WO2019143219A1 - Composition pharmaceutique pour la prévention ou le traitement du diabète, contenant du biglycane en tant que principe actif - Google Patents

Composition pharmaceutique pour la prévention ou le traitement du diabète, contenant du biglycane en tant que principe actif Download PDF

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WO2019143219A1
WO2019143219A1 PCT/KR2019/000867 KR2019000867W WO2019143219A1 WO 2019143219 A1 WO2019143219 A1 WO 2019143219A1 KR 2019000867 W KR2019000867 W KR 2019000867W WO 2019143219 A1 WO2019143219 A1 WO 2019143219A1
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diabetes
ampk
bigley
phosphorylation
present
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PCT/KR2019/000867
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Korean (ko)
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김현수
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고려대학교 산학협력단
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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
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • 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 pharmaceutical composition for preventing or treating insulin resistance-specific diabetes mellitus containing biglycan as an active ingredient, and more particularly to a pharmaceutical composition for preventing or treating insulin resistance-specific diabetes mellitus by inducing blood glucose lowering through AMPK phosphorylation and glucose uptake It concerns the use of Viglycans.
  • Type 2 diabetes is a disease that affects patients' mortality by inducing various complications due to the inadequate utilization of glucose absorbed into the body.
  • HbA1c the target of HbA1c of 7.0% or less.
  • incretin hormone-based therapeutics are widely used.
  • GLP-1 glucone-like peptide-1
  • GIP glucose dependent insulinotropic polypeptide
  • DPP-4 dipeptidyl peptidase-4
  • Akt Akt substrate 160
  • PKCzeta Akt substrate 160
  • PKCzeta Akt substrate 160
  • Akt substrate 160 Akt substrate 160
  • PKCzeta Akt substrate 160
  • PKCzeta Akt substrate 160
  • the pathogenesis at the molecular level for glucose, sugar, and urine is considered to be the cause of the disease rather than the defect of the insulin receptor itself, since the signal transduction between proteins through the receptor-mediated process, especially the PI-3 kinase (phosphoinositide-3 kinase) have. Therefore, since the therapeutic effect of insulin on diabetes is limited, it is important to discover new target proteins and their molecular mechanisms related to glucose control.
  • AMP-activated protein kinase is a member of the serine / threonine kinase and is mainly distributed in the skeletal muscle, heart, liver and other metabolic organs. Activation of AMPK and AMPK kinase (AMPKK) Gt; phosphorylation < / RTI > In addition, AMPK is an energy sensor that responds sensitively to small changes in AMP concentration in the cell.
  • AMPK is an important target herbal protein in diabetes therapy research (Kahn BB et al., Cell Metab. 1: 15-25 2005).
  • Biglycan is a small proteoglycan with a mixed chain of chondroitin sulfate / dermantane sulfate, and its function is not known.
  • Leucine is a structure containing 24 amino acids and has 12 repeats. Similar proteoglycans include decolin (PG-II) and pibromodulin. There is a marked difference in the binding capacity between the tissue distribution and the collagen fibers.
  • Proteoglycans are highly glycosylated proteins, a generic term for molecular groups in which glycosaminoglycan side chains are covalently attached to proteins. Proteoglycans are found in connective tissue and are responsible for a variety of cellular physiological functions (Fisher LW et al., J. Biol. Chem. 264: 4571-4576, 1989).
  • Bigley Kahn is one of the new myokine proteins, and myocaine is an active substance expressed, synthesized and secreted from the skeletal muscle according to physical activity, i.e., exercise (Pedersen et al., Journal of Applied Physiology, 103 (3): 1093-98, 2007).
  • IL-6 is known as a representative mycaine, and this myocaine improves immunity, prevents weight control and arteriosclerosis. Therefore, it can be seen that the effect of preventing diabetes and the like due to exercise is due to the secretion of myocaine such as Vlyglycane.
  • the present inventors have made intensive efforts to develop a new therapeutic agent for diabetes through the modulation of AMPK activity.
