KR101121954B1 - Composition for preventing or treating diabetes comprising 1,2,3-Benzentricarboxylic acid - Google Patents
Composition for preventing or treating diabetes comprising 1,2,3-Benzentricarboxylic acid Download PDFInfo
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- KR101121954B1 KR101121954B1 KR1020100045116A KR20100045116A KR101121954B1 KR 101121954 B1 KR101121954 B1 KR 101121954B1 KR 1020100045116 A KR1020100045116 A KR 1020100045116A KR 20100045116 A KR20100045116 A KR 20100045116A KR 101121954 B1 KR101121954 B1 KR 101121954B1
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- Prior art keywords
- diabetes
- insulin
- bta
- acid
- preventing
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/111—Aromatic compounds
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/035—Organic compounds containing oxygen as heteroatom
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/328—Foods, ingredients or supplements having a functional effect on health having effect on glycaemic control and diabetes
Abstract
본 발명은 항당뇨 효과를 갖는 1,2,3-Benzentricarboxylic acid(이하 ‘BTA’라 한다)의 사용용도에 관한 것이다. 당뇨병 발생 모델 생쥐인 C57BLKS/J- db/db에 BTA를 4주간 투여시 탁월한 혈당강하 효능을 나타내었다. 특히 BTA를 투여한 db/db 생쥐군에서 인슐린을 분비하는 췌장의 베타세포는 파괴되지 않고 보존되는 효과가 나타났다. 즉, BTA는 혈당강하, 베타세포 보전, 포도당 자극 인슐린 분비 증가에 뚜렷한 효능이 있었으므로 BTA는 당뇨병 예방 또는 당뇨병 치료용 조성물로 사용할 수 있을 것으로 사료된다.The present invention relates to the use of 1,2,3-Benzentricarboxylic acid (hereinafter referred to as 'BTA') having an anti-diabetic effect. Diabetic model mice, C57BLKS / J-db / db, showed an excellent hypoglycemic effect when BTA was administered for 4 weeks. In particular, the beta cells of the insulin-releasing pancreas in BTA-administered db / db mice were preserved without destruction. That is, BTA has a marked effect on lowering blood sugar, preserving beta cells, and increasing glucose-stimulated insulin secretion, and thus, BTA may be used as a composition for preventing or treating diabetes.
Description
본 발명은 1,2,3-Benzentricarboxylic acid를 유효성분으로 포함하는 당뇨병 예방 또는 치료용 조성물에 관한 것으로서, 더욱 상세하게는 1,2,3-Benzentricarboxylic acid (BTA) 투여에 의한 db/db mice의 혈당강하, 베타세포 보존, 포도당 자극 인슐린 분비 증가 효과를 가진 당뇨병 치료 또는 예방용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating diabetes comprising 1,2,3-Benzentricarboxylic acid as an active ingredient, and more particularly, to db / db mice by 1,2,3-Benzentricarboxylic acid (BTA) administration. The present invention relates to a composition for treating or preventing diabetes having an effect of lowering blood sugar, preserving beta cells, and increasing glucose-stimulated insulin secretion.
당뇨병은 혈중 당농도가 증가하여 발병하는 만성 대사 질환이다. 혈중 당농도는 주로 인슐린과 글루카곤이라는 호르몬에 의해서 조절되는데 식사 후 혈중 당농도가 높은 상황이 되면 췌장 베타세포는 높아진 포도당 농도를 인식하여 인슐린을 분비하고 분비된 인슐린은 표적세포 (지방, 근육)에서 포도당의 흡수를 촉진하여 혈당을 낮추게 된다. 음식물 섭취 후 혈액 내 증가된 포도당 농도를 낮추지 못하거나 공복 시 포도당을 많이 생산하게 되면 혈액내 당이 높아지게 되고 이런 상태가 당뇨병이다. 혈액 내에 포도당이 지속적으로 증가되면 눈, 신장 및 신경 손상뿐만 아니라 뇌경색, 협심증 및 말초혈관질환 등의 심각한 합병증이 초래되고, 삶의 질을 저하시키게 되며 사망률 또한 증가된다. 제 2형 당뇨병은 세계적으로 가파르게 증가하고 있는 질병으로 25년 후에는 당뇨 질환 환자가 지금의 2배에 이를 것으로 추정되며, 현재 우리나라에서도 사망에 이르는 원인 4위를 차지하고 있다. Diabetes is a chronic metabolic disease caused by an increase in blood sugar levels. Blood glucose levels are controlled mainly by hormones called insulin and glucagon. When blood glucose levels are high after meals, pancreatic beta cells recognize high glucose levels and secrete insulin, and secreted insulin is released from target cells (fats, muscles). It accelerates the absorption of glucose and lowers blood sugar. If you fail to lower the increased glucose levels in your blood after eating, or if you produce a lot of glucose on an empty stomach, your blood sugar will rise and this condition is diabetes. The continuous increase in glucose in the blood leads to serious complications such as eye injuries, kidneys and nerves as well as cerebral infarction, angina and peripheral vascular disease, poor quality of life and increased mortality.
