  • GLP-1 GLP-1
  • the present invention relates to the use of lysophosphatidylinositol or a salt thereof for the production of a GLP-1 secretion promoter.
  • the present invention also relates to the use of lysophosphatidylinositol or a salt thereof for producing a glucagon secretion inhibitor.
  • the present invention also relates to the use of lysophosphatidylinositol or a salt thereof for the production of an appetite suppressant.
  • the present invention also relates to the use of lysophosphatidylinositol or a salt thereof for the prevention of postprandial hyperglycemia and / or the manufacture of an ameliorating agent.
  • the present invention also relates to the use of lysophosphatidylinositol or a salt thereof for the manufacture of an agent for preventing and / or improving diabetes.
  • the present invention relates to the use of lysophosphatidylinositol or a salt thereof for promoting GLP-1 secretion.
  • the present invention also relates to the use of lysophosphatidylinositol or a salt thereof for suppressing glucagon secretion.
  • the present invention also relates to the use of lysophosphatidylinositol or a salt thereof for appetite suppression.
  • the present invention also relates to the use of lysophosphatidylinositol or a salt thereof for preventing and / or improving postprandial hyperglycemia.
  • the present invention also relates to the use of lysophosphatidylinositol or a salt thereof for the prevention and / or improvement of diabetes.
  • the present invention relates to lysophosphatidylinositol or a salt thereof for use in promoting GLP-1 secretion.
  • the present invention also relates to lysophosphatidylinositol or a salt thereof for use in suppressing glucagon secretion.
  • the present invention also relates to lysophosphatidylinositol or a salt thereof for use in appetite suppression.
  • the present invention also relates to lysophosphatidylinositol or a salt thereof for use in preventing and / or improving postprandial hyperglycemia.
  • the present invention also relates to lysophosphatidylinositol or a salt thereof for use in the prevention and / or improvement of diabetes.
  • the present invention relates to a method for promoting GLP-1 secretion, comprising administering or ingesting lysophosphatidylinositol or a salt thereof to a subject.
  • the present invention also relates to a method for inhibiting glucagon secretion, comprising administering or ingesting lysophosphatidylinositol or a salt thereof to a subject.
  • the present invention also relates to an appetite suppression method comprising administering or ingesting lysophosphatidylinositol or a salt thereof to a subject.
  • the present invention also relates to a method for improving postprandial hyperglycemia comprising administering or ingesting lysophosphatidylinositol or a salt thereof to a subject.
  • the present invention also relates to a method for improving diabetes, which comprises administering or ingesting lysophosphatidylinositol or a salt thereof to a subject.
  • GLP-1 secretion promoting action in NCI-H716 cells by LPI *: P ⁇ 0.05, ***: p ⁇ 0.001. GLP-1 secretion promoting effect in mice by LPI. *: P ⁇ 0.05. Inhibition of postprandial blood glucose elevation by LPI. *: P ⁇ 0.001.
  • the present invention provides a substance that promotes secretion of GLP-1, and promotes GLP-1 secretion, glucagon secretion suppression, appetite suppression, or postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorder, neuropathy, etc. Or it relates to the use of the substance in the prevention and / or improvement of the condition.
  • the present invention also provides GLP-1 secretion promotion, glucagon secretion suppression, appetite suppression, or prevention of diseases or conditions such as postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorders, and neurological disorders by administering the substance. And / or to provide a method of improvement.
  • the present inventors examined a material capable of promoting the secretion of GLP-1, and found that lysophosphatidylinositol (LPI) or a salt thereof can promote the secretion of GLP-1.
  • LPI lysophosphatidylinositol
  • the GLP-1 secretion promoter of the present invention has an excellent GLP-1 secretion promoting action, and suppresses glucagon secretion, suppresses appetite, or postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorder, It is useful for preventing and / or improving diseases such as neurological disorders.
  • GLP-1 secretion promotion means promoting GLP-1 secretion in vivo caused by ingesting a meal, particularly a meal rich in carbohydrates or lipids.