  • Bigley can induce blood glucose lowering through AMPK phosphorylation and glucose uptake, and thus Bigley can be used as an agent for treating diabetes mellitus And completed the present invention.
  • the present invention provides a pharmaceutical composition for preventing or treating insulin resistance-specific diabetes mellitus containing biglycan as an active ingredient.
  • the present invention also provides a health functional food for preventing or ameliorating insulin resistance-specific diabetes mellitus containing biglycans as an active ingredient.
  • the present invention also provides a method of preventing or treating insulin resistance-specific diabetes mellitus comprising the step of administering a biglycann to an individual.
  • the present invention also provides the use of a biglycans for use in the prevention or treatment of insulin resistance-specific diabetes.
  • the present invention also provides the use of biglycans for the manufacture of a medicament for the prophylaxis or treatment of insulin resistance-specific diabetes.
  • Figure 1 shows the results of confirming the increase of AMPK phosphorylation (A and B) and glucose uptake (C-E) by Bigley Kahn.
  • Fig. 2 shows the result of confirming the change in calcium caused by Vlyglykane in muscle cells.
  • Figure 3 shows the result of confirming AKT phosphorylation by Bigley Kahn.
  • Fig. 4 shows the results of confirming Glut4 migration by the Viglickan in the muscle cells.
  • FIG. 5 shows the results of AMPK phosphorylation (A), Viglickan expression (B), Ionomycin and Forskolin induced AMPK phosphorylation (C) and Viglykane expression (D) by electrical stimulation in muscle cells.
  • FIG. 6 shows the result of confirming AMPK phosphorylation (A) and calcium change (B) by the Viglycans in primary cells.
  • FIG. 7 shows the result of measuring the concentration of Bigley Kahn in the mouse after exercise.
  • FIG. 8 shows the results of confirming the phosphorylation (A-B) of smad3 induced by TGF- ⁇ and the decrease of smad3 phosphorylation (C) by Bigley Kahn.
  • Figure 9 compares AMPK phosphorylation by salmon proteoglycan with the Bigley Kahn of the present invention.
  • FIG. 10 is a result of intraperitoneal glucose intubation test after administering the Viglickan of the present invention to a mouse of type 2 diabetes mellitus.
  • FIG. 11 shows blood glucose levels measured after administering the Bigley Kahn of the present invention to a mouse of type 2 diabetes mellitus.
  • biglycan a muscle cell secretion protein that induces blood glucose lowering through AMPK phosphorylation and glucose uptake increase, and that the concentration of beaglurane in the blood of the excreted animal was also increased .
  • insulin resistance was inhibited by the administration of Vlyglycan in a diabetic animal model, and the effect of treating Vyglycaine in diabetes was confirmed.
  • the present invention relates to a pharmaceutical composition for preventing or treating insulin resistance-specific diabetes mellitus containing biglycan as an active ingredient from an aspect.
  • the Bigley Kahn may be characterized by being represented by the amino acid sequence of SEQ ID NO: 3.
  • the composition may be characterized by increasing the expression or activity of AMP-activated protein kinase (AMPK).
  • AMPK AMP-activated protein kinase
  • the increased activity of AMPK is phosphorylation of AMPK, which may be characterized by increased glucose uptake of muscle.
  • phosphorylation of AMPK may be characterized by increased phosphorylation of ACC (acetyl-coA).
  • ACC is a protein that is activated by phosphorylated AMPK and is known to inhibit the synthesis of fatty acids.
  • the diabetes is preferably type 2 diabetes, but the present invention is not limited thereto.
  • TGF-beta plays an important role in inducing diabetic complications such as insulin-resistant diabetes mellitus and eye, kidney and nerve of the present invention (Huei-Min Lin et al., J. Biol. Chem. ): 12246-57, 2009). That is, TGF- ⁇ induces insulin resistance through phosphorylation of smad3.
  • the Bigley Kahn of the present invention may be characterized by decreasing the phosphorylation of smad3, which is increased by TGF-ss.
  • the composition containing the Bigley Kahn of the present invention may further comprise an appropriate carrier, excipient or diluent according to a conventional method.
