KR102141125B1 - Composition for Preventing or Treating Diabetes Comprising Biglycan - Google Patents
Composition for Preventing or Treating Diabetes Comprising Biglycan Download PDFInfo
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- KR102141125B1 KR102141125B1 KR1020190007425A KR20190007425A KR102141125B1 KR 102141125 B1 KR102141125 B1 KR 102141125B1 KR 1020190007425 A KR1020190007425 A KR 1020190007425A KR 20190007425 A KR20190007425 A KR 20190007425A KR 102141125 B1 KR102141125 B1 KR 102141125B1
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- biglycan
- ampk
- leu
- phosphorylation
- diabetes
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Abstract
본 발명은 비글리칸 (biglycan)을 유효성분으로 함유하는 당뇨병 예방 또는 치료용 약학 조성물에 관한 것이다. 본 발명에 따른 비글리칸은 AMPK 인산화 및 글루코스 흡수 증가를 통해 혈당강하를 유도하므로, 인슐린 저항성 당뇨병의 치료제로 유용하다.The present invention relates to a pharmaceutical composition for the prevention or treatment of diabetes containing biglycan (biglycan) as an active ingredient. The aglycan according to the present invention induces hypoglycemia through AMPK phosphorylation and increased glucose absorption, and thus is useful as a therapeutic agent for insulin-resistant diabetes.
Description
본 발명은 비글리칸 (biglycan)을 유효성분으로 함유하는 인슐린 저항성 특이적 당뇨병의 예방 또는 치료용 약학 조성물에 관한 것으로, 더욱 자세하게는 AMPK 인산화 및 글루코스 흡수 (glucose uptake) 증가를 통해 혈당강하를 유도하는 비글리칸의 용도에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of insulin-resistant specific diabetes, which contains a biglycan as an active ingredient, and more specifically, to induce blood glucose lowering through AMPK phosphorylation and increased glucose uptake. It relates to the use of non-glycans.
제2형 당뇨병은 체내로 흡수된 포도당을 제대로 이용하지 못하여 여러 합병증을 유발시켜 환자의 사망률에 영향을 주는 질병이다. 실제 임상에서는 당뇨병 치료의 가장 중요한 부분인 혈당 조절이 어려운 실정으로, 당뇨병 환자의 약 40%만이 당화혈색소 목표치인 7.0% 미만에 도달되어 있어 혈당관리를 위한 다각적 노력이 필요한 상태이다. 이러한 당뇨병을 치료하기 위해, 인크레틴 호르몬 기반 치료제들이 널리 사용되고 있다. 그러나, 대표적인 인크레틴 호르몬인 glucagon-like peptide-1(GLP-1)과 glucose dependent insulinotropic polypeptide(GIP)은 dipeptidyl peptidase-4(DPP-4)에 의하여 빠르게 분해되기 때문에 치료 목적으로 사용하기에 어렵다는 문제점이 있다 (Kazafeos K, Diabetes Res Clin Pract ., 93; Suppl 1:S32-6, 2011). 이러한 문제점을 극복하기 위해, 새로운 당뇨병 치료제 개발이 필요하다.
현재까지 혈당조절에 관여하는 주요 단백질로는 Akt, AS(Akt substrate) 160, PKCzeta 등이 있고, 주로 포도당 수송체(glucose transporter) 단백질의 수송에 작용한다고 알려져 있다. 또한, 당, 뇨 등에 대한 분자 수준에서의 발생기전은 인슐린 수용체 자체의 결함보다는 수용체 이후의 과정, 특히 PI-3 kinase(phosphoinositide-3 kinase)를 통한 단백질들 간의 신호전달 이상이 질병의 원인으로 여겨지고 있다. 따라서, 당뇨에 대한 인슐린의 치료 효과는 제한적이므로 혈당 조절과 관련된 신규 타켓 단백질 발굴 및 그 분자적 메커니즘을 밝히는 것이 중요하다.To date, the main proteins involved in blood sugar control include Akt, AS (Akt substrate) 160, PKCzeta, etc., and are known to mainly act on the transport of glucose transporter proteins. In addition, the mechanism of development at the molecular level for sugar, urine, etc. is considered to be the cause of the disease, not the defect of the insulin receptor itself, but the signaling process between the proteins after the receptor, especially 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 related to blood sugar control and to reveal their molecular mechanisms.
최근, 인슐린-저항성 환자를 대상으로 하는 치료제 개발의 표적 단백질로 AMPK가 큰 주목을 받고 있다. AMPK(AMP-activated protein kinase)는 serine/threonine 키나아제(kinase)의 일원으로 골격 근, 심장과 간 등 대사성 장기에 주로 분포하고 있으며, 단백질의 활성화는 AMP 및 상방향 키나아제인 AMPK kinase(AMPKK)에 의한 인산화 과정을 통하여 일어난다. 또한, AMPK는 세포 내의 작은 AMP 농도 변화에도 민감하게 반응하는 에너지 센서로, 운동이나 저산소증, 허혈 등 세포 내 에너지가 부족한 상황에서 활성화되어 ATP를 소비하는 과정을 억제하고 ATP를 생성하는 과정을 활성화시킨다. 따라서, AMPK는 당뇨치료제 연구의 중요 표적 허브 단백질이다 (Kahn B.B et al., Cell Metab. 1:15-25 2005).Recently, AMPK has attracted great attention as a target protein for the development of therapeutic agents for insulin-resistant patients. AMPK (AMP-activated protein kinase) is a member of serine/threonine kinase and is mainly distributed in metabolic organs such as skeletal muscle, heart and liver, and protein activation is AMP and kinase AMPK (AMPKK), an upstream kinase. By phosphorylation. In addition, AMPK is an energy sensor that is sensitive to small changes in AMP concentration in cells, and is activated in a situation where energy is insufficient in cells such as exercise, hypoxia, and ischemia, inhibiting the process of consuming ATP and activating the process of generating ATP. . Therefore, AMPK is an important target herb protein in diabetes drug research (Kahn BB et al., Cell Metab. 1:15-25 2005).
한편, 비글리칸 (biglycan)은 콘드로이틴황산/데르만탄황산의 혼성사슬이 있는 소형의 프로테오글리칸으로, 기능은 잘 알려져 있지 않다. 류신이 많은 24개의 아미노산을 포함한 구조로 12회 반복배열이 있으며, 유사한 프로테오글리칸에는 데코린(PG-II)과 피브로모듈린 등이 있는데, 조직분포와 콜라겐 섬유와의 결합능에서 뚜렷한 차이가 있다. 프로테오글리칸은 매우 많이 당화된 단백질로 글리코사미노글리칸 곁사슬이 단백질에 공유결합한 분자군의 총칭이다. 프로테오글리칸은 결합조직에서 발견되며, 다양한 세포생리기능을 담당한다 (Fisher L.W et al., J. Biol. Chem. 264:4571-4576, 1989).On the other hand, biglycan is a small proteoglycan with a hybrid chain of chondroitin sulfate/dermantan sulfate, and its function is not well known. It has a structure containing 24 amino acids with a lot of leucine, and has 12 repetitive arrangements. Similar proteoglycans include decorin (PG-II) and fibromodulin, but there are distinct differences in tissue distribution and binding ability between collagen fibers. Proteoglycan is a highly glycosylated protein and is a generic term for a group of molecules in which glycosaminoglycan side chains are covalently bound to proteins. Proteoglycans are found in connective tissue and are responsible for various cellular physiological functions (Fisher LW et al., J. Biol. Chem. 264:4571-4576, 1989).
