KR20130081929A - Composition comprising dieckol compound for treating insulin resistance or hyperinsulinemia - Google Patents
Composition comprising dieckol compound for treating insulin resistance or hyperinsulinemia Download PDFInfo
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- KR20130081929A KR20130081929A KR1020120003041A KR20120003041A KR20130081929A KR 20130081929 A KR20130081929 A KR 20130081929A KR 1020120003041 A KR1020120003041 A KR 1020120003041A KR 20120003041 A KR20120003041 A KR 20120003041A KR 20130081929 A KR20130081929 A KR 20130081929A
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- South Korea
- Prior art keywords
- insulin
- hyperinsulinemia
- insulin resistance
- compound
- composition
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Abstract
Description
본 발명은 디에콜 화합물의 인슐린 저항성 및 고인슐린 혈증의 치료 및 근육세포에서의 포도당 흡수를 증가시키는 새로운 용도에 관한 것이다.The present invention relates to a novel use of diethol compounds for the treatment of insulin resistance and hyperinsulinemia and to increase glucose uptake in muscle cells.
인슐린은 췌장의 랑겔한스섬 내에 있는 β세포로부터 생성되는 호르몬의 일종이고, 골격근, 간장, 지방 등의 인슐린 표적 조직에 존재하는 인슐린 수용체를 통해 당 대사뿐만 아니라, 지질 대사 및 단백질 대사에 작용하며, 생체의 항상성 유지에 중요한 역할을 담당하고 있다. 각 표적 조직에 있어서의 인슐린의 작용으로서는 근육 세포나 지방 세포로의 혈액중의 글루코스의 도입 촉진, 간장 및 근육 조직에서의 글루코겐 생성의 촉진, 간에 서의 당 신생(gluconeogenesis)의 억제, 지방 세포에 있어서의 글루코스 소비와 지방산 합성의 촉진 및 지질의 분해 억제 등을 들 수 있다.Insulin is a type of hormone produced by β cells in the islet of Langelhans of the pancreas, and acts on lipid metabolism and protein metabolism as well as glucose metabolism through insulin receptors present in insulin target tissues such as skeletal muscle, liver and fat. It plays an important role in maintaining homeostasis. The action of insulin in each target tissue may include the promotion of glucose in the blood into muscle cells or adipocytes, the promotion of glycogen production in the liver and muscle tissues, the suppression of gluconeogenesis in the liver, and the fat cells. Glucose consumption, promotion of fatty acid synthesis, inhibition of lipid degradation, and the like.
인슐린 저항성이란, 세포, 장기, 개체 레벨에서 인슐린의 각종 작용을 수득하는 데 통상적인 양 이상의 인슐린을 필요로 하는 상태, 즉, 인슐린에 대한 감수성이 저하된 인슐린 작용 부전 상태의 것이다. 지금까지의 역학적 검토의 결과로부터, 고혈압, 당뇨병, 고지혈증(고트리글리세라이드혈증, 저HDL 콜레스테롤혈증), 비만 등이 인슐린 저항성에 근거하는 병태라고 생각되고 있다. 인슐린 저항성에 걸리면, 당 대사에 있어서의 인슐린의 작용 부족으로부터 혈당 유지를 위한 대상성의 고인슐린혈증을 발생시키고, 고혈당이나 내당능 장해가 야기되는 동시에, 췌장 β세포의 피폐에 의해 당뇨병이 진행된다. 또한 고인슐린혈증은, 교감 신경 활성 항진이나 신장에 있어서의 나트륨 흡수를 촉진하여 고혈압을 발증시키는 동시에, 식후 고지혈증이나 고뇨산혈증, 플라스미노겐 활성화 저지 인자(PAI-1; plasminogen activator inhibitor-1)의 상승 등도 유도한다.Insulin resistance refers to a condition in which insulin or more is required to obtain various actions of insulin at the cellular, organ, and individual levels, that is, an insulin insufficiency state with reduced sensitivity to insulin. Hypertension, diabetes mellitus, hyperlipidemia (hypertriglycerideemia, hypo-HDL cholesterol), obesity, etc. are considered to be a condition based on insulin resistance from the results of conventional epidemiological examination. Insulin resistance results in a target hyperinsulinemia for blood sugar maintenance due to lack of insulin in glucose metabolism, causes hyperglycemia and impaired glucose tolerance, and progresses diabetes due to pancreatic β cell lung. In addition, hyperinsulinemia promotes sympathetic hyperactivity and the absorption of sodium in the kidneys to develop hypertension, and postprandial hyperlipidemia, hyperuricemia, and plasminogen activator inhibitor-1 (PAI-1). It also raises.
한편, 인슐린 저항성은 인슐린의 작용 부족에 의한 지질 대사 이상을 유도하며, 지방 세포로부터 방출된 유리지방산(FFA; free fatty acid)이 간장에서 증가하여 간장에 있어서의 트리글리세라이드(TG)의 합성이 촉진되어 고 TG혈증이 된다. 또한, 통상적으로는 인슐린 감수성이 높은 리포 단백 리파제(LPL)가, 인슐린 저항성 상태에서는 활성이 저하되는 점에서, TG의 분해가 감소되어 고TG혈증의 악화가 진행된다. 또한, 당뇨병이 진행됨에 따라, 혈관 장해에 의한 망막증이나 신증, 괴저 등의 합병증이 병발하여, 동맥 경화성 질환인 심경색, 뇌경색이 진전되고, 또한 고혈압은 순환기 질환을 진행시킨다. 상기한 바와 같이, 인슐린 저항성이 복합적인 병태의 악화에 크게 관여하고 있다고 생각되고 있다(인슐린 저항성과 생활습관병, 시마모토 카즈아키 편집, 진단과 치료사, 2003년, pp1~5).On the other hand, insulin resistance induces lipid metabolism abnormality due to lack of insulin, and free fatty acid (FFA) released from fat cells increases in the liver, which promotes triglyceride (TG) synthesis in the liver. And become TGemia. In addition, since lipoprotein lipase (LPL), which has high insulin sensitivity, is generally deactivated in an insulin resistant state, degradation of TG is reduced, and hypertension is exacerbated. In addition, as diabetes progresses, complications such as retinopathy, nephropathy, and necrosis due to vascular disorders coexist, and atherosclerosis and cerebral infarction, which are atherosclerosis diseases, progress, and hypertension promotes circulatory disease. As described above, insulin resistance is thought to be greatly involved in the exacerbation of complex conditions (insulin resistance and lifestyle diseases, Shimamoto Kazuaki editorial, diagnosis and therapist, 2003, pp. 1-5).
이에 인슐린 저항성을 개선하는 약제가 다수 개발되어 있는 실정으로 주로 간에 있어서의 당 신생을 억제하는 비구아나이드제와 근육이나 지방 조직의 인슐린 감수성을 개선시키는 티아졸리딘 유도체가 개발되어 있다. 트로글리타존이나 피오글리타존으로 대표되는, 티아졸리딘 유도체는, 핵내 수용체형 전사 인자인 페르옥시솜 증식제 응답성 수용체(PPAR: peroxysome proliferator-activated receptor)의 리간드로서 작용하여, 지방 세포의 분화를 촉진시킴으로써 인슐린 저항성을 개선한다고 생각되고 있다.As a result, many drugs for improving insulin resistance have been developed. In particular, biguanides for inhibiting glycogenesis in the liver and thiazolidine derivatives for improving insulin sensitivity of muscle and adipose tissue have been developed. Thiazolidine derivatives, typified by troglitazone or pioglitazone, act as ligands of the peroxysome proliferator-activated receptor (PPAR), an intranuclear receptor-type transcription factor, promoting insulin differentiation by promoting the differentiation of fat cells. It is thought to improve resistance.