제2형 당뇨병은 제1형 당뇨병과 달리 인슐린이 분비됨에도 불구하고 인슐린 작용이 적절하게 이루어지지 못해 발병하는 질병으로써 발병 후에도 계속 당 조절이 악화되어 혈당이 지속적으로 증가하는 진행성 대사 질환 (progressive metabolic disease)이다. 인슐린의 작용 이상 (인슐린 저항성 : insulin resistance)과 인슐린 분비 이상 (beta-cell dysfunction)은 제2형 당뇨병에서 나타나는 특징이며, 이것은 이미 유전적으로 결정된다고 알려져 있다. 여기에 과영양, 운동부족, 비만과 같은 환경적인 요인이 더해져서 당뇨병이 유발된다 (LeRoith, Beta-cell dysfunction and insulin resistance in type 2 diabetes : Role of metabolic and genetic abnormalities. Am J Med. vol.113, pp.3s-11s, 2002). 비만으로 인해 유도된 인슐린 저항성은 인슐린의 표적기관인 간, 골격근 지방조직에서 인슐린 작용에 결함을 나타내고 이 때문에 혈중 포도당 농도가 높아지게 된다. 이를 극복하려고 처음에는 베타세포의 수가 양적으로 증가하며 인슐린 분비 또한 증가함으로 정상적인 혈당을 유지할 수 있다 (NGT : normal glucose tolerance). 이 단계를 베타세포의 보상작용 (β-cell compensation) 단계라고 한다. 그러나 시간이 지날수록 인슐린 저항성에 대한 베타세포의 보상 작용이 감소하게 되고, 나중에는 베타세포의 기능이상으로 이어져서 인슐린 분비가 감소하고 혈중 포도당 농도는 더욱 더 증가하게 된다 (IGT : impair glucose tolerance) (Prentki M, Nolan CJ. Islet beta-cell failure in type2 diabetes. J Clin Invest. vol.51, ppS245-54, 2002). 증가된 혈중 포도당 농도는 (hyperglycemia: glucotoxicity) 지방산 (free fatty acids: lipotoxicity)과 함께 베타 세포의 양적 감소를 초래하고 (β-cell failure) 포화 지방산, resistin, TNF-α 등은 인슐린 저항성을 악화시켜서 더욱 더 혈중 포도당 농도가 높아지게 된다 (LeRoith. Beta-cells dysfunction and insulin resistance in type 2 diabetes : role of metabolic and genetic abnormalities. Am J Med, vol.113, ppS3-11, 2002). 이 단계에 도달하면 명백한 당뇨병으로 진단되며 고혈당이 지속적으로 유지되고 항당뇨병 약제로도 개선되지 않으며 인슐린 치료 요법을 통한 혈당조절이 필요하다.Unlike
따라서 베타세포의 인슐린 분비능의 지속적인 감소 또는 베타세포의 양적 감소는 제2형 당뇨병의 발병을 결정하는 핵심적인 병인으로 믿어지고 있다. 당뇨병을 치료하기 위한 방안으로 인슐린 민감도를 증진하는 동시에 베타세포의 양적 감소 없이 인슐린 분비를 증강시키는 약물개발이 필요하다.Therefore, the continuous decrease in the insulin secretion capacity of beta cells or the decrease in the amount of beta cells is believed to be a key etiology for determining the onset of
당뇨병의 치료에 사용되는 약제들은 기본적으로 제2형 당뇨병에서 나타나는 감소된 인슐린 저항성과 인슐린 분비의 교정에 초점을 맞추고 있다. 그 동안 많은 약제가 개발되었지만 약제 독성이나 유효성, 안전성 등이 문제 되어 실제 임상에서 사용되는 약제는 따이아졸리딘다이온 (Thiazolidinedions), 바이구아나이드(biguanide), 썰폰요소제 (sulfonylurea) 등이 있다. 따이아졸리딘다이온 계열 (Thiazolidinedions)의 약제 중 대표적인 피오글리타존 (pioglitazone)과 로지글리타존 (rosiglitazone)은 인슐린의 민감도를 증강시키고, 바이구아나이드 (biguanide) 계열의 약제인 메트포민 (metformin)은 인슐린 저항성을 개선시키며 간에서 포도당 생합성을 줄여준다. 베타세포에 초점을 맞춘 약제인 썰폰요소제 (sulfonylurea)는 인슐린 분비를 촉진한다. 그러나 이들 약물 또한 혈당을 조절하는 효과 외에도 다른 부작용이 보고된 바 인슐린 저항성 개선 효과와 동시에 인슐린 분비 촉진과 같이 효과적으로 혈당을 조절하는 새로운 약물에 대한 개발이 필요하다.Drugs used to treat diabetes are primarily focused on correcting the decreased insulin resistance and insulin secretion seen in
1,2,3-Benzentricarboxylic acid (BTA)는 마이토콘드리아 내벽에 존재하는 citrate 운반체의 저해제로 알려져 있다. citrate 운반체는 간에서 지방합성에 중요한 역할을 한다고 알려져 있다. 마이토콘드리아에서 운반된 citrate는 세포질에서 지방 합성과 콜레스테롤 합성에 중요한 기질로 제공된다. 또한 citrate 운반체는 포도당으로부터 유래된 citrate를 마이토콘드리아에서 세포질내로 이동시켜 탄수화물 대사와 지방합성대사를 연결하는 중요한 역할을 한다 (Gabriele V. Gnoni, Paola Priore, Math J. H. Geelen and Luisa Siculella. The mitochondrial citrate carrier : metabolic role and regulation of its activity and expression. IUBMB Life, vol.61, pp987-994. 2009). 1,2,3-Benzentricarboxylic acid (BTA) is known as an inhibitor of citrate carriers in the inner walls of mitochondria. Citrate carriers are known to play an important role in fat synthesis in the liver. Citrate transported from the mitochondria serves as an important substrate for fat synthesis and cholesterol synthesis in the cytoplasm. The citrate carrier also transports glucose-derived citrate from the mitochondria into the cytoplasm and plays an important role in carbohydrate metabolism and liposynthesis (Gabriele V. Gnoni, Paola Priore, Math JH Geelen and Luisa Siculella.The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression.IUBMB Life, vol. 61, pp987-994. 2009).
고농도 포도당에 오랫동안 노출되면 베타세포의 기능이상을 유발한다. 이를 포도당 독성(Glucolipotoxicity), 그리고 포도당 탈감작(Glucose desensitization)이라 일컫는다 (Z Ling, R kieken, T Mahler, F C Schuit, M pipeleers-Marichal, A sener, G Kloppel, W J Malaisse and D G pipeleer Kiekens. Effects of chronically elevated glucose levels on the functional properties of rat pancreatic beta-cells. Diabetes. vol 45, pp1774, 1996)(Robertson R. P,Olson L. K, Zhang H. J. Differentiating glucose toxicity from glucose desensitization : a new message from the insulin gene. Diabetes vol.43, pp10851089. 1994). KATP channel opener로 알려진 diazoxide를 베타세포에 처리하면 세포막의 탈분극을 유도하지 못해 인슐린 분비가 감소한다. diazoxide를 베타세포 주에 미리 처리해주면 고농도 포도당이나 tolbutamide에 의한 베타세포 사멸을 억제하며 (Efanova IB, Zaitsev SV, Zhivotovsky B, Kohler M, Efendic S, Orrenius S, Berggeren PO. Glucose and tolbutamide induce apoptosis in pancreatic beta-cell. A process dependent on intracellular Ca2+ concentration. J Biol Chem, vol.273, pp33501-33507, 1998), 당뇨병으로 진행을 억제할 수 있다고 보고되었다 (Hasem JB, Arkhammar PO, Bodvarsdottir TB, Wahl P. Inhibition of insulin secretion as a new drug target in the treatment of metabolic disorders. vol.11, pp1595-1615, 2004). 이는 인슐린 분비를 억제시킴으로 베타세포를 쉬게 하는 모델로써 당뇨병과 비만을 동시에 예방할 수 있다. Prolonged exposure to high levels of glucose can cause beta cell dysfunction. This is called Glucolipotoxicity, and Glucose desensitization (Z Ling, R kieken, T Mahler, FC Schuit, M pipeleers-Marichal, A sener, G Kloppel, WJ Malaisse and DG pipeleer Kiekens.Effects of chronically elevated glucose levels on the functional properties of rat pancreatic beta-cells.Diabetes.vol 45, pp 1774, 1996) (Robertson R. P, Olson L. K, Zhang HJ Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene Diabetes vol. 43, pp 10851089. 1994). Treatment of diazoxide, also known as K ATP channel opener, on beta cells reduces insulin secretion by inducing depolarization of cell membranes. Pretreatment of diazoxide to beta cell lines inhibits beta cell death by high glucose or tolbutamide (Efanova IB, Zaitsev SV, Zhivotovsky B, Kohler M, Efendic S, Orrenius S, Berggeren PO.Glucose and tolbutamide induce apoptosis in pancreatic beta-cell.A process dependent on intracellular Ca2 + concentration.J Biol Chem, vol. 273, pp33501-33507, 1998), reported to inhibit progression to diabetes (Hasem JB, Arkhammar PO, Bodvarsdottir TB, Wahl P. Inhibition of insulin secretion as a new drug target in the treatment of metabolic disorders.vol. 11, pp 1595-1615, 2004). It is a model that restrains beta cells by inhibiting insulin secretion and can prevent diabetes and obesity at the same time.