또한, 비글리칸은 새로운 마이오카인(myokine) 단백질 중 하나로, 마이오카인은 신체 활동, 즉 운동에 따라 골격근으로부터 발현되거나 합성, 분비되는 활성물질이다 (Pedersen et al., Journal of Applied Physiology, 103(3): 1093-98, 2007). 대표적인 마이오카인으로는 IL-6가 알려져 있고, 이러한 마이오카인은 면역력을 높이고, 체중 조절 및 동맥경화 등을 예방한다. 따라서, 운동에 의해 당뇨 등이 예방되는 효과는 비글리칸과 같은 마이오카인의 분비에 의한 것임을 알 수 있다. In addition, biglycan is one of the new myokine proteins, and myokines are active substances that are expressed, synthesized, and secreted from skeletal muscle according to physical activity ( ie, exercise) (Pedersen et al., Journal of Applied Physiology, 103). (3): 1093-98, 2007). IL-6 is known as a representative myocaine, and this myocaine increases immunity and prevents weight control and arteriosclerosis. Therefore, it can be seen that the effect of preventing diabetes and the like by exercise is due to the secretion of myocaine such as biglycan.
이에, 본 발명자들은 AMPK 활성 조절을 통해 새로운 당뇨병 치료제를 개발하고자 예의 노력한 결과, 비글리칸이 AMPK 인산화 및 글루코스 흡수 증가를 통하여 혈당강하를 유도하므로 비글리칸이 인슐린 저항성 특이적 당뇨병 치료제로 사용될 수 있다는 것을 확인하고, 본 발명을 완성하였다.Accordingly, the present inventors have tried diligently to develop a new diabetes treatment by regulating AMPK activity. As a result, biglycan can be used as a therapeutic agent for insulin resistance-specific diabetes because biglycan induces hypoglycemia through increased AMPK phosphorylation and glucose absorption. Confirmed and completed the present invention.
본 발명의 목적은 AMPK 인산화 및 글루코스 흡수 (glucose uptake) 증가를 통해 혈당강하를 유도하는 비글리칸 (biglycan)을 유효성분으로 함유하는 당뇨병 예방 또는 치료용 약학 조성물 및 건강기능식품을 제공하는데 있다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating diabetes and a health functional food containing biglycan (biglycan) as an active ingredient that induces a drop in blood sugar through AMPK phosphorylation and increased glucose uptake.
상기 목적을 달성하기 위해, 본 발명은 비글리칸 (biglycan)을 유효성분으로 함유하는 인슐린 저항성 특이적 당뇨병의 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of insulin-resistant specific diabetes, containing biglycan (biglycan) as an active ingredient.
본 발명은 또한, 비글리칸을 유효성분으로 함유하는 인슐린 저항성 특이적 당뇨병의 예방 또는 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for the prevention or improvement of insulin-resistant specific diabetes containing biglycan as an active ingredient.
본 발명은 또한, 비글리칸을 개체에 투여하는 단계를 포함하는 인슐린 저항성 특이적 당뇨병의 예방 또는 치료 방법을 제공한다.The present invention also provides a method of preventing or treating insulin-resistant specific diabetes, comprising administering biglycan to a subject.
본 발명은 또한, 인슐린 저항성 특이적 당뇨병의 예방 또는 치료에 사용하기 위한 비글리칸의 용도를 제공한다.The present invention also provides the use of biglycans for use in the prevention or treatment of insulin resistant specific diabetes.
본 발명은 또한, 인슐린 저항성 특이적 당뇨병의 예방 또는 치료용 약제의 제조를 위한 비글리칸의 용도를 제공한다.The present invention also provides the use of biglycans for the manufacture of a medicament for the prevention or treatment of insulin resistance specific diabetes.
본 발명에 따른 비글리칸 (biglycan)은 AMPK 인산화 및 글루코스 흡수 (glucose uptake) 증가를 통해 혈당강하를 유도하므로, 당뇨병 치료제로 유용하다.The biglycan according to the present invention induces a drop in blood sugar through AMPK phosphorylation and increased glucose uptake, and thus is useful as a therapeutic agent for diabetes.
도 1은 비글리칸에 의한 AMPK 인산화 (A 및 B) 및 글루코스 흡수 (C-E) 증가를 확인한 결과이다.
도 2는 근육세포에서 비글리칸에 의한 칼슘 변화를 확인한 결과이다.
도 3은 비글리칸에 의한 AKT 인산화를 확인한 결과이다.
도 4는 근육세포에서 비글리칸에 의한 Glut4 이동을 확인한 결과이다.
도 5는 근육세포에서 전기 자극에 의한 AMPK 인산화 (A), 비글리칸의 발현 (B), Ionomycin과 Forskolin에 의한 AMPK 인산화 (C) 및 비글리칸의 발현 (D) 정도를 나타낸 결과이다.
도 6은 Primary 세포에서 비글리칸에 의한 AMPK 인산화 (A) 및 칼슘 변화 (B)를 확인한 결과이다.
도 7은 운동 후 마우스에서 비글리칸의 농도를 측정한 결과이다.
도 8은 TGF-β로 유도된 smad3의 인산화 (A-B) 및 비글리칸에 의한 smad3 인산화의 감소 (C)를 확인한 결과이다.
도 9는 연어 프로테오글리칸과 본 발명의 비글리칸에 의한 AMPK 인산화를 비교한 것이다.
도 10은 제2형 당뇨 모델 마우스에 본 발명의 비글리칸을 투여한 후, 복강내 당하부 검사를 한 결과이다.
도 11은 제2형 당뇨 모델 마우스에 본 발명의 비글리칸을 투여한 후, 혈중 혈당을 측정한 것이다.1 is a result confirming the increase in AMPK phosphorylation (A and B) and glucose uptake (CE) by biglycan.
2 is a result of confirming the change in calcium by aglycan in muscle cells.
3 is a result of confirming AKT phosphorylation by non-glycan.
Figure 4 is the result of confirming the migration of Glut4 by aglycan in muscle cells.
5 is a result showing the degree of AMPK phosphorylation (A), expression of biglycan (B), AMPK phosphorylation by Ionomycin and Forskolin (C), and expression of biglycan (D) in muscle cells.
6 is a result of confirming the AMPK phosphorylation (A) and calcium change (B) by aglycan in primary cells.
7 is a result of measuring the concentration of non-glycan in mice after exercise.
8 is a result confirming the reduction of phosphorylation (AB) of smad3 induced by TGF-β and reduction of phosphorylation of smad3 by viglycan (C).
9 is a comparison of AMPK phosphorylation by salmon proteoglycan and the non-glycan of the present invention.
FIG. 10 shows the results of an intraperitoneal hypoglycemic test after administration of the biglycan of the present invention to a
FIG. 11 is a measurement of blood glucose level after administration of the biglycan of the present invention to a
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술 분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 가진다. 일반적으로, 본 명세서에서 사용된 명명법은 본 기술 분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. In general, the nomenclature used herein is well known and commonly used in the art.