이 외에도, 관련 선행문헌으로서 아디포넥틴 또는 이들의 유전자를 유효 성분으로 하는 인슐린 저항성 개선제(국제공개특허 WO03/063894), 알로에속 식물의 에틸 아세테이트/부탄올 혼합액 추출물 또는 클로로포름/메탄올 혼합액 추출물, 또는 이들의 분획물을 함유하는 인슐린 저항성 개선제(한국등록특허 0999317호), 봄베신 수용체 서브타입 3(BRS-3)에 친화성을 갖는 물질을 유효 성분으로 하는 인슐린 저항성에 기인하는 질환의 예방 및 치료제(일본 공개특허공보 제(평)10-298100호) 등이 있다.In addition, as related documents, adiponectin or an insulin resistance improving agent (International Patent Publication No. WO03 / 063894) having an active ingredient thereof, an ethyl acetate / butanol mixture extract or chloroform / methanol mixture extract, or a fraction thereof Insulin resistance improving agent (Korean Patent No. 0999317), containing a substance having affinity for bombesin receptor subtype 3 (BRS-3) as an active ingredient preventing and treating diseases caused by insulin resistance (Japanese Patent Publication No. 10-298100).
그러나 지금까지 디에콜 화합물의 근육세포에서의 포도당 흡수 촉진을 근거로 한 인슐린 저항성 개선 용도는 개시된 바 없었다.However, until now, there has been no use for improving insulin resistance based on the promotion of glucose uptake in muscle cells of dietol compounds.
이에 본 발명자들은 디에콜 화합물이 뛰어난 근육세포에서 포도당 흡수 촉진작용을 갖음을 확인하고, 체내 이미 흡수된 포도당의 대사를 신속하게 증가시킬 수 있어 인슐린 저항성 및 고인슐린혈증을 개선 또는 치료할 수 있다는 것을 확인하고 본 발명을 완성하게 되었다.Accordingly, the present inventors confirmed that the dietol compound has a function of promoting glucose absorption in excellent muscle cells, and can rapidly increase the metabolism of glucose already absorbed in the body, thereby improving or treating insulin resistance and hyperinsulinemia. This invention was completed.
따라서, 본 발명의 목적은 디에콜 화합물을 함유하는 고인슐린혈증 및 인슐린 저항성 예방 또는 치료용 조성물을 제공하는데 있다.Accordingly, an object of the present invention is to provide a composition for preventing or treating hyperinsulinemia and insulin resistance containing a diethol compound.
또한, 본 발명의 목적은 디에콜(dieckol) 화합물을 유효성분으로 함유하는 고인슐린혈증 및 인슐린 저항성 예방 또는 개선용 식품을 제공하는데 있다.It is also an object of the present invention to provide a food for preventing or improving hyperinsulinemia and insulin resistance, which contains a dieteck compound as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 디에콜(dieckol) 화합물을 유효성분으로 함유하는 고인슐린혈증 예방 또는 치료용 조성물을 제공한다.In order to achieve the above object, the present invention provides a composition for preventing or treating hyperinsulinemia containing a dieteckol compound as an active ingredient.
본 발명의 일실시예에 있어서, 상기 디에콜 화합물은 Akt, AMPK 및 GLUT4의 발현을 증가시켜 근육세포로의 포도당 흡수를 촉진한다.In one embodiment of the present invention, the diecol compound increases the expression of Akt, AMPK and GLUT4 to promote glucose uptake into muscle cells.
상기 목적을 달성하기 위하여, 본 발명은 디에콜(dieckol) 화합물을 유효성분으로 함유하는 인슐린저항성 예방 또는 치료용 조성물을 제공한다.In order to achieve the above object, the present invention provides a composition for the prevention or treatment of insulin resistance containing a dieckol compound as an active ingredient.
본 발명의 일실시예에 있어서, 상기 디에콜 화합물은 Akt, AMPK 및 GLUT4의 발현을 증가시켜 근육세포로의 포도당 흡수를 촉진한다.In one embodiment of the present invention, the diecol compound increases the expression of Akt, AMPK and GLUT4 to promote glucose uptake into muscle cells.
또한, 본 발명은 디에콜 화합물을 유효성분으로 함유하는 근육세포에서의 포도당 흡수 촉진용 조성물을 제공한다.In addition, the present invention provides a composition for promoting glucose uptake in muscle cells containing a diethol compound as an active ingredient.
또한, 본 발명은 디에콜(dieckol) 화합물을 유효성분으로 함유하는 고인슐린혈증 및 인슐린 저항성 예방 또는 개선용 식품을 제공한다.In addition, the present invention provides a food for preventing or improving hyperinsulinemia and insulin resistance, which contains a dieckol compound as an active ingredient.
본 발명은 디에콜 화합물을 유효성분으로 함유하는 인슐린저항성 및 고인슐린혈증 치료용 조성물에 관한 것으로, 디에콜 화합물은 인슐린 저항성으로 인해 근육세포로의 포도당 흡수가 저하되어 있는 동물모델 내 근육세포로의 포도당 흡수를 촉진시키고, GLUT-4 단백질의 활성을 증가시켜 인슐린 저항성 및 고인슐린혈증을 개선하며 치료할 수 있다는 효과가 있다.The present invention relates to a composition for treating insulin resistance and hyperinsulinemia containing a diethol compound as an active ingredient, wherein the diethol compound is reduced to muscle cells in an animal model in which glucose uptake into muscle cells is reduced due to insulin resistance. It has the effect of promoting glucose uptake and increasing the activity of GLUT-4 protein to improve and treat insulin resistance and hyperinsulinemia.
도 1은 디에콜의 근육세포내로의 포도당 흡수정도를 측정한 그래프이다.
도 2은 디에콜의 근육세포내로의 포도당 흡수 작용기작 구명을 위한 웨스턴 블랏 분석 결과이다.
도 3은 디에콜의 제2형 당뇨병 모델쥐에서의 혈중 인슐린 함량 저해 효과를 측정한 그래프이다.
도 4는 디에콜의 제2형 당뇨병 모델쥐에서의 혈중 포도당 농도 변화를 측정한 그래프이다.1 is a graph measuring the degree of glucose uptake into dietary cells of muscle.
2 is a result of Western blot analysis for the investigation of glucose absorption mechanism mechanism of dietol into muscle cells.
Figure 3 is a graph measuring the effect of inhibiting the blood insulin content of
Figure 4 is a graph measuring the change in blood glucose concentration of
본 발명은 디에콜(dieckol) 화합물을 포함하는 고인슐린혈증 및 인슐린 저항의 예방 및 치료용 조성물에 관한 것으로, 보다 상세하게는 디에콜 화합물이 혈중 포도당의 세포로의 흡수를 촉진시키는 신호전달시스템의 Akt(인슐린의존형)와 AMPK(인슐린비의존형) 단백질의 발현을 촉진시키며, GLUT4 발현을 유발하여 포도당의 근육세포 내로의 흡수를 증가시킴을 통해 인슐린 저항성 및 고인슐린혈증을 해결할 수 있다.The present invention relates to a composition for the prevention and treatment of hyperinsulinemia and insulin resistance comprising a dieteckol compound, and more particularly, to a signaling system for promoting the absorption of glucose into cells in the diethol compound. Insulin resistance and hyperinsulinemia can be resolved by promoting expression of Akt (insulin-dependent) and AMPK (insulin-independent) proteins, and inducing GLUT4 expression to increase glucose uptake into muscle cells.