본 발명은 상기의 문제점을 해결하고 상기의 필요성에 의하여 안출된 것으로서 본 발명의 목적은 당뇨병 예방 또는 치료용 조성물을 제공하는 것이다.The present invention solves the above problems and the object of the present invention is to provide a composition for preventing or treating diabetes.
상기의 목적을 달성하기 위하여 본 발명은 1,2,3-벤젠트리카르복실산(Benzentricarboxylic acid)을 유효성분으로 포함하는 당뇨병 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising 1,2,3-benzenetricarboxylic acid as an active ingredient.
본 발명의 일 구현예에 있어서, 상기 본 발명의 화합물의 유효량은 0.001~10 그램/kg 체중인 것이 바람직하고, 0.05~0.1 그램/kg 체중인 것이 더욱 바람직하나 이에 한정되지 아니한다. In one embodiment of the present invention, the effective amount of the compound of the present invention is preferably 0.001 ~ 10 gram / kg body weight, more preferably 0.05 ~ 0.1 gram / kg body weight, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 당뇨병은 타입 2 당뇨병인 것이 바람직하나 이에 한정되지 아니한다.In one embodiment of the present invention, the diabetes is preferably
본 발명의 일 구현예에 있어서, 상기 화합물은 혈당 강하 효과,췌장 베타세포 보존 효과 및/또는 포도당 자극 인슐린 분비 증가 효과를 나타내는 것을 특징으로 하나 이에 한정되지 아니한다.In one embodiment of the present invention, the compound is characterized by a hypoglycemic effect, pancreatic beta-cell preservation effect and / or glucose-stimulated insulin secretion effect is not limited thereto.
또한 본 발명은 1,2,3-벤젠트리카르복실산(Benzentricarboxylic acid)을 유효성분으로 포함하는 당뇨병 개선용 식품 조성물을 제공한다.In another aspect, the present invention provides a food composition for improving diabetes comprising 1,2,3-benzenetricarboxylic acid (Benzentricarboxylic acid) as an active ingredient.
또한 본 발명은 1,2,3-벤젠트리카르복실산(Benzentricarboxylic acid)을 유효성분으로 포함하는 당뇨병 예방 또는 치료용 사료 조성물을 제공한다.In another aspect, the present invention provides a feed composition for preventing or treating diabetes, comprising 1,2,3-benzenetricarboxylic acid as an active ingredient.
본 발명의 화합물을 유효 성분으로서 함유하는 것을 특징으로 하는 당뇨병의 예방 또는 치료제는 본 발명의 화합물을 함유하고,필요에 따라서 약리학적으로 허용되는 1종 또는 그 이상의 담체, 추가로 필요에 따라서 다른 예방 또는 치료를 위한 유효 성분을 더 함유할 수도 있다. 또한, 본 발명의 당뇨병의 예방 또는 치료제에는 당뇨병의 예방 또는 치료에 유효한 임의의 다른 성 분이 첨가되어 있을 수도 있다.A prophylactic or therapeutic agent for diabetes, which comprises the compound of the present invention as an active ingredient, contains one or more pharmacologically acceptable carriers of the present invention, and further other prophylaxis, if necessary. Or may further contain an active ingredient for treatment. In addition, any other component effective for preventing or treating diabetes may be added to the prophylactic or therapeutic agent for diabetes of the present invention.
본 발명의 당뇨병의 예방제 또는 치료제는 본 발명의 화합물 및 필요에 따라서 다른 유효 성분을 약리학적으로 허용되는 1종 또는 그 이상의 담체와 함께 혼합하여, 제제학의 기술 분야에서 잘알려져 있는 임의의 방법에 의해 제조된다.The prophylactic or therapeutic agent for diabetes of the present invention may be mixed with a compound of the present invention and, if necessary, other active ingredients with one or more pharmaceutically acceptable carriers, by any method well known in the art of formulation. Are manufactured.
본 발명의 당뇨병의 예방제 또는 치료제의 투여 경로는 당뇨병의 예방 또는 치료에 효과적인 것을 사용하는 것이 바람직하고, 예를 들면 경구 투여 또는 예를 들면 정맥내 투여 등의 비경구 투여를 들 수 있다.The administration route of the prophylactic or therapeutic agent for diabetes of the present invention is preferably one that is effective for the prevention or treatment of diabetes, for example, oral administration or parenteral administration such as intravenous administration.
투여 형태로서는 예를 들면 정제, 산제, 과립제, 환제, 현탁제, 유제, 침제, 캡슐제, 시럽제, 주사제, 액제, 엘릭시르제,엑기스제, 팅크제, 유동 엑기스제 등을 들 수 있다.Examples of the dosage form include tablets, powders, granules, pills, suspensions, emulsions, emulsifiers, capsules, syrups, injections, solutions, elixirs, extracts, tinctures, liquid extracts, and the like.