본 발명에서는 AMPK 인산화 및 글루코스 흡수 (glucose uptake) 증가를 통해 혈당강하를 유도하는 근육세포 분비 단백질인 비글리칸 (biglycan)을 발굴하고, 운동한 동물의 혈액 내에서도 비글린칸의 농도가 증가함을 확인하였다. 또한, 당뇨 동물모델에서 비글리칸의 투여에 의해 인슐린 저항성을 억제하는 것을 확인하고, 비글리칸의 당뇨 치료 효과를 규명하였다.In the present invention, a muscle cell secretion protein, biglycan, which induces a decrease in blood sugar through AMPK phosphorylation and an increase in glucose uptake, was discovered, and it was confirmed that the concentration of biglincan also increased in the blood of an exercised animal. . In addition, in the diabetic animal model, it was confirmed that insulin resistance was suppressed by administration of biglycan, and the effect of treatment with diabetes on biglycan was investigated.
따라서, 본 발명은 일관점에서 비글리칸 (biglycan)을 유효성분으로 함유하는 인슐린 저항성 특이적 당뇨병의 예방 또는 치료용 약학 조성물에 관한 것이다.Accordingly, the present invention relates to a pharmaceutical composition for the prevention or treatment of insulin-resistant specific diabetes containing biglycan as an active ingredient in one aspect.
본 발명에 있어서, 상기 비글리칸은 서열번호 3의 아미노산 서열로 표시되는 것을 특징으로 할 수 있다.In the present invention, the non-glycan may be characterized by being represented by the amino acid sequence of SEQ ID NO: 3.
본 발명에 있어서, 상기 조성물은 AMPK (AMP-activated protein kinase)의 발현 또는 활성을 증가시키는 것을 특징으로 할 수 있다. In the present invention, the composition may be characterized by increasing the expression or activity of AMPK (AMP-activated protein kinase).
상기 AMPK의 활성 증가는 AMPK의 인산화인 것이며, 이러한 인산화는 근육의 글루코스 흡수를 증가시키는 것을 특징으로 할 수 있다.The increased activity of AMPK is phosphorylation of AMPK, and such phosphorylation may be characterized by increasing muscle glucose absorption.
또한, AMPK의 인산화는 ACC (acetyl-co A)의 인산화를 증가시키는 것을 특징으로 할 수 있다. ACC는 인산화된 AMPK에 의하여 활성화되는 단백질로, 지방산의 합성을 억제하는 역할을 하는 것으로 알려져 있다. In addition, phosphorylation of AMPK may be characterized by increasing phosphorylation of ACC (acetyl-co A). ACC is a protein activated by phosphorylated AMPK, and is known to inhibit the synthesis of fatty acids.
본 발명에 있어서, 상기 당뇨병은 제2형 당뇨병인 것이 바람직하나, 이에 한정되는 것은 아니다.In the present invention, the diabetes is preferably
본 발명의 인슐린 저항성 당뇨병 및 눈, 신장, 신경 등에 발생하는 당뇨 합병증의 유발에는 TGF-β가 중요한 역할을 한다고 알려져 있다 (Huei-Min Lin et al., J. Biol . Chem . 1;284(18):12246-57, 2009). 즉, TGF-β는 smad3의 인산화를 통해 인슐린 저항성을 유발한다. It is known that TGF-β plays an important role in inducing insulin-resistant diabetes of the present invention and diabetes complications occurring in the eyes, kidneys, nerves, etc. (Huei-Min Lin et al., J. Biol . Chem . 1;284(18 ):12246-57, 2009). That is, TGF-β induces insulin resistance through phosphorylation of smad3.
따라서, 본 발명의 비글리칸은 TGF-β에 의해 증가한 smad3의 인산화를 감소시키는 것을 특징으로 할 수 있다.Therefore, the aglycan of the present invention may be characterized by reducing phosphorylation of smad3 increased by TGF-β.
본 발명의 비글리칸을 함유하는 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 추가적으로 포함할 수 있다. 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전문, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The composition containing the aglycan of the present invention may further include a suitable carrier, excipient or diluent according to a conventional method. Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, specialty, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 비글리칸을 함유하는 조성물은 통상의 방법에 따라 산제, 환제, 과립제, 캡슐제, 현탁액, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수용액제, 현탁액, 동결 건조제 및 좌제로 구성된 군에서 선택되는 어느 하나의 제형을 가질 수 있다.The composition containing the non-glycan of the present invention is in the group consisting of powders, pills, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, freeze-driers and suppositories according to a conventional method. It can have any one formulation selected.
제제화할 경우에는 보통 사용하는 충진제, 중량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌 글리콜(propylene glycol), 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 60, 카카오지, 라우린지, 글리세롤 제라틴 등이 사용될 수 있다.In the case of formulation, it is prepared using diluents or excipients such as fillers, weights, binders, wetting agents, disintegrating agents and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain at least one excipient in the compound, for example starch, calcium carbonate, sucrose ( It is prepared by mixing sucrose) or lactose, gelatin, etc. In addition, lubricants such as magnesium stearate and talc are used in addition to simple excipients. Liquid preparations for oral use include suspensions, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are common diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents, suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrogol,
본 발명은 다른 관점에서, 비글리칸을 유효성분으로 함유하는 조성물을 투여하는 단계를 포함하는 인슐린 저항성 특이적 당뇨병의 예방 또는 치료 방법에 관한 것이다.In another aspect, the present invention relates to a method for preventing or treating insulin-resistant specific diabetes, comprising administering a composition containing biglycan as an active ingredient.
본 발명은 또 다른 관점에서, 비글리칸을 유효성분으로 함유하는 조성물을 인슐린 저항성 특이적 당뇨병의 예방 또는 치료에 사용하는 용도에 관한 것이다.In another aspect, the present invention relates to the use of a composition containing biglycan as an active ingredient for the prevention or treatment of insulin-resistant specific diabetes.
본 발명의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 화합물은 1일 0.001~100 mg/kg으로 바람직하게는 0.01~10mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 경구 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The preferred dosage of the present invention depends on the patient's condition and body weight, the degree of disease, the type of drug, the route and duration of administration, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention is preferably administered at 0.001 to 100 mg/kg per day, preferably at 0.01 to 10 mg/kg per day. The administration may be administered once a day, or may be divided into several times orally. The above dosage does not limit the scope of the invention in any aspect.
본 발명의 조성물은 당뇨의 예방 또는 치료를 위하여 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormonal therapy, chemotherapy, and biological response modifiers for the prevention or treatment of diabetes.
본 발명은 또 다른 관점에서, 인슐린 저항성 특이적 당뇨병의 예방 또는 치료에 사용하기 위한 비글리칸의 용도에 관한 것이다.In another aspect, the present invention relates to the use of non-glycans for use in the prevention or treatment of insulin resistant specific diabetes.
본 발명은 또 다른 관점에서, 인슐린 저항성 특이적 당뇨병의 예방 또는 치료용 약제의 제조를 위한 비글리칸의 용도에 관한 것이다.In another aspect, the present invention relates to the use of biglycans for the manufacture of a medicament for the prevention or treatment of insulin resistance specific diabetes.
본 발명은 또 다른 관점에서, 비글리칸 (biglycan)을 유효성분으로 함유하는 인슐린 저항성 특이적 당뇨병의 예방 또는 개선용 건강기능식품에 관한 것이다.In another aspect, the present invention relates to a health functional food for the prevention or improvement of insulin-resistant specific diabetes containing bigglycan as an active ingredient.
본 발명에 있어서, 상기 비글리칸은 서열번호 3의 아미노산 서열로 표시되는 것을 특징으로 할 수 있다.In the present invention, the non-glycan may be characterized by being represented by the amino acid sequence of SEQ ID NO: 3.