인슐린은 근육 세포나 지방 세포로의 혈액중의 포도당의 도입을 촉진시키는 역할을 하는바, 인슐린 저항성을 앓고 있는 환자들은 인슐린이 체내로 분비됨에도 불구하고 혈액 중 포도당이 근육 세포 등으로 흡수되지 않아 결과적으로 혈중 고인슐린이 유지되는 증상을 보인다.Insulin plays a role in promoting the introduction of glucose into the blood into muscle cells and adipocytes. Patients with insulin resistance are not absorbed into the muscle cells, etc., even though insulin is secreted into the body. As a result, blood insulin is maintained.
이에, 본 발명자들은 당업계 공지된 디에콜 화합물이 혈중 포도당의 근육 세포로의 흡수를 탁월하게 촉진함을 확인하고, 실제 동물모델에서 디에콜 화합물이 고인슐린혈증을 해소하고 인슐린 저항성을 해결할 수 있음을 토대로 본 발명을 완성하였다. Accordingly, the present inventors have confirmed that the dietol compound known in the art to facilitate the absorption of glucose into the muscle cells in the blood, the dietol compound can solve hyperinsulinemia and resolve insulin resistance in real animal models Based on the present invention was completed.
따라서 본 발명은 디에콜(dieckol) 화합물을 유효성분으로 함유하는 고인슐린혈증 또는 인슐린 저항성의 예방 또는 치료용 조성물을 제공함에 그 특징이 있다.Therefore, the present invention is characterized by providing a composition for the prevention or treatment of hyperinsulinemia or insulin resistance, which contains a dieteck compound as an active ingredient.
상기 디에콜(dieckol) 화합물은 C36H22O18의 분자식을 가지고 있고 플로로글루시놀, 탄닌(phloroglucinol, tannin) 계열의 화합물로서 감태(학명 Ecklonia cava)와 같은 에클로니아(Ecklonia) 종의 해조류에 많이 포함되어 있다고 알려져 있으며, 구조식은 Dibenzo[b,e][1,4]dioxin-1,3,6,8-tetrol,4-[4-[6-(3,5-dihydroxyphenoxy)-4,7,9-trihydroxydibenzo[b,e][1,4]dioxin-2-yl]oxy]-3,5-dihydroxyphenoxy]- 이며, 화학식은 다음과 같다.The dieckol compound has a molecular formula of C 36 H 22 O 18 and is a phloroglucinol and tannin-based compound and is an algae of Ecklonia species such as Ecklonia cava. It is known to contain a lot of structural formula, Dibenzo [b, e] [1,4] dioxin-1,3,6,8-tetrol, 4- [4- [6- (3,5-dihydroxyphenoxy) -4 , 7,9-trihydroxydibenzo [b, e] [1,4] dioxin-2-yl] oxy] -3,5-dihydroxyphenoxy]-and the chemical formula is as follows.
<화학식>≪
본 발명에 따른 상기 디에콜(dieckol) 화합물은 염, 바람직하게는 약학적으로 허용 가능한 염의 형태로 사용될 수 있다. 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의하여 형성된 산 부가염이 바람직하며, 상기 유리산으로는 유기산과 무기산을 사용할 수 있다. 상기 유기산은 이에 제한되는 것은 아니나, 구연산, 초산, 젖산, 주석산, 말레인산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플로오로아세트산, 벤조산, 글루콘산, 메타술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 글루탐산 및 아스파르트산을 포함한다. 또한 상기 무기산은 이에 제한되는 것은 아니나, 염산, 브롬산, 황산 및 인산을 포함한다.The diecol compound according to the invention may be used in the form of a salt, preferably a pharmaceutically acceptable salt. The salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid, and the free acid may be an organic acid or an inorganic acid. The organic acids include, but are not limited to, citric, acetic, lactic, tartaric, maleic, fumaric, formic, propionic, oxalic, trifluroacetic, benzoic, gluconic, methosulfonic, glycolic, succinic, Glutamic acid and aspartic acid. The inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid.
본 발명에 따른 디에콜(dieckol)은 천연으로부터 분리되거나 당업계에 공지된 화학적 합성법으로 제조할 수 있으며, 바람직하게는 천연 식물로부터 분리 및 정제할 수 있다. 즉, 종래의 물질을 추출하고 분리하는 방법을 이용하여 식물 또는 식물의 일부로부터 수득 될 수 있다. 천연 식물의 줄기, 뿌리 또는 잎은 목적하는 추출물을 획득하기 위하여 적절히 건조하여 침연(macerated)하거나 단지 건조시켜 적절한 유기용매로 추출하고, 목적하는 추출물은 본 발명이 속하는 기술 분야의 당업자에게 알려진 정제 방법을 이용하여 정제될 수 있다. 가장 바람직하게는 본 발명의 디에콜(dieckol) 화합물은 감태로부터 분리 및 정제할 수 있다.Dieeckol according to the present invention can be isolated from nature or prepared by chemical synthesis known in the art, and preferably can be isolated and purified from natural plants. That is, it can be obtained from a plant or part of a plant using a method of extracting and separating conventional materials. The stems, roots or leaves of natural plants are appropriately dried and macerated or only dried to obtain the desired extracts and extracted with a suitable organic solvent, and the desired extracts are known to those skilled in the art. It can be purified using. Most preferably the dieckol compounds of the present invention can be isolated and purified from ecstasy.
오늘날 당뇨병이 급증함에 따라, 구체적인 여러 병증 및 근본원인의 해결을 위하여 특이적인 각각의 치료제들이 개발되고 있는 실정이다. 단순히 혈당을 감소시키는 약제가 아닌, 고인슐린혈증이나 인슐린 저항성과 같이 당뇨병을 유도할 수 있는 사전 병증들에 대한 개별적인 연구가 진행되고 있다.As diabetes increases rapidly today, specific therapeutic agents are being developed to solve specific diseases and root causes. Individual studies are being conducted on pre-conditions that can lead to diabetes, such as hyperinsulinemia or insulin resistance, rather than just drugs that reduce blood sugar.
인슐린 저항성은 골격근·지방세포·간장에서 인슐린의 주요한 작용인 당의 흡수 촉진 작용이 약한 상태를 나타낸다. 인슐린 저항성은 인슐린에 대한 근육, 간, 지방 등의 전신 조직의 감수성이 저하된 상태를 나타낸다. 인슐린 저항성이 발병한 상태에서는, 조직의 인슐린 감수성이 저하되어, 인슐린 의존적인 당 흡수(uptake) 능력이 저하된다. 그 결과, 인슐린에 의한 혈당 저하 효과가 감소된다. Insulin resistance indicates a weak state of glucose absorption promoting action, which is the main action of insulin in skeletal muscle, fat cells and liver. Insulin resistance refers to a condition in which systemic tissues, such as muscle, liver, and fat, are insensitive to insulin. In the state where insulin resistance develops, the insulin sensitivity of a tissue falls and insulin-dependent sugar uptake ability falls. As a result, the effect of lowering blood sugar by insulin is reduced.
이는, 대상성 고인슐린혈증(compensatory hyperinsulinemia)을 발병시키게 되며, 특히 2형 당뇨병 환자에서는 질병의 병태의 본질인 것으로 이해되고 있다. 그러므로 2형 당뇨병의 약물 치료시에는 혈당강하제와 같은 당뇨병 치료제 뿐만 아니라 인슐린 저항성 개선제를 별도로 사용하여 조직의 인슐린 의존적인 당 흡수력을 높이는 것이 유용한 것으로 여겨지고 있으며, 실제 다수의 약제가 개발되어 임상에 이용되고 있다.This leads to the development of compensatory hyperinsulinemia and is understood to be the essence of the condition of the disease, especially in
한편, 고인슐린혈증은 혈중 인슐린치가 높은 상태를 말하는데 기질적과 기능적으로 나뉘어진다. 전자는 랑게르한스섬의 증식(선종, 비대)에 의해, 췌장에서 인슐린이 과잉으로 분비되기 때문에 생기고 자발성 저혈당증이 된다. 저혈당증상(떨림, 식은땀, 탈진, 의식상실등)이 조기 공복시에 생기고 그때의 혈당치는 50㎎/㎗이하로 낮고 당류를 주면 그것이 즉시 회복한다(위플의 3징). On the other hand, hyperinsulinemia refers to a high state of insulin levels in blood and is divided into organic and functional. The former is caused by proliferation (adenoma, hypertrophy) of the island of Langerhans, resulting in excessive secretion of insulin from the pancreas and spontaneous hypoglycemia. Hypoglycemic symptoms (vibration, cold sweats, exhaustion, loss of consciousness) occur at an early fasting time, and the blood sugar level is lower than 50 mg / ㎗ and the sugars are recovered immediately (when whipping).