  • carriers, excipients and diluents that can be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, specialty, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • composition containing the Bigley Kahn of the present invention may be prepared by a conventional method in the group consisting of powders, pills, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, And can have any one of the formulations selected.
  • a diluent or excipient such as a filler, a weighting agent, a binder, a wetting agent, a disintegrant, a surfactant, and the like is usually used.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, sucrose), lactose, gelatin, and the like.
  • lubricants such as magnesium stearate and talc are also used.
  • the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
  • As the base of the suppository witepsol, macrogol, tween 60, cacao paper, laurin, glycerol gelatin and the like can be used.
  • the present invention relates to a method for the prophylactic or therapeutic treatment of insulin resistance-specific diabetes mellitus, which comprises the step of administering a composition containing biglycane as an active ingredient.
  • the present invention relates to a use of a composition containing biglycans as an active ingredient for the prophylactic or therapeutic treatment of insulin resistance-specific diabetes mellitus.
  • the preferred dosage of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the drug form, the administration route and the period, but can be appropriately selected by those skilled in the art.
  • the compound of the present invention is preferably administered at a daily dose of 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg.
  • the administration may be carried out once a day, or in several divided doses orally.
  • the dose is not intended to limit the scope of the invention in any way.
  • composition of the present invention can be used alone or in combination with methods for the prevention or treatment of diabetes or using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
  • the present invention relates to the use of a Bigley carcinoma for use in the prevention or treatment of insulin resistance-specific diabetes.
  • the present invention relates to the use of a biglycaine for the manufacture of a medicament for the prophylactic or therapeutic treatment of insulin resistance-specific diabetes.
  • the present invention relates to a health functional food for preventing or ameliorating insulin resistance-specific diabetes mellitus containing biglycan as an active ingredient.
  • the Bigley Kahn may be characterized by being represented by the amino acid sequence of SEQ ID NO: 3.
  • the diabetes is preferably type 2 diabetes, but the present invention is not limited thereto.
  • the food of the present invention can be manufactured in all forms such as functional food, nutritional supplement, health food and food additives.
  • the Viglycans of the present invention can be prepared in the form of tea, juice and drink and then consumed for drinking, granulated, encapsulated and powdered.
  • Functional foods also include beverages (including alcoholic beverages), fruits and processed foods (such as canned fruits, bottled, jam, marmalade, etc.), fish, meat and processed foods such as ham, sausages, , Breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, sugar, dairy products such as butter, chitzs, edible vegetable fats, margarine, vegetable protein, , Frozen foods, various kinds of seasonings (e.g., soybean paste, soy sauce, sauce, etc.) by adding the Viglycane of the present invention.
  • beverages including alcoholic beverages
  • fruits and processed foods such as canned fruits, bottled, jam, marmalade, etc.
  • fish meat and processed foods
  • meat and processed foods such as ham, sausages, , Breads and noodles (eg udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, sugar, dairy
  • the health functional food also includes various forms such as a functional food, a nutritional supplement, a health food, a food additive and the like as a food composition.
  • the health functional food may be prepared in various forms according to a conventional method known in the art, for example, It can be prepared in the form of tea, juice or drink, granulated, encapsulated, powdered or added to various foods such as beverages, fruit and processed foods, fish oil, meat and processed foods, breads, noodles and seasonings ≪ / RTI >
  • Example 1 Increased AMPK phosphorylation and glucose uptake by Bigley Kahn
  • L6 muscle precursor cells were cultured in DMEM supplemented with 10% FBS, and then cultured in DMEM containing 0.1 ⁇ g / ml, 0.3 ⁇ g / ml, 0.5 ⁇ g / ml and 1 ⁇ g / ml of Flarebio , US) were each treated for 1 hour. Changes in AMPK and ACC activity were measured using Western blot in cell lysates. AMPK phosphorylated antibody (Threonine 172, Millipore-Upstate, US) and ACC phosphorylated antibody (Millipore-Upstate, US) were used for detection of phosphorylated AMPK protein and ACC protein, respectively.