  • GLP-1 secretion promotion means to enhance the increase in blood GLP-1 concentration accompanying GLP-1 secretion in vivo mainly occurring after meals, or to maintain the increased GLP-1 concentration, or Suppressing the decrease in the increased GLP-1 concentration.
  • “after meal” in the present invention refers to the time until carbohydrates in the ingested meal are generally absorbed, from immediately after taking the meal (0 minutes) to 6 hours later, preferably after 5 hours, More preferably, it refers to the time until 4 hours, and more preferably after 3 hours (Diabete Care, 2001, 24 (4): 775-778).
  • non-therapeutic is a concept that does not include a medical act, that is, a treatment act on the human body by treatment.
  • “improvement” means improvement of a disease, symptom or condition, prevention or delay of deterioration of the disease, symptom or condition, or reversal, prevention or delay of progression of the disease or symptom.
  • prevention means prevention or delay of the onset of a disease or symptom in an individual, or reduction of the risk of onset of a disease or symptom in an individual.
  • lysophosphatidylinositol or LPI refers to a compound represented by the following formula.
  • R represents a saturated or unsaturated straight chain hydrocarbon chain having 13 to 19 carbon atoms, preferably a straight chain saturated hydrocarbon chain having 15 carbon atoms or a straight chain unsaturated hydrocarbon having 17 carbon atoms. It is a hydrogen chain or a mixture thereof.
  • the salt of LPI is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts of alkali metals such as sodium, potassium and lithium, and alkaline earth metals such as calcium and magnesium. Examples thereof include salts and ammonium salts.
  • LPI uses phospholipase A 2 as a raw material from natural phospholipids derived from soybeans, egg yolks, etc., or hydrolyzed, hydrogenated, transesterified, solvent fractionated, purified, and enzyme-treated phospholipids.
  • a catalyst obtained by a method of decomposing a bond at the 2-position of phospholipid can be used.
  • a phospholipid such as a phosphate obtained by phosphorylation of monoglyceride or diglyceride can be used.
  • the LPI or salt thereof thus obtained may be a crude product as long as it conforms to the standards acceptable on pharmaceuticals or foods and exhibits the effects of the present invention. These purities may be increased by appropriately combining purification methods. Examples of the purification means include organic solvent precipitation, centrifugation, ultrafiltration membrane, high performance liquid chromatograph, column chromatograph and the like. Commercially available LPI or a salt thereof can also be used.
  • LPI or a salt thereof has an action of promoting GLP-1 secretion from gastrointestinal cells. Therefore, LPI or a salt thereof is useful for promoting GLP-1 secretion. Furthermore, it is known that the promotion of GLP-1 secretion leads to suppression of glucagon secretion and appetite, and an effect on the nervous system is known (Non-Patent Documents 1 to 3). Therefore, LPI or a salt thereof is also useful for glucagon secretion suppression, appetite suppression, or prevention and / or improvement of neurological diseases.
  • LPI or a salt thereof in animals administered with LPI or a salt thereof together with a glucose solution, GLP-1 secretion was promoted immediately after administration, and postprandial blood glucose elevation caused by administration of the glucose solution was suppressed. That is, LPI or a salt thereof promptly promotes GLP-1 secretion when ingested, and has an action of suppressing a temporary increase in blood sugar due to diet via the secreted GLP-1. Furthermore, it has been reported that the rate of developing diabetes is reduced by continuously suppressing postprandial blood glucose elevation (Foods Food Ingredients J. Jpn., 310 (12), 2005). Therefore, LPI or a salt thereof is useful for preventing and / or improving postprandial hyperglycemia, and further preventing and / or improving diseases such as diabetes and insulin resistance.
  • postprandial hyperglycemia has been reported to be an independent risk factor for cardiovascular events (Diabetes Care. 1999; 22: 920-924).
  • cardiovascular events For example, when vascular endothelial cells are cultured in a hyperglycemic state, it is reported that cell apoptosis occurs more frequently when the vascular endothelial cell is intermittently hyperglycemic than when it is continuously hyperglycemic.