본 발명에 있어서, 상기 당뇨병은 제2형 당뇨병인 것이 바람직하나, 이에 한정되는 것은 아니다.In the present invention, the diabetes is preferably
본 발명의 식품은, 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등의 모든 형태로 제조할 수 있다. 예를 들면, 건강식품으로는 본 발명의 비글리칸을 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. 또한, 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마말레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지, 콘비프 등), 빵류 및 면류(예: 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 버터, 치츠 등), 식용식물유지, 마가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등에 본 발명의 비글리칸을 첨가하여 제조할 수 있다.Food of the present invention, functional food (functional food), nutritional supplements (nutritional supplement), health foods (health food) and food additives (food additives) can be prepared in all forms. For example, as a healthy food, the non-glycan of the present invention may be prepared in the form of tea, juice, and drink to be consumed or granulated, encapsulated, and powdered. In addition, functional foods include beverages (including alcoholic beverages), fruits and processed foods thereof (e.g. canned fruits, canned foods, jams, marmalades, etc.), fish, meat, and processed foods (e.g. ham, sausages, corn beef, etc.) , Breads and noodles (e.g. udon, buckwheat noodles, ramen, spaghetti, macaroni, etc.), juice, various drinks, cookies, syrup, dairy products (e.g. butter, cheats, etc.), edible plant oils, margarine, vegetable protein, retort foods , Frozen food, various seasonings (eg, miso, soy sauce, sauce, etc.) can be prepared by adding the biglycan of the present invention.
상기 건강 기능식품 또한, 식품조성물로써 기능성 식품, 영양보조제, 건강식품, 식품 첨가제 등의 다양한 형태를 포함하는 것이며, 당업계에 공지된 통상적인 방법에 따라 다양한 형태, 예컨대, 앞서 언급한 비글리칸을 차, 쥬스, 드링크의 형태로 제조하거나, 과립화, 캡슐화, 분말화 하거나, 이러한 화합물 또는 추출물을 음료, 과실 및 가공식품, 어유, 육류 및 그 가공식품, 빵류, 면류, 조미료 등 각종 식품에 첨가하여 제조함으로써 제공될 수 있다.The health functional food also includes various types of functional foods, nutritional supplements, health foods, and food additives as food compositions, and various forms according to conventional methods known in the art, such as the above-mentioned non-glycan. Prepared in the form of tea, juice, drink, granulated, encapsulated, powdered, or added to various foods such as beverages, fruit and processed foods, fish oil, meat and its processed foods, breads, noodles, seasonings, etc. It can be provided by manufacturing.
[[ 실시예Example ]]
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.
실시예Example 1: One: 비글리칸에To the big 의한 by AMPKAMPK 인산화 및 Phosphorylation and 글루코스Glucose 흡수 증가 Increased absorption
1-1: 1-1: 비글리칸에To the big 의한 by AMPKAMPK 인산화 Phosphorylation
L6 근육전구세포 (ATCC, US)를 10% FBS가 포함된 DMEM에 배양 후, 0㎍/ml, 0.1㎍/ml, 0.3㎍/ml, 0.5㎍/ml, 1㎍/ml의 비글리칸 (Flarebio, US)을 각각 1시간 동안 처리하였다. 세포 용해물에서 웨스턴 블롯을 이용하여 AMPK와 ACC 활성 변화를 측정하였다. 인산화된 AMPK 단백질과 ACC 단백질 검출에는 각각 AMPK 인산화 항체 (Threonine 172번, Millipore-Upstate, US)와 ACC 인산화 항체 (Millipore-Upstate, US)를 사용하였다. L6 muscle progenitor cells (ATCC, US) were cultured in DMEM containing 10% FBS, followed by 0 μg/ml, 0.1 μg/ml, 0.3 μg/ml, 0.5 μg/ml, and 1 μg/ml nonglycan (Flarebio , US) for 1 hour each. In cell lysates, changes in AMPK and ACC activity were measured using Western blot. For the detection of phosphorylated AMPK protein and ACC protein, AMPK phosphorylated antibody (
그 결과, 비글리칸의 농도에 따라 AMPK와 ACC의 인산화는 증가하였고, AMPK 인산화의 최대치는 0.3㎍/ml 비글리칸에서 나타났다 (도 1A).As a result, phosphorylation of AMPK and ACC increased according to the concentration of biglycan, and the maximum value of AMPK phosphorylation was found in 0.3 μg/ml biglycan (FIG. 1A).
그 다음, 0.3㎍/ml 비글리칸을 각각 0시간, 0.5시간, 1시간, 3시간 동안 처리한 후, AMPK와 ACC 활성 변화를 측정하였다.Then, 0.3 µg/ml biglycan was treated for 0 hours, 0.5 hours, 1 hour, and 3 hours, respectively, and AMPK and ACC activity changes were measured.
그 결과, AMPK 인산화는 비글리칸 처리 1시간에서 최대치를 나타냈다 (도 1B). As a result, AMPK phosphorylation showed a maximum at 1 hour of non-glycan treatment (Fig. 1B).
1-2: 1-2: 비글리칸에To the big 의한 by 글루코스Glucose 흡수 absorption
L6 근육전구세포를 10% FBS가 포함된 DMEM에 배양 후, 다음날부터 2일마다 한번씩 2% FBS가 포함된 DMEM에서 6일 동안 분화시켰다. 0㎍/ml, 0.1㎍/ml, 0.3㎍/ml, 0.5㎍/ml, 1㎍/ml의 비글리칸을 각각 1시간 동안 처리하여 글루코스 흡수를 동위원소를 이용해 측정하였다. L6 muscle progenitor cells were cultured in DMEM containing 10% FBS, and then differentiated for 6 days in DMEM containing 2% FBS once every 2 days from the next day. The glucose uptake was measured using isotopes by treating 0 µg/ml, 0.1 µg/ml, 0.3 µg/ml, 0.5 µg/ml, and 1 µg/ml of biglycan for 1 hour, respectively.
그 결과, 0.3㎍/ml 비글리칸에서 글루코스 흡수 최대치를 나타냈다 (도 1C).As a result, the maximum glucose uptake in 0.3 μg/ml aglycan was shown (FIG. 1C ).
그 다음, 0.3㎍/ml 비글리칸을 각각 0시간, 0.5시간, 1시간, 3시간, 18시간 동안 처리한 후, 글루코스 흡수를 측정하였다. Then, 0.3 μg/ml biglycan was treated for 0 hours, 0.5 hours, 1 hour, 3 hours, and 18 hours, respectively, and glucose absorption was measured.
그 결과, 글루코스 흡수는 비글리칸 처리 1시간에서 최대치를 나타냈다 (도 1D). As a result, glucose uptake showed a maximum at 1 hour of non-glycan treatment (FIG. 1D).
AMPK의 저해제인 Compound C (CC) 30μM (Merck, US)를 비글리칸과 같이 처리한 결과 AMPK의 인산화가 감소하는 것을 확인하였다 (도 1E).It was confirmed that phosphorylation of AMPK was decreased as a result of treating 30 μM (Merck, US) of Compound C (CC), an inhibitor of AMPK, as a biglycan (FIG. 1E).
이러한 결과는 비글리칸이 AMPK의 인산화를 증가시키며, 글루코스 흡수 또한 증가시킴을 나타낸다.These results indicate that biglycan increases phosphorylation of AMPK and also increases glucose uptake.