기능성 고인슐린혈증은 랑게르한스섬 선종등이 없이 자율신경, 소화기계의 기능장애에 의해서 주로 식후의 인슐린치가 높아지고 식후 2~4시간뒤에 저혈당을 일으킨다(위절제후 뇌졸중, 간염일때 등). 드물게 인슐린 자기항체가 있기 때문에 혈증 인슐린치가 높은 것(인슐린 자기면역증후군), 가벼운 당뇨병에서 이상 인슐린이 존재하기 때문에 혈중 인슐린치가 높은 예. 인슐린 수용기의 이상 때문에 고인슐린혈증. 저혈당을 보게되는 예가 보고 되고 있다. Functional hyperinsulinemia is caused by autonomic nerves and dysfunction of the digestive system, mainly due to autonomic nerves and dysfunction of the digestive system, causing hypoglycemia 2-4 hours after eating (when gastrointestinal stroke, hepatitis, etc.). High blood insulin levels due to the rare presence of insulin autoantibodies (insulin autoimmune syndrome), high blood insulin levels due to the presence of abnormal insulin in mild diabetes. Hyperinsulinemia due to abnormalities in insulin receptors. An example of seeing hypoglycemia is reported.
이와 같이 고인슐린혈증은 단순히 당뇨병에만 국한되어 발병하는 질병이 아니라 여러 원인에 의해 발병하게 되며, 지질대사 장애, 고혈압 및 관상동맥경화 병인을 일으키는 중요한 원인으로 알려져 있다. As such, hyperinsulinemia is not limited to diabetes but is caused by various causes, and is known as an important cause of lipid metabolism disorder, hypertension and coronary atherosclerosis.
따라서, 고인슐린혈증 및 인슐린 저항성은 현대인의 건강을 위협하는 대사성 질환 중 하나로, 이의 예방 및 치료는 매우 중요하다. Therefore, hyperinsulinemia and insulin resistance are one of the metabolic diseases that threaten the health of modern people, and their prevention and treatment are very important.
그러나, 현재 사용되는 고인슐린혈증 및 인슐린 저항성 개선제 중에는 계속적인 치료를 어렵게 하는 심각한 부작용을 유발할 가능성이 있는 것도 적지 않다. 실제로, 간 기능 장해, 부종, 체중 증가, 지방조직 중량 증가 등의 부작용이 발생하여, 치료 중지나 판매 중지를 피할 수 없게 된 경우도 다수건 보고되어 있으며, 이러한 점은 이들의 응용 범위를 제한하는 하나의 요인이 되고 있다.However, not all of the currently used hyperinsulinemia and insulin resistance improving agents have the potential to cause serious side effects that make continuous treatment difficult. In fact, many cases of side effects such as liver dysfunction, edema, weight gain, and fat tissue weight increase have been reported, and discontinuation or discontinuation of treatment has been reported. It is a factor.
이에 연구자들은 부작용이 없이 환자들의 건강한 생활유지가 가능한 인슐린 저항성, 고인슐린혈증의 치료를 위해 우리 몸의 45%를 차지하는 근육에 관심을 갖기 시작하고 있다. 기존 인슐린 저항성 개선제의 경우, 인슐린혈중 농도를 낮추고 조직 저항성을 개선하기 위해, 지방 세포로의 포도당 흡수 증가, 간 조직에서의 글리코겐 합성 촉진과 같은 인슐린 의존적 반응으로만 매개되는 인슐린의 기능 회복을 유도하고자 힘썼다. 그러나 인슐린의 반응으로만 포도당의 유입이 증가되는 지방이나 간세포와 달리 근육 세포는 인슐린 의존적 및 인슐린 비의존적인 경로를 통해 포도당이 유입될 수 있기 때문이다. Researchers are beginning to pay attention to the muscles that make up 45% of our body for the treatment of insulin resistance and hyperinsulinemia, which can keep patients healthy without any side effects. Existing insulin resistance modifiers are intended to induce functional recovery of insulin mediated only by insulin-dependent responses, such as increased glucose uptake into fat cells and promoting glycogen synthesis in liver tissues to lower insulin blood levels and improve tissue resistance. I tried. However, unlike fat or hepatocytes, where glucose is increased only by the response of insulin, muscle cells can enter glucose through insulin-dependent and insulin-independent pathways.
인슐린 의존적 Akt 경로인 경우 혈당조절을 위해 분비된 인슐린이 세포막에 있는 insulin recepter (IR)와 결합하면 이것이 일련의 인슐린 신호전달체계인 insulin receptor substrate-1(IRS-1) - phosphatidylinositol-3-kinase (PI3-Kinase)를 통해, 최종적으로 Akt의 과정을 활성화 시키고 세포질 내에 있는 포도당수송운반체인 GLUT4의 세포막으로의 이동을 증가시켜 포도당 흡수를 증가시킨다. In the insulin-dependent Akt pathway, when insulin secreted for glycemic control is combined with the insulin recepter (IR) on the cell membrane, it is a series of insulin signaling systems, insulin receptor substrate-1 (IRS-1)-phosphatidylinositol-3-kinase ( PI3-Kinase) finally activates the process of Akt and increases glucose uptake by increasing the transport of glucose transporter GLUT4 into the cell membrane in the cytoplasm.
반면, 인슐린 비의존적인 경로의 AMPK (AMP-activated protein kinase)는 energy-sensing enyme(에너지감지효소)로서 세포내 당대사에 중요한 요소로 작용한다. 최근 인슐린과 함께 근육 세포에서 포도당 유입을 증가시키는 대표적인 자극으로 알려진 운동이 AMPK 활성화를 통해, 기존 인슐린 신호전달체계와는 별개의 독립된 경로를 통해서 포도당수송운반체인 GLUT4를 세포막으로의 이동을 증가시켜 근육 세포 내의 포도당 유입을 증가시키는 것으로 알려져 있다. 실제로 metformin이나 rosiglitazone 같은 제 2형 당뇨병의 대표적인 치료제들이 근육내 AMPK의 활성화를 통해서 인슐린저항성 개선을 유도한다는 보고가 있으며 당뇨병 분야에서 이 효소의 작용에 대한 관심이 고조되고 있다. On the other hand, AMPK (AMP-activated protein kinase), an insulin-independent pathway, is an energy-sensing enyme and acts as an important factor for intracellular glucose metabolism. Recently, exercise, known as a typical stimulus to increase glucose influx in muscle cells along with insulin, increases the transport of glucose transporter GLUT4 to the cell membrane through a path independent of the existing insulin signaling system through AMPK activation. It is known to increase glucose uptake in cells. Indeed, there are reports that representative treatments of
이에, 본 발명에 따른 디에콜 화합물은 상기 인슐린 의존적인 Akt 경로는 물론 인슐린 비의존적인 AMPK 경로까지 모두 활성화시키는 뛰어난 효과가 있으며, 이를 통해 포도당수송운반체인 GLUT4의 세포막 이동을 탁월하게 증가시켜 근육세포로의 포도당 수송을 원활하게 하여, 인슐린 저항성으로 인한 고인슐린혈증을 탁월하게 치료할 수 있다는 효과가 있다.In this regard, the diecol compound according to the present invention has an excellent effect of activating both the insulin-dependent Akt pathway as well as the insulin-independent AMPK pathway, thereby excellently increasing the cell membrane migration of the glucose transporter GLUT4 into muscle cells. By smoothing the transport of glucose, there is an effect that can be excellently treated for hyperinsulinemia due to insulin resistance.