  • Am. J Physiol. Endocrinol. Metab. 2001; 281: E924-93 the risk factor for cardiovascular disorders is thought to be postprandial hyperglycemia rather than fasting hyperglycemia.
  • LPI or a salt thereof can be used, for example, with or before or after a meal, preferably from 30 minutes before to 30 minutes after a meal, more preferably a meal. It can be administered or ingested from 10 minutes before to 10 minutes later.
  • GLP-1 secretion caused by the meal can be promoted or glucagon secretion can be suppressed, and appetite for the meal can be suppressed.
  • postprandial hyperglycemia caused by the meal can be prevented and / or improved, and further, diseases such as diabetes, insulin resistance and cardiovascular disorders can be prevented and / or improved. Can do.
  • LPI or a salt thereof is not only for patients with diabetes or insulin resistance, but also for subjects not suffering from diabetes or insulin resistance, such as healthy subjects, high postprandial hyperglycemia but fasting blood glucose. It can be applied to subjects with no abnormalities, subjects who do not need to lower fasting blood glucose but want to reduce postprandial hyperglycemia, etc., and postprandial hyperglycemia or diabetes or insulin resistance, circulation in the subject It is possible to prevent and / or improve diseases such as organ disorders. Moreover, according to the present invention, LPI or a salt thereof can be applied to a subject not suffering from insulin resistance caused by suppression of insulin and leptin signaling accompanying activation of PTP1B. It can prevent and / or improve postprandial hyperglycemia, or diseases such as diabetes, insulin resistance, and cardiovascular disorders.
  • the present invention provides the use of LPI or a salt thereof for promoting GLP-1 secretion.
  • the present invention also provides use of LPI or a salt thereof for glucagon secretion suppression or appetite suppression.
  • the present invention also provides use of LPI or a salt thereof for preventing and / or improving postprandial hyperglycemia.
  • the present invention also provides use of LPI or a salt thereof for the prevention and / or amelioration of diseases such as diabetes, insulin resistance and cardiovascular disorders.
  • the use may be in humans or non-human animals, or specimens derived therefrom, and may be therapeutic or non-therapeutic.
  • the present invention provides LPI or a salt thereof for use in promoting GLP-1 secretion.
  • the present invention also provides LPI or a salt thereof for use in glucagon secretion suppression or appetite suppression.
  • the present invention also provides LPI or a salt thereof for use in preventing and / or improving postprandial hyperglycemia.
  • the present invention also provides LPI or a salt thereof for use in the prevention and / or amelioration of diseases such as diabetes, insulin resistance and cardiovascular disorders.
  • LPI or a salt thereof is administered or ingested with or before or after a meal, preferably from 30 minutes before to 30 minutes after meal, more preferably from 10 minutes before to 10 minutes after meal, GLP-1 secretion caused by a meal is promoted or glucagon secretion is suppressed, appetite for the meal is suppressed, or postprandial hyperglycemia due to the meal is prevented and / or improved.
  • the administration is preferably oral administration. Such administration or ingestion is preferably performed at each meal.
  • LPI or a salt thereof is a subject not afflicted with diabetes or insulin resistance, such as a healthy subject or a subject with high postprandial hyperglycemia but no abnormal fasting blood glucose, or activation of PTP1B It can be applied to subjects not suffering from insulin resistance caused by the inhibition of insulin and leptin signaling associated with, and can prevent and / or improve postprandial hyperglycemia.
  • the present invention provides the use of LPI or a salt thereof for the production of a GLP-1 secretion promoter.
  • the present invention also provides an LPI or a salt thereof, a glucagon secretion inhibitor, an appetite suppressant, a postprandial hyperglycemia preventive and / or ameliorating agent, or a preventive and / or ameliorating agent for diseases such as diabetes, insulin resistance and cardiovascular disorders.
  • the glucagon secretion inhibitory action, the appetite suppressive action and the preventive and / or ameliorating action of diseases such as postprandial hyperglycemia, diabetes, insulin resistance and cardiovascular disorders are brought about by the promotion of GLP-1 secretion. That is, glucagon secretion suppression, appetite suppression, and prevention and / or improvement of diseases such as neurological diseases, postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorders, etc. are promoted by GLP-1 secretion. Brought about by.