실시예Example 2: 2: 비글리칸에To the big 의한 칼슘 변화 Caused by calcium changes
L6 근육전구세포를 배양하여 다음날 칼슘 지표인 fluo-3 AM (Invitrogen, US) 5μM로 세포를 1시간 동안 염색한 후, 비글리칸을 처리하고 공초점현미경을 이용해 실시간으로 세포를 관찰 하였다.After culturing L6 muscle progenitor cells, the next day, the cells were stained with fluo-3 AM (Invitrogen, US) 5 μM for 1 hour, and then treated with aglycan and observed cells in real time using a confocal microscope.
그 결과, 비글리칸이 세포 내 칼슘을 증가시키는 것을 확인하였다 (도 2A).As a result, it was confirmed that biglycan increased intracellular calcium (FIG. 2A ).
그 다음, CaMKK를 선택적으로 저해하는 STO-609 5μM (SignalChem, US)를 비글리칸과 함께 처리한 후, 실시예 1과 동일한 방법으로 AMPK의 인산화 및 글루코스 흡수를 측정하였다.Then, STO-609 5μM (SignalChem, US), which selectively inhibits CaMKK, was treated with biglycan, and then phosphorylation and glucose uptake of AMPK were measured in the same manner as in Example 1.
그 결과, AMPK의 인산화가 감소하는 것을 확인하였으며 (도 2B), STO-609는 비글리칸에 의해 증가한 글루코스 흡수를 저해하는 것을 알 수 있었다 (도 2C).As a result, it was confirmed that phosphorylation of AMPK decreases (FIG. 2B ), and it was found that STO-609 inhibits increased glucose uptake by biglycan (FIG. 2C ).
이러한 결과는 비글리칸이 세포 내 칼슘을 증가시킴을 나타낸다.These results indicate that biglycan increases intracellular calcium.
실시예Example 3: 3: 비글리칸에To the big 의한 by AKTAKT 인산화 Phosphorylation
실시예 1과 동일한 방법으로 비글리칸에 의한 AKT 인산화 정도 측정하였다. 0㎍/ml, 0.1㎍/ml, 0.3㎍/ml, 0.5㎍/ml, 1㎍/ml의 비글리칸의 농도와 0시간, 0.5시간, 1시간, 3시간에서 확인하였다. 인산화된 AKT 단백질 검출에는 AKT 인산화 항체 (Serine 473번, cell signaling, US)를 사용하였다. In the same manner as in Example 1, the degree of AKT phosphorylation by biglycan was measured. The concentrations of biglycan at 0 µg/ml, 0.1 µg/ml, 0.3 µg/ml, 0.5 µg/ml, and 1 µg/ml were confirmed at 0 hours, 0.5 hours, 1 hour, and 3 hours. AKT phosphorylated antibody (Serine 473, cell signaling, US) was used to detect phosphorylated AKT protein.
그 결과, 비글리칸의 농도에 따라 AKT의 인산화는 증가하였고, AKT 인산화의 최대치는 0.3㎍/ml 비글리칸에서 나타났다 (도 3A). 또한, AKT 인산화는 비글리칸 처리 1시간에서 최대치를 나타냈다 (도 3B). As a result, phosphorylation of AKT was increased according to the concentration of biglycan, and the maximum value of AKT phosphorylation was found in 0.3 μg/ml biglycan (FIG. 3A). In addition, AKT phosphorylation showed a maximum at 1 hour of non-glycan treatment (Fig. 3B).
그 다음, AKT 저해제인 LY-294002 20μM (Sigma, US)를 비글리칸과 함께 처리한 후, 실시예 1과 동일한 방법으로 글루코스 흡수를 측정하였다.Next, after the AKT inhibitor LY-294002 20 μM (Sigma, US) was treated with biglycan, glucose uptake was measured in the same manner as in Example 1.
그 결과, 비글리칸에 의해 증가했던 글루코스 흡수가 LY-294002에 의해 저해되었다 (도 3C).As a result, glucose uptake increased by glycan was inhibited by LY-294002 (FIG. 3C ).
이러한 결과는 비글리칸에 의한 AKT의 인산화가 글루코스 흡수에 중요하다는 것을 알 수 있다. These results indicate that phosphorylation of AKT by biglycan is important for glucose uptake.
실시예Example 4: 4: 비글리칸에To the big 의한 by Glut4Glut4 이동 (translocation) Translocation
Myc-Glut4가 세포표면에 발현하는 L6 근육전세포를 10% FBS가 포함된 DMEM에 배양 후, 다음날부터 2일마다 한번씩 2% FBS가 포함된 DMEM에서 6일 동안 분화시켰다. 0.3㎍/ml 비글리칸을 처리한 후, 세포표면으로 이동하는 Glut4를 Myc 단백질 항체 (Santa cruz, US)를 이용해 측정하였다. L6 myoblasts expressed on the cell surface of Myc-Glut4 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 μg/ml bigglycan, Glut4 moving to the cell surface was measured using Myc protein antibody (Santa cruz, US).
그 결과, 비글리칸에 의해 Glut4 이동 (translocation)이 증가하는 것을 확인하였다 (도 4A). 그러나, AMPK 억제제인 Compound C 30μM를 비글리칸과 함께 처리하거나 (도 4B), CaMKK 억제제인 STO-609 5μM를 비글리칸과 함께 처리하였을 때 (도 4C), 또는 AKT 억제제인 LY-29004를 비글리칸과 함께 처리하였을 때도 (도 4D) Glut4 이동이 감소하는 것을 알 수 있었다.As a result, it was confirmed that Glut4 translocation was increased by non-glycan (FIG. 4A). However, when 30 μM of Compound C, an AMPK inhibitor, was treated with biglycan (FIG. 4B), or when 5 μM of STO-609, a CaMKK inhibitor, was treated with biglycan (FIG. 4C), or the AKT inhibitor LY-29004 was treated with nonglycan. Even when treated with (Fig. 4D), it was found that Glut4 migration decreases.
실시예Example 5: 전기자극에 의한 5: by electrical stimulation AMPKAMPK 인산화 및 Phosphorylation and 비글리칸의Non-glycan 발현 Manifestation
L6 근육전구세포에 세포 내 운동과 비슷한 효과를 주는 전기자극을 ionomycin 0.5μM (Sigma, US)과 forskolin 1μM (Sigma, US)과 함께 1시간, 3시간, 6시간 동안 처리 후, 실시예 1과 동일한 방법으로 AMPK의 인산화를 측정하였다.After electrostimulation of L6 muscle progenitor cells with an effect similar to intracellular exercise was treated with ionomycin 0.5 μM (Sigma, US) and
그 결과, AMPK의 인산화는 전기 자극 (IonOptix, US) 25V/㎝, 5ms, 1Hz 을 준 시간 대비 증가하였고, 3시간에서 최대치를 나타냈다 (도 5A).As a result, the phosphorylation of AMPK was increased compared to the time given the electrical stimulation (IonOptix, US) 25V/cm, 5ms, 1Hz, and showed the maximum at 3 hours (Fig. 5A).