경구 투여에 적합한, 예를 들면 시럽제와 같은 액체 제조물은 물, 슈크로오스, 솔비트, 과당 등의 당류, 폴리에틸렌글리콜, 프로필렌글리콜 등의 글리콜류, 참기름, 올리브유, 대두유 등의 기름류 등의 희석제, p-히드록시벤조산에스테르류 등의 방부제, 파라옥시벤조산메틸 등의 파라옥시벤조산 유도체, 벤조산나트륨 등의 보존제, 딸기향, 페퍼민트 등의 향료 등을 사용하여 제조할 수 있다.Suitable liquid preparations for oral administration, for example, syrups include water, sucrose, sorbet, sugars such as fructose, glycols such as polyethylene glycol and propylene glycol, diluents such as oils such as sesame oil, olive oil and soybean oil, preservatives such as p-hydroxybenzoic acid esters, paraoxybenzoic acid derivatives such as methyl paraoxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint.
또한, 경구 투여에 적합한 정제, 산제 및 과립제 등은 유당, 백당, 포도당, 슈크로오스, 만니톨, 소르비톨 등의 당류, 감자, 밀, 옥수수 등의 전분, 탄산칼슘, 황산칼슘, 탄산수소나트륨, 염화나트륨 등의 무기물, 결정 셀룰로오스, 감초 분말,겐티아나 분말 등의 식물 분말 등의 부형제, 전분, 한천, 젤라틴 분말, 결정 셀룰로오스, 카르멜로오스나트륨, 카르멜로오스칼슘, 탄산칼슘, 탄산수소나트륨, 알긴산나트륨 등의 붕해제, 스테아르산마그네슘, 탈크, 수소 첨가 식물유, 마크로골, 실리콘유 등의 활택제, 폴리비닐알코올, 히드록시프로필셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스, 카르멜로오스, 젤라틴, 전분 풀액 등의 결합제, 지방산 에스테르 등의 계면활성제, 글리세린 등의 가소제 등을 사용하여 제조할 수 있다.In addition, tablets, powders and granules suitable for oral administration include lactose, sugar, glucose, sucrose, saccharides such as mannitol and sorbitol, starch such as potatoes, wheat and corn, calcium carbonate, calcium sulfate, sodium bicarbonate and sodium chloride. Excipients such as inorganic powders, plant powders such as crystalline cellulose, licorice powder, gentian powder, starch, agar, gelatin powder, crystalline cellulose, sodium carmellose, carmellose calcium, calcium carbonate, sodium hydrogencarbonate, sodium alginate Disintegrating agents, such as magnesium stearate, talc, hydrogenated vegetable oil, macrogol, silicone oil and other lubricants, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carmellose, gelatin, starch liquor, etc. It can manufacture using surfactant, such as a binder and fatty acid ester, and plasticizer, such as glycerin.
비경구 투여에 적합한 제제는, 바람직하게는 수용자의 혈액과 등장인 활성 화합물을 포함하는 멸균 수성제로 이루어진다. 예를 들면, 주사제의 경우에는 염 용액, 포도당 용액 또는 염수와 포도당 용액의 혼합물로 이루어지는 담체 등을 사 용하여 주사용 용액을 제조한다.Formulations suitable for parenteral administration preferably consist of sterile aqueous agents comprising the active compound that is isotonic with the blood of the recipient. For example, in the case of injectables, an injectable solution is prepared using a salt solution, a glucose solution or a carrier composed of a mixture of saline and glucose solution.
또한, 이들 비경구 제제에 있어서도, 경구 제제에서 예시한 희석제, 방부제, 보존제, 향료류, 부형제, 붕해제, 활택제,결합제, 계면활성제, 가소제 등으로부터 선택되는 1종 또는 그 이상의 보조 성분을 첨가할 수도 있다.Also in these parenteral preparations, one or more auxiliary ingredients selected from diluents, preservatives, preservatives, flavors, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified in the oral preparations are added. You may.
본 발명의 당뇨병 예방제 또는 치료제의 투여량 및 투여 횟수는, 투여 형태, 환자의 연령, 체중, 치료해야 할 증상의 성질 또는 중증도에 의해 다르지만, 성인 한 사람에 대하여 본 발명의 화합물로서 바람직하게는 0.001 g 내지 10 g, 보다 바람직하게는 0.05 g 내지 0.1 g을 하루 1회 내지 수회 투여한다. The dosage and frequency of administration of the anti-diabetic or therapeutic agent of the present invention vary depending on the dosage form, the age, weight of the patient, the nature or severity of the symptom to be treated, and preferably 0.001 as a compound of the present invention for an adult. g to 10 g, more preferably 0.05 g to 0.1 g, is administered once to several times a day.
본 발명의 당뇨병의 예방제를 일상적으로 투여함으로써 당뇨병을 예방할 수 있다. 이미 당뇨병이 발병되어 있는 경우에는, 본 발명의 당뇨병의 치료제를 일상적으로 투여함으로써 당뇨병의 증상을 완화, 치유하는 등, 당뇨병을 치료할 수 있다. 본 발명의 당뇨병의 예방제 또는 치료제의 투여 기간은 통상 1주간 내지 5년간, 바람직하게는 1개월간 내지 1년간이다.Diabetes can be prevented by routinely administering the preventive agent of diabetes of the present invention. If diabetes has already developed, diabetes can be treated by routinely administering the diabetic therapeutic agent of the present invention to alleviate and cure the symptoms of diabetes. The administration period of the prophylactic or therapeutic agent for diabetes of the present invention is usually 1 week to 5 years, preferably 1 month to 1 year.
또한, 본 발명의 당뇨병의 예방제 또는 치료제는 사람 뿐만 아니라 사람이외의 동물에 대해서도 사용할 수 있다. 동물에게 사용하는 경우의 투여량은 특별히 제한은 없지만, 본 발명의 화합물로서 바람직하게는 0.001 내지 10 g/kg이다.In addition, the prophylactic or therapeutic agent for diabetes of the present invention can be used not only for humans but also for animals other than humans. Although the dosage in the case of using for an animal is not restrict | limited, Preferably it is 0.001-10 g / kg as a compound of this invention.
본 발명의 화합물을 유효 성분으로서 함유하는 것을 특징으로 하는 당뇨병의 예방 또는 치료용 식품 또는 사료로서는 본 발명의 화합물을 식품 또는 사료에 첨가한 것을 들 수 있다. 상기 식품 또는 사료는 건강 식품, 기능성 식품으로서 당뇨병의 예방 또는 치료를 위해 사용된다.Examples of the food or feed for preventing or treating diabetes, which contain the compound of the present invention as an active ingredient, include the compound of the present invention added to a food or feed. The food or feed is used for the prevention or treatment of diabetes as a health food, a functional food.
본 발명의 식품 또는 사료는, 본 발명의 화합물을 첨가하는 것 이외에는 일반적인 식품 또는 사료의 제조 방법을 이용함으로써 제조할 수 있다.The food or feed of the present invention can be produced by using a general food or feed production method except adding the compound of the present invention.