즉, 본 발명의 일실시예에 따르면, 디에콜 화합물이 분화된 근육세포내로 포도당 흡수를 농도 의존적으로 증가시킴을 확인할 수 있었으며(도 1 참조), 구체적인 포도당 흡수 촉진 작용기작을 규명한 결과, 근육 내로의 포도당 흡수에 있어 반드시 필요한 Akt(인슐린의존형)와 AMPK(인슐린비의존형)을 모두 활성화시켰으며, 포도당수송운반체인 GLUT4의 발현도 증가시켜 GLUT4가 세포막으로 이동하여 세포내로 포도당이 흡수 작용을 용이하게 함을 확인하였다(도 2 참조). That is, according to one embodiment of the present invention, it was confirmed that the dietol compound increases the glucose uptake into concentration-dependently into differentiated muscle cells (see FIG. 1), and as a result of elucidating the specific mechanism of promoting glucose uptake, muscle Activated both Akt (insulin-dependent) and AMPK (insulin-independent), which are essential for glucose uptake into the cell, and also increased expression of GLUT4, a glucose transporter, allowing GLUT4 to move to the cell membrane and facilitate glucose uptake into cells. Was confirmed (see FIG. 2).
또한, 본 발명의 일실시예에 따르면, 고인슐린혈증을 나타내는 동물모델에 본 발명에 따른 디에콜 화합물을 섭취시킨 결과, 인슐린의 혈중 농도를 탁월하게 낮춤을 확인할 수 있었으며(도 3 참조). 이를 통해 혈중 포도당의 농도도 낮아지며(도 4 참조) 결과적으로 디에콜 화합물을 통해 고인슐린혈증이 개선됨을 확인할 수 있었다. 또한, 인슐린 민감성 떨어져 발생하는 근육세포로의 포도당 흡수 작용을 해결하는바 인슐린 저항성을 개선할 수 있음을 확인할 수 있었다. In addition, according to an embodiment of the present invention, as a result of ingesting the diecol compound according to the present invention in an animal model showing hyperinsulinemia, it was confirmed that the blood concentration of insulin was excellently lowered (see FIG. 3). As a result, the concentration of glucose in the blood was also lowered (see FIG. 4). As a result, it was confirmed that the hyperinsulinemia was improved through the diecol compound. In addition, it was confirmed that the insulin resistance can be improved by solving the glucose absorption action into muscle cells that occur off insulin sensitivity.
따라서, 본 발명은 디에콜 화합물을 유효성분으로 함유하는 고인슐린 혈증 또는 인슐린 저항성 예방 또는 치료용 조성물로 사용될 수 있으며, 상기 디에콜 화합물은 Akt, AMPK 및 GLUT4의 발현을 증가시켜 근육세포로의 포도당 흡수를 촉진시키는 것을 특징으로 한다.Therefore, the present invention can be used as a composition for preventing or treating hyperinsulinemia or insulin resistance, which contains a diethol compound as an active ingredient, wherein the diethol compound increases the expression of Akt, AMPK and GLUT4 to glucose into muscle cells. It is characterized by promoting absorption.
그리하여 본 발명은 디에콜 화합물을 유효성분으로 함유하는 근육세포에서의 포도당 흡수 촉진용 조성물을 제공한다.Thus, the present invention provides a composition for promoting glucose uptake in muscle cells containing a diecol compound as an active ingredient.
상기 본 발명의 조성물은 고인슐린혈증 또는 인슐린 저항성의 예방 또는 치료를 위한 약학적 조성물로 사용될 수 있다. 상기 조성물은 조성물 총 중량에 대하여 디에콜 화합물을 0.1내지 50 % 중량으로 포함할 수 있다. The composition of the present invention can be used as a pharmaceutical composition for the prevention or treatment of hyperinsulinemia or insulin resistance. The composition may comprise 0.1 to 50% by weight of the dietol compound relative to the total weight of the composition.
또한, 본 발명에 따른 상기 조성물은 약학적으로 유효한 양의 디에콜 화합물을 단독으로 포함하거나 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다. 상기에서 약학적으로 유효한 양이란 인슐린 저항성 또는 고인슐린혈증을 예방, 개선 및 치료하기에 충분한 양을 말한다. 본 발명에 따른 디에콜 화합물의 약학적으로 유효한 양은 0.5~100 mg/day/체중kg, 바람직하게는 0.5~5 mg/day/체중kg이다. 그러나 상기 약학적으로 유효한 양은 질환의 증상 정도, 환자의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등에 따라 적절히 변화될 수 있다.In addition, the composition according to the present invention may include a pharmaceutically effective amount of a diecol compound alone or may include one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutically effective amount herein refers to an amount sufficient to prevent, ameliorate and treat insulin resistance or hyperinsulinemia. The pharmaceutically effective amount of the diethol compound according to the present invention is 0.5-100 mg / day / kg body weight, preferably 0.5-5 mg / day / kg body weight. However, the pharmaceutically effective amount may be appropriately changed depending on the symptom of the disease, the age, body weight, health condition, sex, administration route and treatment period of the patient.
또한, 상기에서 "약학적으로 허용되는" 이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필 하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In addition, "pharmaceutically acceptable" as used herein refers to a composition which is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorders, dizziness or the like when administered to a human. Examples of such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.
또한, 본 발명의 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴캅셀, 멸균 주사용액, 멸균 분말의 형태일 수 있다.In addition, the compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. The formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
본 발명에 따른 조성물은 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있으며, 활성 성분의 투여량은 투여 경로, 환자의 연령, 성별, 체중 및 환자의 중증도 등의 여러 인자에 따라 적절히 선택될 수 있다. The composition according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous or muscular, and the dose of the active ingredient may be varied depending on various factors such as route of administration, age, sex, And the like.
또한, 본 발명의 조성물은 인슐린저항성 또는 고인슐린혈증을 예방, 개선 또는 치료하는 효과를 가지는 공지의 화합물과 병행하여 투여할 수 있다.In addition, the composition of the present invention can be administered in parallel with known compounds having the effect of preventing, improving or treating insulin resistance or hyperinsulinemia.
나아가 본 발명에 따른 조성물은 상기 우수한 근육세포로의 포도당 흡수 촉진 효과를 통해 인슐린 저항성 또는 고인슐린혈증을 완하시키는 효과를 제공할 뿐만 아니라, 인체내 별다른 독성 및 부작용도 없어 장기간 복용시에도 안심하고 사용할 수 있다.Furthermore, the composition according to the present invention not only provides the effect of relieving insulin resistance or hyperinsulinemia through the effect of promoting glucose uptake into the excellent muscle cells, but also has no other toxicity and side effects in the human body, so it can be used safely in long-term use. Can be.
따라서 본 발명의 조성물은 고인슐린혈증 및 인슐린 저항성의 예방 또는 치료를 목적으로 하는 식품에 첨가할 수 있으므로, 고인슐린혈증 또는 인슐린 저항성 증상의 예방 및 개선을 위한 식품용 조성물로 사용할 수 있다.Therefore, the composition of the present invention can be added to a food for the purpose of preventing or treating hyperinsulinemia and insulin resistance, and thus can be used as a food composition for the prevention and improvement of hyperinsulinemia or insulin resistance symptoms.