  • the agent is administered or ingested with or before or after a meal, preferably 30 minutes to 30 minutes after meal, more preferably 10 minutes to 10 minutes after meal, depending on the meal.
  • the administration is preferably oral administration. Such administration or ingestion is preferably performed at each meal.
  • the postprandial hyperglycemia prevention and / or amelioration agent is a subject who does not suffer from diabetes or insulin resistance, such as a healthy subject or a subject who has high postprandial hyperglycemia but no abnormal fasting blood glucose.
  • it can be applied to subjects not suffering from insulin resistance caused by inhibition of insulin and leptin signaling associated with the activation of PTP1B.
  • LPI or a salt thereof is used to promote GLP-1 secretion, suppress glucagon secretion, suppress appetite, or postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorders, etc. It can be blended as a raw material in a composition for prevention and / or improvement of a drug, a medicine, a quasi-drug, a food or drink, or its raw material, or a feed or its raw material, or can be used for its production .
  • composition, medicine, quasi-drug, food / beverage product, feed, or the raw material of the food / beverage product or feed can be produced or used for human or non-human animals.
  • LPI or a salt thereof is blended as a raw material of the composition, medicine, quasi-drug, food / drink, feed, or food / drink or feed, and promotes GLP-1 secretion, suppresses glucagon secretion, and appetite It may be an active ingredient for suppression or prevention and / or improvement of diseases such as postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorders and the like.
  • the above-mentioned medicine or quasi-drug contains LPI or a salt thereof as an active ingredient.
  • the pharmaceutical or quasi drug can be administered in any dosage form.
  • the dosage form may be oral or parenteral.
  • the said pharmaceutical and quasi-drug may contain LPI or its salt independently, or may contain it in combination with a pharmaceutically acceptable carrier.
  • the drug or quasi-drug may contain other active ingredients and pharmacological ingredients as long as the GLP-1 secretion promoting action of LPI or a salt thereof is not lost.
  • the above-mentioned medicine or quasi-drug can be produced by a conventional method from LPI or a salt thereof, or in combination with the above carrier and / or other active ingredients and pharmacological ingredients as necessary.
  • the content of LPI or a salt thereof in the drug or quasi-drug is preferably 0.0001 to 30% by mass, more preferably 0.001 to 25% by mass, and 0.01 to 20% by mass. More preferably, it is made into%.
  • the above food and drink and feed have functions such as promotion of GLP-1 secretion, suppression of glucagon secretion, suppression of appetite, or prevention and / or improvement of diseases such as postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorders, It may be a food, a functional food, a food for a sick person, a food for specified health use, a pet food or the like that displays the function as necessary.
  • the food and drink or feed, or their raw materials may contain LPI or a salt thereof alone, or other foods, solvents, softeners, oils, emulsifiers, preservatives, fragrances, stabilizers, You may contain combining additives, such as a coloring agent, antioxidant, a moisturizer, and a thickener.
  • the content of LPI or a salt thereof in the food or drink or feed is preferably 0.0001 to 30% by mass, more preferably 0.001 to 10% by mass, and 0.001 to 5% by mass. More preferably.
  • LPI or a salt thereof is used to promote GLP-1 secretion, to suppress glucagon secretion, to suppress appetite, or to treat diseases such as postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorders, etc. For prevention and / or improvement, it is administered in an effective amount to a subject in need thereof.
  • LPI or a salt thereof can prevent and / or improve diseases such as postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorder, etc., for promoting GLP-1 secretion, for suppressing glucagon secretion, for suppressing appetite Therefore, it is ingested in an effective amount by subjects who need them.
  • the present invention further provides a method for promoting GLP-1 secretion, comprising administering or ingesting LPI or a salt thereof to a subject.
  • the present invention also provides a method for suppressing glucagon secretion or a method for suppressing appetite, which comprises administering or ingesting LPI or a salt thereof to a subject.