그 다음, 1시간, 3시간, 6시간 동안 전기 자극을 준 L6 근육전구세포에서 RNA를 RNeasy Mini Kit (Qiagen, US)를 이용해 분리하고, 분리한 RNA를 이용해 cDNA를 AMV Reverse Transcripatse (Promega, US) 이용해 합성한 후, cDNA를 이용해 비글리칸의 mRNA 발현 정도를 PCR로 확인하였다. PCR 조건은 95℃에서 10분 동안 초기 변성; ⅰ) 95℃에서 30초 동안 변성, ⅱ) 58℃에서 30초 동안 어닐링 및 ⅲ) 72℃에서 1분 동안 연장의 30주기; 및 72℃에서 10분 동안 최종 연장;의 단계로 수행하였다. 프라이머는 F :5′-TGT GGC TAC TCA CCT TGC TG-3′ (서열번호 1) 및 R: 5′-ACT TTG CTT ATA CGG TTG TC- 3′ (서열번호 2)를 사용하였다.Then, RNA was isolated from L6 muscle progenitor cells that had been electrically stimulated for 1 hour, 3 hours, and 6 hours using an RNeasy Mini Kit (Qiagen, US), and cDNA was isolated using isolated RNA to AMV Reverse Transcripatse (Promega, US ), and then cDNA was used to confirm the expression level of biglycan mRNA by PCR. PCR conditions were initial denaturation at 95° C. for 10 min; Iii) denaturation at 95° C. for 30 seconds, ii) 30 cycles of annealing at 58° C. for 30 seconds and iii) extension of 72° C. for 1 minute; And final extension for 10 minutes at 72°C. For the primers, 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) were used.
그 결과, 전기 자극 3시간 후에 비글리칸 발현의 최대치가 나타났다 (도 5B). As a result, the maximum value of non-glycan expression appeared 3 hours after electrical stimulation (FIG. 5B).
실시예Example 6: 일차배양 근육 세포에서 6: in primary cultured muscle cells 비글리칸에To the big 의한 by AMPKAMPK 인산화 및 Phosphorylation and 비글리칸의Non-glycan 발현 Manifestation
생후 3-5일 된 BALB/c 마우스 대퇴부에서 분리한 근육조직 세포에 0.3㎍/ml의 비글리칸을 각각 0시간, 0.1시간, 0.5시간, 1시간, 3시간 동안 처리한 후, AMPK, ACC, AKT 인산화 정도를 실시예 1 및 3과 동일한 방법으로 확인하였다. After treatment with 0.3 μg/ml biglycan in muscle tissue cells isolated from the femoral region of BALB/c mice aged 3-5 days after treatment for 0 hours, 0.1 hours, 0.5 hours, 1 hour, and 3 hours, respectively, AMPK, ACC, The degree of AKT phosphorylation was confirmed by the same method as Examples 1 and 3.
그 결과, AMPK, ACC, AKT 인산화는 비글리칸 처리 1시간에서 최대치를 나타냈다 (도 6A). As a result, AMPK, ACC, and AKT phosphorylation showed a maximum at 1 hour of non-glycan treatment (Fig. 6A).
그 다음, 실시예 2와 동일한 방법으로 일차배양 근육 세포에 비글리칸을 처리하고, 공초점현미경을 이용해 실시간으로 세포에서 칼슘의 발현을 확인하였다.Next, the primary cultured muscle cells were treated with biglycan in the same manner as in Example 2, and the expression of calcium in the cells was confirmed in real time using a confocal microscope.
그 결과, 비글리칸이 세포 내 칼슘을 증가시키는 것을 확인하였다 (도 6B).As a result, it was confirmed that biglycan increases intracellular calcium (FIG. 6B ).
실시예Example 7: 운동 후 혈액 내 7: In the blood after exercise 비글리칸의Non-glycan 농도 density
운동 후 혈액 내 비글리칸의 농도를 확인하기 위하여, BALB/c 마우스를 하루에 1시간씩 한 달간 운동시킨 다음, 운동을 시킨 마우스와 시키지 않은 마우스 각각 6마리의 혈액을 채취하였다. 혈액을 원심분리하여 분리한 후, 분리한 혈액을 마우스 BGN ELISA kit (Elabscience, China)를 이용하여 혈액으로 나오는 비글리칸의 농도를 측정하였다.To check the concentration of biglycan in the blood after exercise, BALB/c mice were exercised for one hour per month for one day, and then six blood samples were collected for each exercised and non-executed mouse. After separating the blood by centrifugation, the concentration of biglycan released into the blood was measured using the mouse BGN ELISA kit (Elabscience, China).
그 결과, 비글리칸은 운동을 하지 않은 그룹에 비해 운동을 한 그룹에서 농도가 증가하는 것을 확인하였다 (도 7A).As a result, it was confirmed that the concentration of the non-glycan group in the exercise group was increased compared to the non-work group (FIG. 7A).
실시예Example 8: 8: TGFTGF -β에 의한 -β smad3smad3 인산화에 대한 For phosphorylation 비글리칸의Non-glycan 효과 effect
L6 근육 전구세포에 인슐린 저항성 유발에 중요한 역할을 하는 TGF-β (sigma, US)를 0㎍/ml, 0.1㎍/ml, 0.3㎍/ml, 1㎍/ml, 3㎍/ml, 5㎍/ml, 10㎍/ml 씩 농도별로 1시간 동안 처리하고, TGF-β 1㎍/ml을 시간별로 0분, 10분, 30분, 60분, 180분 동안 처리하였다. TGF-β는 smad3의 인산화를 유발하여 인슐린 저항성을 유발한다고 알려져 있기 때문에, 그 사실을 확인하기 위하여 인산화된 smad3 단백질 검출에는 smad3 인산화 항체 (Serine 423번/425번, cell signaling, US)를 사용하였다. TGF-β (sigma, US), which plays an important role in inducing insulin resistance in L6 muscle progenitor cells, is 0 μg/ml, 0.1 μg/ml, 0.3 μg/ml, 1 μg/ml, 3 μg/ml, 5 μg/ Each concentration of ml, 10 µg/ml was treated for 1 hour, and 1 µg/ml of TGF-β was treated for 0 minutes, 10 minutes, 30 minutes, 60 minutes, and 180 minutes per hour. Since TGF-β is known to induce smad3 phosphorylation and induce insulin resistance, smad3 phosphorylation antibody (Serine 423/425, cell signaling, US) was used to detect phosphorylated smad3 protein to confirm the fact. .
그 결과, TGF-β 농도에 따라 smad3의 인산화는 증가하였고, smad3 인산화의 최대치는 1㎍/ml TGF-β에서 나타났다 (도 8A). 또한, smad3 인산화는 TGF-β 처리 1시간에서 최대치를 나타냈다 (도 8B).As a result, the phosphorylation of smad3 increased with the concentration of TGF-β, and the maximum value of smad3 phosphorylation was found at 1 μg/ml TGF-β (FIG. 8A ). In addition, smad3 phosphorylation showed a maximum at 1 hour of TGF-β treatment (Fig. 8B).
다음으로, TGF-β 1㎍/ml을 1시간 처리한 L6 근육 전구 세포에 비글리칸 0.3㎍/ml을 1시간 처리한 결과, smad3의 인산화가 감소함을 확인할 수 있었다 (도 8C). 이 결과는 비글리칸이 인슐린 저항성을 극복할 수 있음을 보여주고 당뇨병 합병증의 진행 또한 억제할 수 있음을 의미한다. Next, as a result of treatment with 0.3 μg/ml of biglycan for 1 hour in L6 muscle progenitor cells treated with 1 μg/ml of TGF-β for 1 hour, it was confirmed that phosphorylation of smad3 decreased (FIG. 8C ). This result shows that biglycan can overcome insulin resistance, and it can also inhibit the progression of diabetes complications.