즉, 본 발명은 하기 화학식으로 표시되는 디에콜(dieckol) 화합물을 유효성분으로 함유하는 고인슐린혈증 및 인슐린 저항성 예방 또는 개선용 식품을 제공한다.That is, the present invention provides a food for preventing or improving hyperinsulinemia and insulin resistance containing a dieteckol compound represented by the following formula as an active ingredient.
<화학식>≪
상기 디에콜 화합물은 상기 고인슐린혈증 또는 인슐린 저항성 증상의 예방 및 개선에 효과가 있는 식품, 예컨대, 식품의 주원료, 부원료, 식품 첨가제, 기능성 식품 또는 음료로 용이하게 활용할 수 있다.The diecol compound may be easily used as a food, such as a main ingredient, an auxiliary ingredient, a food additive, a functional food or a beverage, which is effective in preventing and improving the hyperinsulinemia or insulin resistance symptoms.
본 발명에서 상기 “식품”이란, 영양소를 한 가지 또는 그 이상 함유하고 있는 천연물 또는 가공품을 의미하며, 바람직하게는 어느 정도의 가공 공정을 거쳐 직접 먹을 수 있는 상태가 된 것을 의미하며, 통상적인 의미로서, 식품, 식품 첨가제, 기능성 식품 및 음료를 모두 포함하는 것을 말한다.In the present invention, the "food" means a natural product or processed product containing one or more nutrients, and preferably means a state in which it can be directly eaten through a certain processing step, and a general meaning As used herein, it refers to food, food additives, functional foods and beverages.
본 발명에 따른 조성물을 첨가할 수 있는 식품으로는 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 기능성 식품 등이 있다. 추가로, 본원발명에서 식품에는 특수영양식품(예, 조제유류, 영,유아식 등), 식육가공품, 어육제품, 두부류, 묵류, 면류(예, 라면류, 국수류 등), 빵류, 건강보조식품, 조미식품(예, 간장, 된장, 고추장, 혼합장 등), 소스류, 과자류(예, 스넥류), 캔디류, 쵸코렛류, 껌류, 아이스크림류, 유가공품(예, 발효유, 치즈 등), 기타 가공식품, 김치, 절임식품(각종 김치류, 장아찌 등), 음료(예, 과실 음료, 채소류 음료, 두유류, 발효음료류 등), 천연조미료(예, 라면 스프 등)을 포함하나 이에 한정되지 않는다. 상기 식품, 음료 또는 식품첨가제는 통상의 제조방법으로 제조될 수 있다.Foods to which the composition according to the present invention can be added include, for example, various foods, beverages, gums, tea, vitamin complexes, and functional foods. In addition, in the present invention, the food may include special nutritive foods (e.g., crude oil, spirits, baby food, etc.), meat products, fish meat products, tofu, mackerel, noodles (Such as soy sauce, soybean paste, kochujang, mixed potatoes), sauces, confectionery (eg, snacks), candies, chocolate, gums, ice cream, milk products (eg, fermented milk, cheese, But are not limited to, pickled foods (various kinds of kimchi, pickles, etc.), beverages (e.g., fruit drinks, vegetable beverages, beverages, fermented beverages and the like) and natural seasonings (e.g. The food, beverage or food additive may be prepared by a conventional production method.
또한, 상기 “기능성 식품”이란 식품에 물리적, 생화학적, 생물 공학적 수법 등을 이용하여 해당 식품의 기능을 특정 목적에 작용, 발현하도록 부가가치를 부여한 식품군이나 식품 조성이 갖는 생체방어리듬조절, 질병방지와 회복 등에 관한 체내조절기능을 생체에 대하여 충분히 발현하도록 설계하여 가공한 식품을 의미하며, 구체적으로는 건강 기능성 식품일 수 있다. 상기 기능성 식품에는 식품학적으로 허용 가능한 식품 보조 첨가제를 포함할 수 있으며, 기능성 식품의 제조에 통상적으로 사용되는 적절한 담체, 부형제 및 희석제를 더욱 포함할 수 있다.In addition, the term "functional food" refers to the control of biological defense rhythms and disease prevention of food groups or food compositions that have added value to the food by using physical, biochemical, or biotechnological techniques to act and express the function of the food for a specific purpose. It means a food that is designed and processed to fully express the body's regulatory function regarding recovery and the like, and specifically, it may be a health functional food. The functional food may include a food-acceptable food-aid additive, and may further comprise suitable carriers, excipients and diluents conventionally used in the production of functional foods.
또한, 본원발명에서 상기 “음료”란 갈증을 해소하거나 맛을 즐기기 위하여 마시는 것의 총칭을 의미하며 기능성 음료를 포함한다. 상기 음료는 지시된 비율로 필수 성분으로서 본 발명에 따른 상기 조성물을 포함하는 것 외에 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.In addition, in the present invention, the term "beverage" refers to a generic term for drinking to quench thirst or to enjoy a taste and includes a functional drink. The beverage is not particularly limited in addition to including the composition according to the present invention as an essential ingredient in the ratio indicated, and may contain various flavors or natural carbohydrates and the like as additional ingredients, as in the usual beverage.
나아가 상기 기술한 것 이외에 본원발명의 조성물을 함유하는 식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있으며, 상기 성분은 독립적으로 또는 조합하여 사용할 수 있다.Furthermore, the food containing the composition of the present invention in addition to the above-mentioned composition can be used as a food such as various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and fillers (cheese, And carbonates used in alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonated drinks, etc., and these components may be used independently or in combination Can be used.
본원발명의 조성물을 함유하는 식품에 있어서, 상기 본 발명에 따른 조성물의 양은 전체 식품 중량의 0.001중량% 내지 90중량%로 포함할 수 있으며, 바람직하게는 0.1중량% 내지 40중량%로 포함할 수 있고, 음료의 경우, 100ml를 기준으로 0.001g 내지 2g, 바람직하게는 0.01g 내지 0.1g의 비율로 포함할 수 있으나, 건강 및 위생을 목적으로 하거나 건강 조절을 목적으로 하는 장기간 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로 사용될 수 있으므로 상기 범위에 한정되는 것은 아니다.In the food containing the composition of the present invention, the amount of the composition according to the present invention may be 0.001% by weight to 90% by weight, preferably 0.1% by weight to 40% by weight, And in the case of beverages, it may be contained in a proportion of 0.001 g to 2 g, preferably 0.01 g to 0.1 g based on 100 ml. However, in the case of long-term intake for health and hygiene purposes or for health control purposes, And since the active ingredient has no problem in terms of safety, it can be used in an amount of more than the above range, so it is not limited to the above range.
그러므로 본 발명은 본 발명에 따른 디에콜 화합물을 유효성분으로 함유하는 인슐린 저항성 또는 고인슐린혈증 예방 또는 개선용 건강기능식품을 제공할 수 있으며, 상기 식품의 형태는 이에 제한되지는 않으나, 분말, 과립, 정제, 캡슐 또는 음료 형태일 수 있다.
Therefore, the present invention can provide a dietary supplement for preventing or improving insulin resistance or hyperinsulinemia containing a dietary alcohol compound according to the present invention, but the form of the food is not limited thereto. , Tablet, capsule or beverage form.
이하, 본 발명을 하기 실시예 및 실험예에 의해 상세히 설명한다. 단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실험예에 의해 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail with reference to the following examples and experimental examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following Experimental Examples.
<< 실시예Example 1> 1>
본 발명의 The 디에콜이Diecole 근육세포내로의Into muscle cells 포도당 흡수에 미치는 영향 측정 Determination of the effect on glucose absorption
본 발명의 디에콜이 근육세포내로의 포도당 흡수에 미치는 영향을 알아보기 위하여 하기와 같은 실험을 수행하였다.