또한, 상기 식품 또는 사료는 일반적인 식품 또는 사료를 예를 들면 성형조립 등의 가공 방법으로 가공할 수도 있다. 가공 방법으로서는 유동층 조립, 교반 조립, 압출 조립, 전동 조립, 기류 조립, 압축 성형 조립, 파쇄 조립, 분무조립, 분사 조립 등의 조립 방법, 팬 코팅, 유동층 코팅, 건식 코팅 등의 코팅 방법, 퍼프 드라이, 과잉 수증기법, 폼 매트 방법, 마이크로파 가열 방법 등의 팽화 방법 등을 들 수 있다.In addition, the food or feed may be processed to a general food or feed by a processing method such as molding assembly. Processing methods include fluidized bed granulation, stirring granulation, extrusion granulation, electric granulation, airflow granulation, compression molding granulation, crushing granulation, spray granulation, granulation methods such as spray granulation, coating methods such as fan coating, fluidized bed coating and dry coating, and puff dry. And expansion methods such as an excess water vapor method, a foam mat method, and a microwave heating method.
본 발명의 식품 또는 사료에 첨가하는 본 발명의 화합물은 본 발명의 식품 또는 사료가 당뇨병의 예방 또는 치료 작용을 갖는 것이라면, 첨가량에 특별히 제한은 없지만, 예를 들면 0.01 내지 50 중량%, 바람직하게는 0.1 내지 10 중량%를 함유하도록 첨가된다.The compound of the present invention added to the food or feed of the present invention is not particularly limited as long as the food or feed of the present invention has a prophylactic or therapeutic effect of diabetes, for example, 0.01 to 50% by weight, preferably It is added to contain 0.1 to 10% by weight.
식품에 본 발명의 화합물을 첨가하여 얻어지는 식품으로서는 예를 들면 본 발명의 화합물을 첨가한 건강 식품, 건강 음료, 쥬스류, 청량 음료수,스프류, 차류, 유산균 음료, 발효유, 빙과, 버터, 치즈, 요구르트, 가공유, 탈지 분유 등의 유제품, 햄, 소세지, 햄버거 등의 축육 제품, 어육 혼합 제품, 계란말이, 달걀 두부 등의 알제품, 쿠키, 젤리, 스낵 과자, 츄잉껌 등의 과자류, 빵류, 국수류, 김치류, 훈제품, 건물, 해산물 조림, 조미료 등을 들 수 있다.Examples of the foods obtained by adding the compounds of the present invention to foods include, for example, health foods, health drinks, juices, soft drinks, soups, teas, lactic acid bacteria beverages, fermented milk, ice cream, butter, cheese, and yogurt. Dairy products such as processed milk, skimmed milk powder, meat products such as ham, sausages, hamburgers, mixed products of fish meat, egg products such as egg rolls, egg tofu, cookies, jelly, snack snacks, sweets such as chewing gum, breads, noodles, kimchi, Smoked products, buildings, boiled seafood, seasonings.
식품의 형태로서는 본 발명의 화합물을 함유하고 있다면 특별히 제한은 없고, 예를 들면 분말 식품, 시트상 식품, 병조림 식품, 통조림 식품, 레토르트 식품, 캡슐 식품, 정제상 식품, 유동 식품, 드링크제 등을 들 수 있다.There is no restriction | limiting in particular as a form of food, if it contains the compound of this invention, For example, powdered food, sheet-like food, canned food, canned food, retort food, capsule food, tablet food, liquid food, a drink, etc. are mentioned. Can be.
본 발명의 식품에는 필요에 따라서 일반적인 식품에 사용되는 감미료, 착색료, 보존료, 증점 안정제, 산화 방지제,발색제, 표백제, 곰팡이 방지제, 검베이스, 고미료, 효소, 광택제, 산미료, 조미료, 유화제, 강화제, 제조용 제제, 향료,향신료 추출물 등의 첨가물을 첨가할 수도 있다.In the food of the present invention, sweeteners, coloring agents, preservatives, thickeners, antioxidants, coloring agents, bleaches, fungicides, gum bases, high seasonings, enzymes, varnishes, acidulants, seasonings, emulsifiers, reinforcing agents, Additives, such as a preparation for preparation, a fragrance, and a fragrance extract, can also be added.
감미료로서는 아스파탐, 감초, 스테비아, 크실로오스 등을 들 수 있다.As sweetener, aspartame, licorice, stevia, xylose, etc. are mentioned.
착색료로서는 카로티노이드나 쿠르쿠민 색소, 후라보노이드, 카라멜 색소, 시콘 색소, 스피룰리나 색소, 엽록소, 퍼플스윗 감자(Purple sweet potato) 색소, 퍼플 스윗 산감자 색소, 들깨(Perilla) 색소, 블루베리 색소 등을 들 수 있다.Examples of the colorant include carotenoids, curcumin pigments, flavonoids, caramel pigments, sycon pigments, spirulina pigments, chlorophyll, purple sweet potato pigments, purple sweet acid potato pigments, perilla pigments, and blueberry pigments. .
보존료로서는 아황산나트륨, 벤조산류, 독활(aralia cordata) 추출물, 에고노기 추출물, 사철쑥 추출물, 소르빈산류,프로피온산류 등을 들 수 있다.Examples of the preservative include sodium sulfite, benzoic acid, aralia cordata extract, egonogi extract, cedar extract, sorbic acid and propionic acid.
증점 안정제로서는 아라비아 검이나 크산탄 검 등의 검류, 알긴산류, 키틴, 키토산, 알로에 추출물, 구아 검, 히드록시프로필셀룰로오스, 카제인나트륨, 옥수수 전분, 카르복시메틸셀룰로오스류, 젤라틴, 한천, 덱스트린, 메틸셀룰로오스,폴리비닐알코올, 미소 섬유상 셀룰로오스, 미결정 셀룰로오스, 해초 셀룰로오스, 폴리아크릴산 소다, 폴리인산나트륨,카라기난, 효모 세포벽, 곤약 감자 추출물, 나타드코코(Nata de coco), 만난 등을 들 수 있다.Examples of thickeners include gums such as gum arabic and xanthan gum, alginic acid, chitin, chitosan, aloe extract, guar gum, hydroxypropyl cellulose, sodium casein, corn starch, carboxymethylcellulose, gelatin, agar, dextrin and methylcellulose. , Polyvinyl alcohol, microfibrous cellulose, microcrystalline cellulose, seaweed cellulose, soda polyacrylate, sodium polyphosphate, carrageenan, yeast cell wall, konjac potato extract, Nata de coco, mannan and the like.