  • Viglycane was treated for 0 hour, 0.5 hour, 1 hour and 3 hours, respectively, and the changes of AMPK and ACC activity were measured.
  • L6 muscle precursor cells were cultured in DMEM containing 10% FBS, and then differentiated for 6 days in DMEM containing 2% FBS every 2 days from the next day.
  • the glucose uptake was measured using isotope by treating each of 0, 1, 0.1, 1, 0, 1, and 1 ug / ml of Bigley kernels for 1 hour.
  • glucose uptake was measured after 0.3 ⁇ g / ml Bigley kernels were treated for 0 h, 0.5 h, 1 h, 3 h and 18 h, respectively.
  • glucose uptake showed a maximum value at 1 hour of the Bigley cut treatment (Fig. 1D).
  • L6 muscle precursor cells were cultured and the cells were stained with 5 ⁇ M of fluo-3 AM (Invitrogen, US) for the next day, and the cells were observed in real time using a confocal microscope.
  • AKT phosphorylation by Bigley-Kahn was measured in the same manner as in Example 1. 0, 0.5, 1, and 3 hours with concentrations of 0, 1, 1, and 1 ⁇ g / ml of Bigley kernels.
  • AKT phosphorylated antibody Serine 473, cell signaling, US was used for detection of phosphorylated AKT protein.
  • Pre-L6 muscle cells expressing Myc-Glut4 on the cell surface were cultured in DMEM containing 10% FBS, and then differentiated for 6 days in DMEM containing 2% FBS once every two days from the next day. After treatment with 0.3 ⁇ g / ml Viglican, Glut4 migrating to the cell surface was measured using Myc protein antibody (Santa Cruz, US).
  • Glut4 translocation was increased by biglycane (Fig. 4A). 4C), or when the AKT inhibitor LY-29004 was treated with Viglykane (Fig. 4B), or when 5 ⁇ M of the CaMKK inhibitor was treated with Viglykane (Fig. 4C) (Fig. 4D), Glut4 migration was also decreased.
  • Example 5 Expression of AMPK phosphorylation and Bigley Kahn by electrical stimulation
  • PCR conditions were: initial denaturation at 95 ° C for 10 min; i) 30 cycles of denaturation at 95 DEG C for 30 seconds, ii) annealing at 58 DEG C for 30 seconds, and iii) extension at 72 DEG C for 1 minute; And final extension at 72 [deg.] C for 10 min.
  • the primers were F: 5'-TGT GGC TAC TCA CCT TGC TG-3 '(SEQ ID NO: 1) and R: 5'-ACT TTG CTT ATA CGG TTG TC-3' (SEQ ID NO: 2).
  • the primary cultured muscle cells were treated with Bigley carcans in the same manner as in Example 2, and the expression of calcium was confirmed in cells in real time using a confocal microscope.
  • mice were allowed to exercise for 1 hour a day for one month, and then 6 blood samples were taken from each of the mice with and without exercise. The blood was separated by centrifugation, and the separated blood was measured for the concentration of Bigley kernels exiting the blood using a mouse BGN ELISA kit (Elabscience, China).
  • TGF- ⁇ insulin resistance induction in L6 muscle precursor cells
  • smad3 phosphorylation was increased according to the concentration of TGF- ⁇ and the maximum value of smad3 phosphorylation was 1 ⁇ g / ml of TGF- ⁇ (FIG. 8A).
  • smad3 phosphorylation showed the maximum value at 1 hour of TGF-beta treatment (Fig. 8B).
  • L6 muscle precursor cells were treated with 0 g / ml, 0.1 g / ml, 0.3 g / ml, 0.5 g / ml and 1 g / ml of Bigley Kahn and salmon nasal derived proteoglycan (Cosmobio, Respectively. Changes in AMPK activity were measured in cell lysates using Western blot. AMPK phosphorylated antibody (Threonine 172, Millipore-Upstate, US) was used for detection of phosphorylated AMPK protein.
  • Viglickan is more potent in regulating sugar than the salmon naturally occurring proteoglycan, because the degree of increase of AMPK phosphorylation, which is a sugar-regulated target protein, is stronger.