In order to determine the effect of the dietary alcohol of the present invention on glucose uptake into muscle cells, the following experiment was performed.
<1-1> 세포배양 및 분화<1-1> Cell Culture and Differentiation
실험에 사용한 근육세포(L6)는 한국세포주은행에서 구입하였고 10% FBS와 1% antibiotics를 첨가한 DMEM 배지에서 37℃, 5% 이산화탄소(CO2) 배양기에서 배양한다. 미분화 상태의 근육세포(L6)가 70~80% 자라면 2% 말혈청 (horse serum)을 첨가한 DMEM 배지로 교체한 후 7일 동안 분화를 유도하였으며 2일 마다 배지를 갈아주었다. The muscle cells (L6) used in the experiment were purchased from Korean Cell Line Bank and cultured in DMEM medium supplemented with 10% FBS and 1% antibiotics at 37 ° C in a 5% CO 2 incubator. If the undifferentiated muscle cells (L6) were 70 to 80%, DMEM medium supplemented with 2% horse serum was added and the differentiation was induced for 7 days and the medium was changed every 2 days.
<1-2> <1-2> 근육세포내로의Into muscle cells 포도당 흡수 측정 Glucose absorption measurement
분화된 근육세포를 무혈청 DMEM배지에서 4시간 starvation 시킨 후 PBS로 세척하였다. 이후 다시 새로운 무혈청 DMEM으로 교체하고 디에콜 화합물을 처리하고 30분 동안 배양하고 대조군으로 사용한 인슐린은 처리한 후 10분 동안 반응시켰다. 포도당 흡수 측정은 배지내에 함유된 포도당 양을 측정하여 세포내로 이동한 포도당 양을 계산하였다. 계산된 디에콜의 근육세포내로의 포도당 흡수정도를 도 1에 나타내었다.Differentiated muscle cells were starvated in serum-free DMEM medium for 4 hours and washed with PBS. Subsequently, it was replaced with fresh serum-free DMEM, treated with a diecol compound, incubated for 30 minutes, and insulin treated as a control was reacted for 10 minutes. Glucose uptake was measured by measuring the amount of glucose contained in the medium to calculate the amount of glucose transferred into the cells. The calculated degree of glucose uptake into the muscle cells of dietol is shown in FIG.
그 결과, 도 1로부터 디에콜은 농도 의존적으로 근육세포내로의 포도당 흡수를 증가시키는 것을 확인하였으며, 디에콜 50 uM의 농도에서 인슐린과 유사한 포도당 흡수 효과를 나타냈다. 이 결과로부터 디에콜이 근육세포내로의 포도당 흡수촉진 작용 효과를 가진다는 것을 확인하였다. As a result, it was confirmed that dietol increased glucose uptake into muscle cells in a concentration-dependent manner, and showed a glucose-like glucose uptake effect at dietol 50 uM concentration. From this result, it was confirmed that dietol has the effect of promoting glucose uptake into muscle cells.
<1-3> <1-3> 근육세포내로의Into muscle cells 포도당 흡수 작용기작 구명을 위한 For following glucose absorption mechanism 웨스턴Western 블랏Blat 분석 analysis
분화된 근육세포를 무혈청 DMEM배지에서 4시간 starvation 시킨 후 PBS로 세척하였다. 이후 다시 새로운 무혈청 DMEM으로 교체하고 디에콜(50uM)을 처리하고 30분 동안 배양하고 대조군으로 사용한 인슐린은 처리한 후 10분 동안 반응시켰다. 반응 종료 후 세포들을 수거하여 용해완충액으로 세포를 용출시켰다. 이 세포 용출액을 다시 세포막과 세포질로 분리하여 각각 단백질 함량을 측정한 후 동량의 세포막 단백질에 함유된 GLUT4 발현양상을 안티-GLUT4 항체를 사용하였고 동량의 세포질 단백질에 함유된 phospho-Akt와 phospho-AMPK의 발현양상은 각각 안티-phospho-Akt(Ser 473)과 안티-phospho-AMPK(Thr 172)를 사용하여 immunoblotting 방법으로 측정하였다. 측정된 각각의 단백질 발현양상을 도 2에 나타내었다. Differentiated muscle cells were starvated in serum-free DMEM medium for 4 hours and washed with PBS. Subsequently, it was replaced with fresh serum-free DMEM, treated with diecol (50 uM), incubated for 30 minutes, and the insulin used as a control was reacted for 10 minutes after treatment. After the completion of the reaction, the cells were collected and the cells were eluted with lysis buffer. The cell eluate was separated into cell membrane and cytoplasm again, and the protein content was measured, respectively. The expression of GLUT4 contained in the same amount of membrane protein was determined using anti-GLUT4 antibody, and the phospho-Akt and phospho-AMPK contained in the same amount of cytoplasmic protein The expression patterns of were measured by immunoblotting using anti-phospho-Akt (Ser 473) and anti-phospho-AMPK (Thr 172), respectively. Each protein expression pattern measured is shown in FIG. 2.
그 결과, 도 2로부터 디에콜은 근육 내로의 포도당 흡수에 있어 반드시 필요한 Akt(인슐린의존형)와 AMPK(인슐린비의존형) 및 GLUT4의 단백질 발현 양을 모두 증가시킨다는 사실을 확인하였다. 근육세포내로의 포도당 흡수는 Akt와 AMPK의 활성화에 의해 포도당수송운반체인 GLUT4가 세포막으로 이동하여 세포 내로 포도당이 흡수되는 것으로 알려져 있다. 이에 본 실시예에서는 디에콜이 Akt와 AMPK을 모두 활성화 시켰으며 GLUT4의 발현도 증가하여 GLUT4가 세포막으로 이동하여 세포내로 포도당이 흡수 작용을 용이하게 함을 규명하였다.
As a result, it was confirmed from Figure 2 that dietol increases the amount of protein expression of Akt (insulin-dependent) and AMPK (insulin-independent) and GLUT4, which are essential for glucose uptake into muscle. Glucose uptake into muscle cells is known that GLUT4, a glucose transporter, moves to the cell membrane by the activation of Akt and AMPK, and glucose is absorbed into cells. In this example, it was found that dietol activated both Akt and AMPK, and GLUT4 expression was also increased, and GLUT4 moved to the cell membrane to facilitate glucose uptake into cells.
<< 실시예Example 2> 2>
본 발명에 따른 According to the invention 디에콜Diecol 화합물의 동물 모델에서의 In animal models of compounds 고인슐린혈증Hyperinsulinemia 개선 효과 Improvement effect
5주령의 수컷 ICRC57BL/6 db/db mice를 (주)중앙실험동물에서 구입하여 4주일간 일반식이로 적응시킨 후 실험에 사용하였다. 실험군은 대조군과 디에콜 10 mg/kg B.W 투여군, 디에콜 20 mg/kg B.W 투여군으로 무작위 배정하였다. 실험은 총 2주간 실시하였으며 디에콜 투여군은 1일 1회 상기의 용량으로 각각 복강내 투여 하였다. 사육실의 온도와 습도는 20±2℃, 50±10%로 유지하였고, 명암은 12시간 간격으로 조절하였으며, 식이와 식수는 자유롭게 섭취하도록 하였다. Five-week-old male ICRC57BL / 6 db / db mice were purchased from a central laboratory animal and used for experiments after adapting to a general diet for 4 weeks. The experimental group was randomly assigned to the control group, dietol 10 mg / kg B.W administration group, dietol 20 mg / kg B.W administration group. The experiment was conducted for a total of two weeks, and the diecol-administered group was administered intraperitoneally once a day at the above doses. The temperature and humidity of the breeding room were maintained at 20 ± 2 ° C and 50 ± 10%, and the darkness and the humidity were adjusted at intervals of 12 hours.