산화 방지제로서는 비타민 C, 에틸렌디아민 사아세트산나트륨, 에틸렌디아민 사아세트산칼슘, 에리소르빈산, 오리자놀, 카테친(catechin), 퀘르세틴(quercetin), 클로브 추출물, 효소 처리 루틴, 사과 추출물, 참기름 추출물, 디부틸히드록시톨루엔, 회향 추출물, 서양고추냉이 추출물, 미나리 추출물, 차 추출물, 템페 추출물, 약모밀 추출물, 토코트리에놀, 토코페롤류, 평지 기름 추출물, 원두 커피 추출물, 해바라기 종자, 페룰산, 부틸히드록시아니솔, 블루베리잎 추출물, 프로폴리스 추출물, 고사리은행나무 추출물, 헤스페리틴, 후추 추출물, 봉선화 추출물, 갈산, 소귀나무 추출물,유칼립투스 추출물, 로즈마리 추출물 등을 들 수 있다.As antioxidants, vitamin C, ethylenediamine sodium tetraacetate, ethylenediamine calcium tetraacetate, erythorbic acid, oryzanol, catechin, quercetin, clove extract, enzyme treatment routine, apple extract, sesame oil extract, dibutylhydroxy Toluene, Fennel Extract, Horseradish Extract, Buttercup Extract, Tea Extract, Tempe Extract, Hair Buckwheat Extract, Tocotrienol, Tocopherols, Colza Oil Extract, Ground Coffee Extract, Sunflower Seed, Ferulic Acid, Butylhydroxyanisole, Blueberry Leaf Extracts, propolis extracts, fern ginkgo biloba extracts, hesperidin, pepper extracts, balsam extracts, gallic acid, bark extracts, eucalyptus extracts, rosemary extracts and the like.
발색제로서는 아질산나트륨 등을 들 수 있다.표백제로서는 아황산나트륨 등을 들 수 있다.곰팡이 방지제로서는 오르토페닐페놀 등을 들 수 있다.Sodium nitrite etc. are mentioned as a coloring agent. Sodium sulfite etc. are mentioned as a bleaching agent. Ortho phenyl phenol etc. are mentioned as a mold inhibitor.
껌베이스로서는 아세틸리시놀산메틸, 옻 왁스, 에스테르 검, 엘레미(elemi) 수지, 오우리큐우릴로우, 오조케라이트(Ozokerite), 오포파낙스(Opopanax) 수지, 카우리 검, 카르나우바 왁스, 구아이악(guaiac) 수지, 구타카츄, 구타한칸,구타페르카(Guttapercha), 글리세린지방산 에스테르, 고래 왁스, 코파오바 발삼, 코팔(copal) 수지, 고무, 라이스 왁스, 사탕수수 왁스, 쉘락, 젤톤, 슈크로오스지방산 에스테르, 소르바, 소르비탄산지방산 에스테르, 탈크, 탄산칼슘, 담마(Dammar) 검, 치클(chicle), 치르테, 쯔누(tunu), 저분자 고무, 파라핀 오일, 퍼 발삼, 프로필렌글리콜지방산 에스테르, 분말 펄프, 분말 벼겨, 호호바 오일, 폴리이소부틸렌, 폴리부텐, 마이크로크리스탈 왁스, 유향수(mastic), 맛사란드쵸콜 레이트, 황랍, 인산칼슘 등을 들 수 있다.Examples of the gum base are methyl acetyl ricinoleate, lacquer wax, ester gum, elemi resin, urikyuurilow, ozokerite, oppopanax resin, kauri gum, carnauba wax, and guar. Guiac resins, guttachuchu, guttahankan, guttapercha, glycerin fatty acid esters, whale wax, copaova balsam, copal resin, rubber, rice wax, sugar cane wax, shellac, geltone, Sucrose fatty acid ester, sorbate, sorbitan fatty acid ester, talc, calcium carbonate, dammar gum, chicle, thyrte, tunu, low molecular rubber, paraffin oil, per balsam, propylene glycol Fatty acid esters, powdered pulp, powdered rice bran, jojoba oil, polyisobutylene, polybutene, microcrystal wax, frankincense, masticane chocolate, yellow wax, calcium phosphate and the like.
고미료로서는 이소 알파 고미산, 카페인, 구름버섯 추출물, 키나(kina) 추출물, 황다랑어 추출물, 겐티아나 추출물, 향신료 추출물, 효소 처리 나린진, 쟈마이카 카시아 추출물, 데오브로민, 나린진, 비가끼 추출물, 약쑥 추출물, 방아풀 추출물, 아가리쿠스 버섯, 버섯 추출물, 보라페트, 메틸티오아데노신, 영지 추출물, 올리브차, 광귤 추출물, 홉 추출물,머그워트(mugwort) 추출물 등을 들 수 있다.As high-fertilizers, iso alpha gomic acid, caffeine, cloud mushroom extract, kina extract, yellowfin tuna extract, gentiana extract, spice extract, enzyme treatment naringin, jamaica cassia extract, deobromine, naringin, rain moss extract, Wormwood extract, plant extract, agaricus mushroom, mushroom extract, boraphet, methylthio adenosine, ganoderma lucidum extract, olive tea, tangerine extract, hop extract, mugwort extract and the like.
효소로서는 아밀라아제, 트립신, 린넷, 유산균 등을 들 수 있다.Examples of enzymes include amylase, trypsin, linnet, and lactic acid bacteria.
광택제로서는 옻 왁스, 목랍 등을 들 수 있다.Lacquer wax, wax, etc. are mentioned as a brightening agent.
산미료로서는 아디프산, 이타콘산, 시트르산류, 숙신산류, 아세트산나트륨, 타르타르산류, 이산화탄소, 락트산, 피틴산, 푸마르산, 말산, 인산 등을 들 수 있다.Examples of the acidulant include adipic acid, itaconic acid, citric acid, succinic acid, sodium acetate, tartaric acid, carbon dioxide, lactic acid, phytic acid, fumaric acid, malic acid and phosphoric acid.