  • the present invention also provides a method for preventing and / or improving postprandial hyperglycemia, including administering or ingesting LPI or a salt thereof to a subject, or preventing and / or preventing diseases such as diabetes, insulin resistance and cardiovascular disorders. Or provide an improvement method.
  • the subject to be administered or ingested LPI or a salt thereof is an animal suffering from a disease or condition such as postprandial hyperglycemia, diabetes, insulin resistance, cardiovascular disorder, or an animal suspected thereof Or animals at high risk.
  • the administration or ingestion target can be an animal that requires GLP-1 secretion promotion, glucagon secretion suppression, appetite suppression, gastric excretion suppression, or gastric acid secretion suppression.
  • the animal is preferably a human or non-human mammal, more preferably a human.
  • the human who wants to improve lifestyle-related diseases is also the subject in the GLP-1 secretion promotion method, glucagon secretion suppression method or postprandial hyperglycemia prevention and / or improvement method of the present invention.
  • the target animal is a human
  • patients with reflux esophagitis, hyperacidity, gastric ulcer and duodenal ulcer are subjects in the method for inhibiting gastric acid secretion.
  • the method may be performed non-therapeutically with the intention of improving health and the like.
  • Preferred dosages and intakes may vary according to the subject's species, weight, sex, age, condition or other factors.
  • the dose, route, interval, and amount and interval of intake can be determined appropriately by those skilled in the art.
  • the administration or intake is preferably 0.005 g to 50 g / day, more preferably 0.1 g to 10 g / day, as LPI or a salt thereof per adult. .
  • LPI or a salt thereof is added with or before or after a meal, preferably from 30 minutes before to 30 minutes after the meal, more preferably from 10 minutes before to 10 minutes after the meal.
  • the administration is preferably oral administration. Such administration or ingestion is preferably performed at each meal.
  • a subject who administers or ingests LPI or a salt thereof is a subject who does not suffer from diabetes or insulin resistance, such as a healthy subject or a postprandial high level. It can be a subject with high blood glucose but no abnormal fasting blood glucose, or a subject not suffering from insulin resistance caused by suppression of insulin and leptin signaling associated with PTP1B activation.
  • the obtained chloroform solution was concentrated and further washed with 600 mL of methanol to obtain 15 g of purified phosphatidylinositol.
  • 200 mL of hexane and 100 mL of ethyl acetate were added and dissolved, and then 100 mL of 200 mM TRIS-hydrochloric acid buffer (pH 8.5), 100 mL of 80 mM calcium chloride aqueous solution, and phospholipase A 2 (Lecitase 10 L) 2 ml of Novozymes) was added and stirred at 40 ° C. for 15 hours.
  • the constituent fatty acids of purified lysophosphatidylinositol were analyzed by gas chromatography.
  • the analysis of the constituent fatty acid composition was carried out according to the standard fat analysis method (Japan Oil Chemists' Society) 3.2.3_1996. That is, the sample was hydrolyzed with 0.5 M potassium hydroxide-methanol solution, methyl esterified with boron trifluoride-methanol reagent, and the resulting fatty acid methyl ester was analyzed by gas chromatography.
  • Gas chromatography analysis conditions are as follows.
  • Example 1 GLP-1 Secretion Promoting Action in Cells by LPI
  • the purified LPI obtained in Production Example 1 was dissolved in 50% ethanol water to a concentration of 10 mM to prepare a test sample.
  • 50% ethanol water was used.
  • NCI-H716 cells human colon-derived cells; purchased from ATCC, developed by Dr. Herbert K. Oie et al., Supplied by agenetics of the United States Public Health Service
  • RPMI1640 containing 10% fetal bovine serum, high glucose; Invitrogen
  • the medium was collected in a microcentrifuge tube to which diprotin-A (DPP4 inhibitor, Sigma) and PMSF (Phenylmethylsulfonylfluoride, serine protease inhibitor, Sigma) were added, and after floating cells were removed, until GLP-1 quantification Stored at -80 ° C.
  • GLP-1 in the medium was quantified by ELISA using GLUCAGON-LIKE PEPTIDE-1 (ACTIVE) ELISA KIT (LINCO Research). Significance test was performed using Student t-test. The results are shown in FIG. LPI significantly promoted GLP-1 secretion at concentrations of 10 ⁇ M and higher.