  • the salmon nodal proteoglycan (Gene bank Accession No. AB571294) is 1324 amino acids (Ikuko Kakizak et al., Archives of Biochemistry and Biophysics, 506: 58-65, 2011) (SEQ ID NO: 3) is 394 amino acids in length and sequence.
  • the anti-diabetic effect of myoglobin biglycane was confirmed in a model of type 2 diabetes induced by high fat diet.
  • mice Six-week-old mice were used as the type 2 diabetic animal. The mice were divided into two groups: high fat diet (HFD) control group and high glycemic control group (HGD + BGN) Obesity was induced. Then qlrmfflzks administration was peritoneally administered at 2 mg / kg three times a week for 4 weeks.
  • HFD high fat diet
  • HGD + BGN high glycemic control group
  • mice were fasted for 16 hours before the administration of Viglykane or physiological saline for 2 weeks, and glucose was intraperitoneally administered at a dose of 2 g / kg. Blood was collected through tail monitoring until 120 minutes per hour after glucose administration. Blood glucose was measured using an Accu-Chek Go blood glucose meter. After the intraperitoneal glucose intubation test was completed, the animals were fasted for 16 hours and then inhaled using an experimental ether. Anesthesia was performed using a syringe to remove blood through cardiac blood collection, centrifugal separation, and blood plasma blood glucose was analyzed .
  • the biglycan according to the present invention induces blood glucose lowering through AMPK phosphorylation and glucose uptake increase, and thus is useful as a therapeutic agent for diabetes.

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement du diabète, contenant du biglycane en tant que principe actif. Selon la présente invention, le biglycane induit une diminution de la glycémie par phosphorylation de l'AMPK et une augmentation de l'absorption du glucose, et se révèle donc utile en tant qu'agent pour le traitement du diabète insulino-résistant.
PCT/KR2019/000867 2018-01-22 2019-01-22 Composition pharmaceutique pour la prévention ou le traitement du diabète, contenant du biglycane en tant que principe actif WO2019143219A1 (fr)

Applications Claiming Priority (4)

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KR10-2018-0007619 2018-01-22
KR20180007619 2018-01-22
KR1020190007425A KR102141125B1 (ko) 2018-01-22 2019-01-21 비글리칸을 유효성분으로 함유하는 당뇨병 예방 또는 치료용 약학 조성물
KR10-2019-0007425 2019-01-21

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010808A1 (fr) * 1991-12-04 1993-06-10 La Jolla Cancer Research Foundation INHIBITION DU FACTEUR DE CROISSANCE TRANSFORMATEUR β AFIN DE PREVENIR L'ACCUMULATION DE LA MATRICE EXTRACELLULAIRE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010808A1 (fr) * 1991-12-04 1993-06-10 La Jolla Cancer Research Foundation INHIBITION DU FACTEUR DE CROISSANCE TRANSFORMATEUR β AFIN DE PREVENIR L'ACCUMULATION DE LA MATRICE EXTRACELLULAIRE

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BOLTON, K.: "The small leucine-rich proteoglycan, biglycan, is highly expressed in adipose tissue of Psammomys obesus and is associated with obesity and type 2 diabetes", BIOLOGIES: TARGETS & THERAPY, vol. 6, 30 March 2012 (2012-03-30), pages 67 - 72, XP055624923 *
HIUKKA, A. ET AL.: "ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan", DIABETES, vol. 58, no. 9, September 2009 (2009-09-01), pages 2018 - 2026, XP055624931 *
KIM, J.: "Enhanced biglycan gene expression in the adipose tissues of obese women and its association with obesity-related genes and metabolic parameters", SCIENTIFIC REPORTS, vol. 6, no. 30609, 28 July 2016 (2016-07-28), pages 1 - 11, XP055624927 *
WU, Y.-F.: "High glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway", SCIENTIFIC REPORTS, vol. 7, no. 44199, 7 March 2017 (2017-03-07), pages 1 - 12, XP055624936 *

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