조미료로서는 아스파라긴, 아스파라긴산류, 글루탐산, 글루타민, 알라닌, 이소류신, 글리신, 세린, 시스틴, 티로신, 류신, 프롤린 등의 아미노산, 이노신산나트륨, 우리딜산나트륨, 구아닐산나트륨, 시티딜산나트륨, 리보뉴클레오티드 칼슘, 리보뉴클레오티드 나트륨 등의 핵산, 시트르산, 숙신산 등의 유기 산, 염화칼륨, 염수 호수 저염 나트륨액, 조제(粗製) 해수 염화칼륨, 유청 미네랄, 인산삼칼륨, 인산수소이칼륨, 인산이수소칼륨, 인산수소이나트륨,, 인산이수소나트륨, 인산삼나트륨, 클로렐라 추출물 등을 들 수 있다.As seasoning, asparagine, aspartic acid, glutamic acid, glutamine, alanine, isoleucine, glycine, serine, cystine, tyrosine, leucine, amino acids such as proline, sodium inosine, sodium urinate, sodium guanylate, sodium citrate, ribonucleotide calcium, ribonucleotide Nucleic acids such as sodium, organic acids such as citric acid and succinic acid, potassium chloride, salt lake low salt sodium salt, prepared sea salt potassium chloride, whey mineral, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid Sodium dihydrogen, trisodium phosphate, chlorella extract and the like.
유화제로서는 지방산 모노글리세라이드, 소르비탄 지방산 에스테르 등을 들 수 있다.Examples of the emulsifier include fatty acid monoglycerides and sorbitan fatty acid esters.
강화제로서는 아연 염류, 비타민 C, 각종 아미노산, 5-아데닐산, 염화철, 헤스페리딘, 각종 소성 칼슘, 각종 미소성 칼슘, 디벤조일티아민, 수산화칼슘, 탄산칼슘, 티아민염산염, 듀나리에라 카로틴, 토코페롤, 니코틴산, 당근 카로틴, 팜유카로틴, 판토텐산칼슘, 비타민 A, 히드록시프롤린, 피롤린산이수소칼슘, 피롤린산 제1철, 피롤린산 제2철, 페리틴, 햄철, 메나퀴논, 엽산, 리보플라빈 등을 들 수 있다.Enhancers include zinc salts, vitamin C, various amino acids, 5-adenylic acid, iron chloride, hesperidin, various calcined calcium, various uncalculated calcium, dibenzoylthiamine, calcium hydroxide, calcium carbonate, thiamine hydrochloride, dunariera carotene, tocopherol, nicotinic acid, carrot Carotene, palm eucarotene, calcium pantothenate, vitamin A, hydroxyproline, calcium dihydrogen pyrroline, ferrous pyrroline, ferric pyrolate, ferritin, ham iron, menaquinone, folic acid, riboflavin and the like.
제조용 제제로서는 아세톤, 이온 교환 수지 등의 가공 조제, 무화과 나뭇잎 추출물, 볏짚 재 추출물, 카올린, 글리세린지방산 에스테르, 뽕나무 추출물, 골회, 들깨 추출물, 생강 추출물, 각종 탄닌, 파파야 추출물, 포도 종자 추출물, 에탄올 등을 들 수 있다.향료로서는 상술한 향료 등을 들 수 있다.Examples of preparations include acetone, processing aids such as ion exchange resins, fig leaf extracts, rice straw extracts, kaolin, glycerin fatty acid esters, mulberry extracts, bone ash, perilla extracts, ginger extracts, various tannins, papaya extracts, grape seed extracts, ethanol, etc. The fragrance mentioned above etc. are mentioned.
향신료 추출물로서는 고추 추출물, 마늘 추출물 등을 들 수 있다.Pepper extract, garlic extract, etc. are mentioned as a spice extract.
상기 식품은 1 일에 1회 또는 수회로 나누어 섭취한다. 상기 음식품을 일상적으로 섭취함으로써 당뇨병을 예방할 수 있다. 이미 당뇨병이 발병되어 있는 경우에는 상기 음식품을 일상적으로 섭취함으로써 당뇨병의 증상을 완화, 치유시키는 등, 당뇨병을 치료할 수 있다.The food is taken once or divided into several times a day. Diabetes can be prevented by taking the food and drink on a daily basis. If diabetes has already developed, it is possible to treat diabetes by alleviating and healing the symptoms of diabetes by taking the food and drink routinely.
본 발명의 화합물을 첨가하여 이루어지는 사료는, 포유류, 조류,파충류, 양서류, 어류 등의 동물, 바람직하게는 포유류에 대한 사료로서 사용된다. 예를 들면, 본 발명의 사료는 개, 고양이, 쥐 등의 애완 동물용 사료, 소, 돼지 등의 가축용 사료 등으로서 사용되고, 바람직하게는 애완 동물용 사료 또는 가축용 사료로서 사용된다.The feed formed by adding the compound of the present invention is used as a feed for animals such as mammals, birds, reptiles, amphibians, fish, and preferably mammals. For example, the feed of the present invention is used as a pet food for dogs, cats, mice, and the like, and for animal feed such as cattle and pigs, and is preferably used as a pet food or a livestock feed.
본 발명의 사료는 사료 원료에 본 발명의 화합물을 적절하게 배합하여 만들 수 있다. 사료 원료로서는 곡물류, 조강류, 식물성 유박류, 동물성 사료 원료, 기타 사료 원료, 정제품 등을 들 수 있다.The feed of the present invention can be made by appropriately blending the compound of the present invention with a feed material. Examples of feed materials include cereal grains, crude steel, vegetable oils, animal feedstuffs, other feedstuffs, and refined products.
곡물류로서는, 예를 들면 마이로, 밀, 보리, 귀리, 호밀, 현미, 메밀, 조, 수수, 피, 옥수수, 대두 등을 들 수 있다.Examples of cereals include maize, wheat, barley, oats, rye, brown rice, buckwheat, buckwheat, sorghum, blood, corn, soybeans and the like.
조강류로서는, 예를 들면 쌀겨, 탈지 쌀겨, 밀기울, 말분, 밀, 배아, 보리겨, 스크리닝, 펠렛, 옥수수겨, 옥수수 배아 등을 들 수 있다.Examples of the crude steel include rice bran, defatted rice bran, wheat bran, horse meal, wheat, embryo, barley bran, screening, pellets, corn bran, and corn embryo.
식물성 유박류로서는, 예를 들면 대두박, 콩가루, 아마박, 면실박, 낙화생 박, 홍화박, 야자박, 팜박, 호마박, 해바라기박, 유채박, 케이폭박, 겨자박 등을 들 수 있다.Examples of vegetable oils include soybean meal, soybean meal, flaxseed meal, cottonseed meal, groundnut meal meal, safflower meal, palm oil palm, palm oil, fomarak, sunflower oil, rapeseed meal, cowpea oil and mustard oil.
동물성 사료 원료로서는, 예들 들면 어분(북양 밀, 수입 밀, 홀 밀, 연안 밀), 피쉬솔불, 육분, 어골분, 혈분, 분해모, 골분, 가축용 처리 부산물, 페더 밀, 누에, 탈지 분유, 카제인, 건조 유장 등을 들 수 있다.As animal feed materials, for example, fish meal (North American wheat, imported wheat, whole wheat, coastal wheat), fish bulrush, meat meal, fish bone meal, blood meal, decomposing hair, bone meal, animal by-products, feather mill, silkworm, skim milk powder, Casein, dried whey, and the like.