실시예Example 9: 9: 비글리칸과Bigglycan 연어 salmon 나잘Well (nasal) 유래 (nasal) origin 프로테오글리칸의Proteoglycan 비교 compare
L6 근육 전구세포에 비글리칸과 연어 나잘 (nasal) 유래 프로테오글리칸 (Cosmobio, US)을 0㎍/ml, 0.1㎍/ml, 0.3㎍/ml, 0.5㎍/ml, 1㎍/ml로 각각 1시간 동안 처리하였다. 세포 용해물에서 웨스턴 블롯을 이용하여 AMPK 활성 변화를 측정하였다. 인산화된 AMPK 단백질 검출에는 AMPK 인산화 항체 (Threonine 172번, Millipore-Upstate, US)를 사용하였다. Biglycan and salmon nasal proteoglycan (Cosmobio, US) were added to L6 muscle progenitor cells at 0µg/ml, 0.1µg/ml, 0.3µg/ml, 0.5µg/ml, and 1µg/ml for 1 hour each. Treatment. In cell lysates, changes in AMPK activity were measured using Western blot. For the detection of phosphorylated AMPK protein, an AMPK phosphorylated antibody (
그 결과, 연어 나잘 프로테오글리칸의 AMPK 인산화의 최대치는 0.1㎍/ml에서 나타났으며, 이는 비글리칸 0.1㎍/ml과 비슷한 AMPK 인산화 정도였다. 그러나, 연어 나잘 프로테오글리칸은 농도 증가에 따라 AMPK와 ACC의 인산화가 더 이상 증가하지 않고 오히려 감소하는 경향을 나타냈다. 반면, 비글리칸은 농도가 증가함에 따라 AMPK 인산화 정도도 함께 증가하였다 (도 9).As a result, the maximum value of AMPK phosphorylation of salmon nasal proteoglycan was 0.1 μg/ml, which was similar to that of biglycan 0.1 μg/ml. However, salmon nasal proteoglycan showed a tendency that phosphorylation of AMPK and ACC did not increase any more and decreased with increasing concentration. On the other hand, the degree of AMPK phosphorylation increased with increasing concentration of biglycan (FIG. 9).
결론적으로 비글리칸이 연어 나잘 프로테오글리칸에 비해 당 조절 표적 단백질인 AMPK 인산화 증가 정도가 더욱 강력하여 당 조절 능력이 우수함을 보여주는 것이다. In conclusion, it shows that the degree of AMPK phosphorylation, which is a sugar-regulating target protein, is more powerful than that of salmon nasal proteoglycan, and thus, the sugar-regulating ability is excellent.
또한, 구조적으로 보았을 때, 연어 나잘 프로테오글리칸 (Gene bank Accession No. AB571294)은 1324개 아미노산이고 (Ikuko Kakizak et al., Archives of Biochemistry and Biophysics, 506:58-65, 2011), 본 발명의 비글리칸 (서열번호 3)은 394개 아미노산으로 길이 및 서열에 차이가 있다.In addition, structurally, salmon nasal proteoglycan (Gene bank Accession No. AB571294) is 1324 amino acids (Ikuko Kakizak et al., Archives of Biochemistry and Biophysics , 506:58-65, 2011), and non-glycan of the present invention (SEQ ID NO: 3) is 394 amino acids in length and sequence.
실시예Example 10: 당뇨 모델에서 10: In the diabetes model 비글리칸의Non-glycan 효과 확인 Check effect
본 실시예에서는 고지방식이로 유도된 제2형 당뇨 동물모델에서 마이오카인인 비글리칸의 항당뇨 효과를 확인하였다.In this example, the anti-diabetic effect of the myocaine bglycan in the
제2형 당뇨 동물모델로는 6 주령 마우스를 사용하였으며, 고지방식 (High fat diet,HFD) 대조군과 비글리칸 (BGN) 투여군 (HFD+BGN)의 총 2그룹으로 나누어 8주간 고지방 식이로 사육하여 비만을 유도하였다. 그 다음, 비글리칸 투여는 2mg/kg으로 일주일에 3번씩 4주간 복강으로 투여하였다.As a
복강내 당하부 검사 (Intraperitoneal Glucose Tolerance Test, IPGTT)를 하기 위하여, 비글리칸 또는 생리식염수를 2주간 투여한 후 마우스를 검사 전 16시간 절식시키고, 포도당을 2g/kg의 용량으로 복강 투여하였다. 혈액은 포도당 투여 후 각 시간 당 120분까지 꼬리 정책을 통하여 채취하였으며, Accu-Chek Go 혈당 측정기를 사용하여 혈당을 측정하였다. 또한, 복강내 당하부 검사 실험이 종료된 후 16시간 절식시킨 다음 실험용 에테르를 이용하여 흡입 마취하고, 주사기를 사용하여 심장채혈을 통해 혈액을 적출 후 원심분리한 뒤 혈장을 얻어 혈중 혈당을 분석하였다.To perform an intraperitoneal Glucose Tolerance Test (IPGTT), mice were fasted for 16 hours before the test after biglycan or physiological saline was administered for 2 weeks, and glucose was given intraperitoneally at a dose of 2 g/kg. Blood was collected through the tail policy up to 120 minutes per hour after glucose administration, and blood glucose was measured using an Accu-Chek Go blood glucose meter. In addition, after an intraperitoneal hypoglycemic test was completed, the patient was fasted for 16 hours, and then anesthetized using experimental ether, blood was collected through cardiac blood collection using a syringe, centrifuged, and plasma was obtained to analyze blood glucose. .
비글리칸 투여에 의한 인슐린 감수성 촉진 효과를 확인하기 위하여 복강내 당하부 검사를 실시하여, 포도당 주입 후 각군의 포도당 처리 추이를 비교하였다.In order to confirm the effect of promoting insulin sensitivity by administration of non-glycan, an intraperitoneal hypoglycemic test was performed to compare the glucose treatment trend of each group after glucose injection.
그 결과, 포도당 주입 60분과 90분 후 비글리칸 투여군의 포도당 처리속도가 비투여군과 비교할 때, 유의적으로 개선되어 비글리칸이 고지방식이로 인해 유발되는 인슐린 저항성을 억제하여 내당능 장애를 개선해주는 것을 확인할 수 있었다 (도 10). 동시에 공복 혈당이 대조군에 비해 비글리칸 투여군에서 감소한 것을 확인할 수 있었다 (도 11).As a result, after 60 and 90 minutes of glucose infusion, the glucose treatment rate of the non-glycan-administered group was significantly improved compared to the non-administered group, thereby improving the glucose tolerance by suppressing insulin resistance caused by the high-fat diet. It was confirmed (Fig. 10). At the same time, it was confirmed that fasting blood sugar was decreased in the non-glycan-administered group compared to the control group (FIG. 11 ).