  • Example 2 GLP-1 Secretion Promoting Action in Mice by LPI
  • the purified LPI obtained in Production Example 1 was dissolved in a 5% glucose solution to a concentration of 1% (w / v) to obtain a test sample.
  • a 5% glucose solution was used as a control.
  • Mice C57BL / 6J male, 12 weeks old were 14 per group, and 5% glucose + 1% LPI solution was orally administered by a sonde (LPI group). A 5% glucose solution was administered to the control group.
  • the blood was immediately collected in a micro blood collection tube (with EDTA) containing DPPIV inhibitor (Millipore) and aprotinin (Wako Pure Chemical Industries), and centrifuged within 30 minutes after blood collection to obtain plasma.
  • Plasma was immediately frozen in liquid nitrogen and stored at ⁇ 80 ° C. until GLP-1 quantification.
  • Plasma GLP-1 was quantified by ELISA using GLUCAGON-LIKE PEPTIDE-1 (ACTIVE) ELISA KIT (Millipore). Significance test was performed using Student t-test. The results are shown in FIG. In mice that received LPI, GLP-1 secretion was increased.
  • Example 3 Inhibitory Effect on Postprandial Blood Glucose Increase in Mice by LPI
  • the purified LPI obtained in Production Example 1 was dissolved in a 5% glucose solution to a concentration of 1% (w / v) to prepare a test sample.
  • a 5% glucose solution was used as a control.
  • Mice C57BL / 6J male, 12 weeks old were 14 per group, and 5% glucose + 1% LPI solution was orally administered by a sonde (LPI group).
  • a 5% glucose solution was administered to the control group.
  • Ten minutes after the administration blood was collected from the orbital venous plexus, and the blood glucose level was measured using Accu Check (Roche Diagnostics). Significance test was performed using Student t-test. The results are shown in FIG. In mice that received LPI, postprandial blood glucose elevation was suppressed.

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  • Organic Chemistry (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une substance utile pour des applications telles que la stimulation de la sécrétion de GLP-1, la suppression de la sécrétion de glucagon, la suppression de l'appétit, ou la prévention et/ou l'atténuation de l'hyperglycémie postprandiale, le diabète, et d'autres maladies ou affections. Un lysophosphatidylinositol ou un sel de celui-ci est utilisé pour stimuler la sécrétion de GLP-1. Un lysophosphatidylinositol ou un sel de celui-ci est utilisé pour produire un sécrétagogue de GLP-1. Un procédé pour stimuler la sécrétion de GLP-1 comprend l'administration ou l'alimentation d'un lysophosphatidylinositol ou un sel de celui-ci à un sujet.
PCT/JP2011/078168 2010-12-22 2011-12-06 Sécrétagogue de glp-1 WO2012086406A1 (fr)

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Cited By (2)

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EP3000471A1 (fr) * 2014-09-28 2016-03-30 Bernhard-Nocht-Institut für Tropenmedizin Nouvelles molécules immunostimulantes
EP3676243A4 (fr) * 2017-09-01 2021-05-26 Curtin University Dérivés synthétiques de oléoyl-lysophosphatidylinositol (oléolyl-lpi) et utilisations associées

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JP7147085B1 (ja) 2022-01-06 2022-10-04 キユーピー株式会社 澱粉含有食品の血糖上昇抑制用添加剤及び澱粉含有食品の製造方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3000471A1 (fr) * 2014-09-28 2016-03-30 Bernhard-Nocht-Institut für Tropenmedizin Nouvelles molécules immunostimulantes
WO2016046419A1 (fr) * 2014-09-28 2016-03-31 Bernhard-Nocht-Institut für Tropenmedizin Nouveaux composés immunostimulants
EP3676243A4 (fr) * 2017-09-01 2021-05-26 Curtin University Dérivés synthétiques de oléoyl-lysophosphatidylinositol (oléolyl-lpi) et utilisations associées

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