실험기간 중 체중 및 공복혈당은 일정한 시간에 측정하였다. 공복혈당 측정은 2일에 한번 db/db mice를 밤 동안 12시간 절식 시킨 후, 꼬리정맥에서 채혈하여 혈당을 간이 혈당계로 측정하였다. 2주간의 실험 종료 후 db/db mice에서 혈액을 수집한 뒤 원심분리 하여 혈장을 분리하였다. 분리된 혈장을 이용하여 인슐린농도를 ELISA법을 따라 Rat/Mouse Insulin ELISA kit를 이용하여 측정하였다. Body weight and fasting blood glucose were measured at a constant time during the experiment. Fasting blood glucose was measured by fasting the db / db mice for 12 hours every night and then collecting blood from the tail vein. After two weeks of experiments, blood was collected from db / db mice and centrifuged to separate plasma. Insulin concentrations were measured using the separated plasma using a Rat / Mouse Insulin ELISA kit following the ELISA method.
우선, 본 발명의 디에콜 화합물을 섭취한 인슐린 저항성을 겪고 있는 인슐린 비의존적 제2형 당뇨 모델쥐에서의 혈중 인슐린 농도 변화를 살펴본 결과, 도 3에서와 같이, 대조군으로서 아무것도 섭취하지 않은 제2형 당뇨 모델쥐에서의 혈중 인슐린 함량은 9.8 ng/ml로서 정상쥐의 혈중 인슐린 함량인 2~3 ng/ml에 비해 매우 높음을 알 수 있다.First, suffer from insulin resistance ingesting the dietol compound of the present invention As a result of examining the change of blood insulin concentration in the insulin-
그러나, 디에콜 화합물을 실험 시작 2주일 동안 투여한 모델쥐의 혈액 내 인슐린의 농도는 크게 저하됨을 알 수 있다. 특히 디에콜을 20 mg/kg 투여군 경우 혈중 인슐린 함량이 5.2 ng/ml 로, 대조군과 비교해 혈중 인슐린 함량이 약 2배 가량 낮아짐을 확인하였다. 상기 결과로부터 본 발명자들은 디에콜 화합물이 고인슐린혈증 및 이를 동반하는 인슐린 저항성 질환을 개선 및 치료하는 효과를 가진다는 것을 알 수 있었다.However, it can be seen that the concentration of insulin in the blood of the model rats administered with the dietol compound for two weeks from the start of the experiment was significantly reduced. Especially In the case of dietol 20 mg / kg administration group, the blood insulin content was 5.2 ng / ml, compared to the control group was confirmed that the blood insulin content is about 2 times lower. From the above results, the inventors have found that the dietol compound has an effect of improving and treating hyperinsulinemia and accompanying insulin resistant diseases.
또한, 추가적으로 상기 모델쥐들의 혈당 변화를 확인한 결과, 도 4에서와 같이 본 발명에 따른 디에콜의 투여군은 대조군에 비하여 지속적인 혈당 감소를 나타냄을 알 수 있었다. In addition, as a result of confirming the change in blood glucose of the model rats, as shown in Figure 4, the administration group of dietol according to the present invention was found to exhibit a continuous decrease in blood glucose compared to the control group.
이에 본 발명자들은 본 발명에 따른 디에콜 화합물이 세포로의 포도당 흡수를 촉진하는 Akt(인슐린의존형)와 AMPK(인슐린비의존형) 및 GLUT4의 발현을 촉진시켜 이미 체내에 흡수된 포도당의 소비를 촉발하므로서, 혈중에 인슐린 함량을 낮추고 인슐린 저항성을 해결하며, 혈중 포도당 농도 또한 낮춤을 확인할 수 있었다.Therefore, the inventors of the present invention, the dietary compound according to the present invention promotes the expression of Akt (insulin-dependent) and AMPK (insulin-independent) and GLUT4 to promote glucose uptake into cells, thereby triggering the consumption of glucose already absorbed into the body. In addition, the insulin content in the blood was lowered and the insulin resistance was resolved. The blood glucose level was also lowered.
본 실시예에 있어서, 모든 실험결과는 SAS 프로그램을 이용하여 평균±표준편차로 나타내었고, 유의성은 one-way ANOVA로 사전 검증한 후 Duncan's multiple range test에 의해 사후 검정하였다. 통계적인 유의수준은 P 값이 0.05 미만인 경우로 하였다.
In this example, all experimental results were expressed as mean ± standard deviation using SAS program, and significance was pretested by one-way ANOVA and post-tested by Duncan's multiple range test. The statistical significance level was obtained when the P value was less than 0.05.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할수 있을 것이다. 그러므로 개시된 실시 예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far I looked at the center of the preferred embodiment for the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
Claims (5)
<화학식>
.A composition for preventing or treating hyperinsulinemia, containing a dieteckol compound represented by the following formula as an active ingredient:
≪
.
상기 디에콜 화합물은 Akt, AMPK 및 GLUT4의 발현을 증가시켜 근육세포로의 포도당 흡수를 촉진하는 것을 특징으로 하는 고인슐린혈증 예방 또는 치료용 조성물.The method of claim 1,
The dietic compound is a composition for preventing or treating hyperinsulinemia, characterized in that to promote the absorption of glucose into muscle cells by increasing the expression of Akt, AMPK and GLUT4.
<화학식>
.A composition for preventing or treating insulin resistance, containing a dieckol compound represented by the following formula as an active ingredient:
≪
.
상기 디에콜 화합물은 Akt, AMPK 및 GLUT4의 발현을 증가시켜 근육세포로의 포도당 흡수를 촉진하는 것을 특징으로 하는 인슐린 저항성 예방 또는 치료용 조성물.The method of claim 3,
The dietary compound is a composition for preventing or treating insulin resistance, characterized in that to promote the absorption of glucose into muscle cells by increasing the expression of Akt, AMPK and GLUT4.
<화학식>
.A food for preventing or improving hyperinsulinemia and insulin resistance containing a dieteck compound represented by the following formula as an active ingredient:
≪
.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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KR101504912B1 (en) * | 2013-06-11 | 2015-03-23 | 주식회사한국야쿠르트 | The products containing probiotic lactobacillus acidophilus HY7037 having activity preventing from insulin resistance, which caused type 2 diabetes mellitus |
KR101535077B1 (en) * | 2013-09-13 | 2015-07-08 | 주식회사한국야쿠르트 | The products containing probiotic Bifidobacterium lactis HY8101 having activity preventing from insulin resistance, which caused type 2 diabetes mellitus |
WO2016047924A3 (en) * | 2014-09-26 | 2016-08-11 | 주식회사 보타메디 | Fluorescent-labeled novel dieckol derivative |
KR20200034938A (en) * | 2018-09-21 | 2020-04-01 | 주식회사 보타메디 | A composition for making kimchi comprising phlorotannin and kimchi made thereof |
-
2012
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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KR101504912B1 (en) * | 2013-06-11 | 2015-03-23 | 주식회사한국야쿠르트 | The products containing probiotic lactobacillus acidophilus HY7037 having activity preventing from insulin resistance, which caused type 2 diabetes mellitus |
KR101535077B1 (en) * | 2013-09-13 | 2015-07-08 | 주식회사한국야쿠르트 | The products containing probiotic Bifidobacterium lactis HY8101 having activity preventing from insulin resistance, which caused type 2 diabetes mellitus |
WO2016047924A3 (en) * | 2014-09-26 | 2016-08-11 | 주식회사 보타메디 | Fluorescent-labeled novel dieckol derivative |
KR20200034938A (en) * | 2018-09-21 | 2020-04-01 | 주식회사 보타메디 | A composition for making kimchi comprising phlorotannin and kimchi made thereof |
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