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시태양일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.Since the specific parts of the present invention have been described in detail above, it is obvious that for those skilled in the art, this specific technique is only a preferred embodiment, whereby the scope of the present invention is not limited. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
<110> Korea University Research and Business Foundation <120> Composition for Preventing or Treating Diabetes Comprising Biglycan <130> P19-B014 <150> KR 10-2018-0007619 <151> 2018-01-22 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> P1 <400> 1 tgtggctact caccttgctg 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> P2 <400> 2 actttgctta tacggttgtc 20 <210> 3 <211> 394 <212> PRT <213> Artificial Sequence <220> <223> biglycan <400> 3 Met Trp Pro Leu Trp Arg Leu Val Ser Leu Leu Ala Leu Ser Gln Ala 1 5 10 15 Leu Pro Phe Glu Gln Arg Gly Phe Trp Asp Phe Thr Leu Asp Asp Gly 20 25 30 Pro Phe Met Met Asn Asp Glu Glu Ala Ser Gly Ala Asp Thr Ser Gly 35 40 45 Val Leu Asp Pro Asp Ser Val Thr Pro Thr Tyr Ser Ala Met Cys Pro 50 55 60 Phe Gly Cys His Cys His Leu Arg Val Val Gln Cys Ser Asp Leu Gly 65 70 75 80 Leu Glu Phe Met Leu Val Val Gly Val Gly Pro Leu Gly Leu Lys Phe 85 90 95 Met Leu Val Met Gly Val Gly Pro Leu Gly Leu Lys Ser Val Pro Lys 100 105 110 Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp Leu Gln Asn Asn Asp Ile 115 120 125 Ser Glu Leu Arg Lys Asp Asp Phe Lys Gly Leu Gln His Leu Tyr Ala 130 135 140 Leu Val Leu Val Asn Asn Lys Ile Ser Lys Ile His Glu Lys Ala Phe 145 150 155 160 Ser Pro Leu Arg Asn Val Gln Lys Leu Tyr Ile Ser Lys Asn His Leu 165 170 175 Val Glu Ile Pro Pro Asn Leu Pro Ser Ser Leu Val Glu Leu Arg Ile 180 185 190 His Asp Asn Arg Ile Arg Lys Val Pro Lys Gly Val Phe Ser Gly Leu 195 200 205 Arg Asn Met Asn Cys Ile Glu Met Gly Gly Asn Pro Leu Glu Asn Ser 210 215 220 Gly Phe Glu Pro Gly Ala Phe Asp Gly Leu Lys Leu Asn Tyr Leu Arg 225 230 235 240 Ile Ser Glu Ala Lys Leu Thr Gly Ile Pro Lys Asp Leu Pro Glu Thr 245 250 255 Leu Asn Glu Leu His Leu Asp His Asn Lys Ile Gln Ala Ile Glu Leu 260 265 270 Glu Asp Leu Leu Arg Tyr Ser Lys Leu Tyr Arg Leu Gly Leu Gly His 275 280 285 Asn Gln Ile Arg Met Ile Glu Asn Gly Ser Leu Ser Phe Leu Pro Thr 290 295 300 Leu Arg Glu Leu His Leu Asp Asn Asn Lys Leu Ala Arg Val Pro Ser 305 310 315 320 Gly Leu Pro Asp Leu Lys Leu Leu Gln Val Val Tyr Leu His Ser Asn 325 330 335 Asn Ile Thr Lys Val Gly Val Asn Asp Phe Cys Pro Met Gly Phe Gly 340 345 350 Val Lys Arg Ala Tyr Tyr Asn Gly Ile Ser Leu Phe Asn Asn Pro Val 355 360 365 Pro Tyr Trp Glu Val Gln Pro Ala Thr Phe Arg Cys Val Thr Asp Arg 370 375 380 Leu Ala Ile Gln Phe Gly Asn Tyr Lys Lys 385 390 <110> Korea University Research and Business Foundation <120> Composition for Preventing or Treating Diabetes Comprising Biglycan <130> P19-B014 <150> KR 10-2018-0007619 <151> 2018-01-22 <160> 3 <170> KoPatentIn 3.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> P1 <400> 1 tgtggctact caccttgctg 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> P2 <400> 2 actttgctta tacggttgtc 20 <210> 3 <211> 394 <212> PRT <213> Artificial Sequence <220> <223> biglycan <400> 3 Met Trp Pro Leu Trp Arg Leu Val Ser Leu Leu Ala Leu Ser Gln Ala 1 5 10 15 Leu Pro Phe Glu Gln Arg Gly Phe Trp Asp Phe Thr Leu Asp Asp Gly 20 25 30 Pro Phe Met Met Asn Asp Glu Glu Ala Ser Gly Ala Asp Thr Ser Gly 35 40 45 Val Leu Asp Pro Asp Ser Val Thr Pro Thr Tyr Ser Ala Met Cys Pro 50 55 60 Phe Gly Cys His Cys His Leu Arg Val Val Gln Cys Ser Asp Leu Gly 65 70 75 80 Leu Glu Phe Met Leu Val Val Gly Val Gly Pro Leu Gly Leu Lys Phe 85 90 95 Met Leu Val Met Gly Val Gly Pro Leu Gly Leu Lys Ser Val Pro Lys 100 105 110 Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp Leu Gln Asn Asn Asp Ile 115 120 125 Ser Glu Leu Arg Lys Asp Asp Phe Lys Gly Leu Gln His Leu Tyr Ala 130 135 140 Leu Val Leu Val Asn Asn Lys Ile Ser Lys Ile His Glu Lys Ala Phe 145 150 155 160 Ser Pro Leu Arg Asn Val Gln Lys Leu Tyr Ile Ser Lys Asn His Leu 165 170 175 Val Glu Ile Pro Pro Asn Leu Pro Ser Ser Leu Val Glu Leu Arg Ile 180 185 190 His Asp Asn Arg Ile Arg Lys Val Pro Lys Gly Val Phe Ser Gly Leu 195 200 205 Arg Asn Met Asn Cys Ile Glu Met Gly Gly Asn Pro Leu Glu Asn Ser 210 215 220 Gly Phe Glu Pro Gly Ala Phe Asp Gly Leu Lys Leu Asn Tyr Leu Arg 225 230 235 240 Ile Ser Glu Ala Lys Leu Thr Gly Ile Pro Lys Asp Leu Pro Glu Thr 245 250 255 Leu Asn Glu Leu His Leu Asp His Asn Lys Ile Gln Ala Ile Glu Leu 260 265 270 Glu Asp Leu Leu Arg Tyr Ser Lys Leu Tyr Arg Leu Gly Leu Gly His 275 280 285 Asn Gln Ile Arg Met Ile Glu Asn Gly Ser Leu Ser Phe Leu Pro Thr 290 295 300 Leu Arg Glu Leu His Leu Asp Asn Asn Lys Leu Ala Arg Val Pro Ser 305 310 315 320 Gly Leu Pro Asp Leu Lys Leu Leu Gln Val Val Tyr Leu His Ser Asn 325 330 335 Asn Ile Thr Lys Val Gly Val Asn Asp Phe Cys Pro Met Gly Phe Gly 340 345 350 Val Lys Arg Ala Tyr Tyr Asn Gly Ile Ser Leu Phe Asn Asn Pro Val 355 360 365 Pro Tyr Trp Glu Val Gln Pro Ala Thr Phe Arg Cys Val Thr Asp Arg 370 375 380 Leu Ala Ile Gln Phe Gly Asn Tyr Lys Lys 385 390
Claims (8)
A pharmaceutical composition for the prevention or treatment of insulin-resistant specific type 2 diabetes containing biglycan as an active ingredient.
The pharmaceutical composition according to claim 1, wherein the non-glycan is represented by the amino acid sequence of SEQ ID NO: 3.
The pharmaceutical composition according to claim 1, wherein the expression or activity of AMPK is increased.
A health functional food for the prevention or improvement of insulin-resistant specific type 2 diabetes containing biglycan as an active ingredient.
According to claim 5, wherein the non-glycan is a health functional food, characterized in that represented by the amino acid sequence of SEQ ID NO: 3.
The health functional food according to claim 5, wherein the expression or activity of AMPK is increased.
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