그 밖의 사료 원료로서는 식물 경엽류(알팔파, 헤이큐브, 알팔파잎 분말, 유사 아카시아 분말 등), 옥수수 가공 공업부산물(콘 글루텐, 밀, 콘 글루텐 피드, 콘스테이프리카 등), 전분 가공품, 설탕, 발효 공업 산물(효모, 맥주박, 맥아근,알코올박, 장유박 등), 농산 제조 부산물(감귤 가공박, 두부박, 커피박, 코코아박 등), 그 외(카사바, 잠두콩, 구아밀, 해조, 크릴, 스피룰리나, 클로렐라, 광물 등) 등을 들 수 있다.Other feedstocks include plant foliage (alfalfa, haycube, alfalfa leaf powder, pseudo acacia powder, etc.), corn processing industrial by-products (corn gluten, wheat, corn gluten feed, corn staple, etc.), starch processed products, sugar, fermentation. Industrial products (yeast, beer foil, malt sprouts, alcohol foil, walnuts, etc.), agricultural production by-products (citrus fruits, tofu, coffee, cocoa, etc.), others (cassava, bean, guam, seaweed, Krill, spirulina, chlorella, minerals, etc.) etc. are mentioned.
정제품으로서는 단백질(카제인, 알부민 등), 아미노산, 당질(전분, 셀룰로오스, 슈크로우스, 글루코오스 등), 미네랄,비타민 등을 들 수 있다.Typical products include proteins (casein, albumin, etc.), amino acids, sugars (starch, cellulose, sucrose, glucose, etc.), minerals, vitamins, and the like.
본 발명의 동물용 사료를 동물에게 일상적으로 섭취시킴으로써 당뇨병을 예방할 수 있다.Diabetes can be prevented by routinely ingesting the animal feed of the present invention in animals.
이하 본 발명을 설명한다.Hereinafter, the present invention will be described.
본 발명은 BTA가 당뇨병 모델 쥐에서 혈당강하 효능이 있는지 알기 위하여 db/db 생쥐에 BTA를 4주간 투여 후 혈당 감소, 베타세포의 보전, 포도당 자극 인슐린 분비 증가 등을 당뇨 대조군과 비교 조사하여 BTA의 항당뇨 효능을 조사하였다.In order to determine whether BTA has a hypoglycemic effect in diabetic model rats, BTA was administered to db / db mice for 4 weeks, and then, blood glucose reduction, beta-cell preservation, and glucose-stimulated insulin secretion were compared with those of diabetic controls. The antidiabetic efficacy was investigated.
본 발명은 항당뇨 효과를 갖는 1,2,3-Benzentricarboxylic acid (이하 ‘BTA’라 한다)의 사용 용도에 관한 것이다. 당뇨병 발생 모델 생쥐(db/db)에 BTA를 4주간 투여한 경우 뚜렷한 혈당강하 효능을 나타냈다. 특히 인슐린을 분비하는 췌장의 베타세포는 BTA를 투여한 db/db 생쥐군에서 뚜렷히 보존되었다. 즉 BTA는 베타세포 보전을 통한 탁월한 혈당 강화 효능이 있었다. 그러므로 BTA는 당뇨병을 억제하는 당뇨병 예방 조성물로 사용할 수 있을 것이다.The present invention relates to the use of 1,2,3-Benzentricarboxylic acid (hereinafter referred to as 'BTA') having an anti-diabetic effect. When diabetic model mice (db / db) were administered BTA for 4 weeks, there was a clear hypoglycemic effect. In particular, the insulin-secreting pancreatic beta cells were clearly conserved in the BTA-administered db / db mice. That is, BTA had an excellent glycemic effect through beta cell conservation. Therefore, BTA may be used as a diabetes prevention composition for inhibiting diabetes.
이하에서는 본 발명의 바람직한 실시형태를 첨부된 도면을 참고로 하여, 상세하게 살펴보기로 한다.Hereinafter, with reference to the accompanying drawings, preferred embodiments of the present invention will be described in detail.
본 발명은 항당뇨 효과를 갖는 1,2,3-Benzentricarboxylic acid (이하 ‘BTA’라 한다)의 사용 용도에 관한 것이다. BTA의 항당뇨 효능을 확인하기 위하여 랩틴 (leptin) 수용체가 제거된 C57BLKS/J-db/db 당뇨모델 생쥐를 이용하였다. C57BLKS/J-db/db 생쥐를 무작위로 3군으로 나누고 대조군으로는 PBS를 투여하였고 실험군으로는 BTA를 0.05g/kg 및 0.1g/kg로 PBS에 녹여서 4주간 복강으로 투여하였다. 투여기간 동안 일주일 단위로 체중과 먹이 섭취량을 측정하였다. PBS 투여군 과 BTA 투여군 사이의 몸무게와 먹이 섭취량은 차이가 없었다. BTA 4주 투여 후 혈당 강하 효능을 측청하기 위하여 복강 내 당부하 검사와 인슐린민감도 검사를 실시하였다. 그 결과 BTA 투여군에서 뚜렷한 혈당강하 효능을 나타냈으며, 인슐린에 대한 민감도는 대조군과 비교하여 BTA 투여군에서 별다른 변화가 없음을 나타냈다. 췌장의 베타세포의 인슐린량이 BTA에 의해 변화가 있었는지 확인하기 위하여 희생 후 췌장 조직의 인슐린 염색을 수행하였다. 그 결과 PBS 대조군에서 소도의 모양이 파괴되고 인슐린이 염색되지 않은 소도가 많았지만 BTA 투여군은 인슐린 염색된 베타세포가 잘 보존되어 있었다. 또한 포도당 자극 인슐린 분비가 PBS 투여군에 비해 BTA 투여군에서 증가되어 있음을 알 수 있었다. The present invention relates to the use of 1,2,3-Benzentricarboxylic acid (hereinafter referred to as 'BTA') having an anti-diabetic effect. C57BLKS / J-db / db diabetic model mice in which leptin receptors were removed were used to confirm the antidiabetic effects of BTA. C57BLKS / J-db / db mice were randomly divided into 3 groups, and PBS was administered as a control group, and BTA was dissolved in PBS at 0.05 g / kg and 0.1 g / kg as an experimental group and administered intraperitoneally for 4 weeks. Body weight and food intake were measured weekly during the administration period. There was no difference in weight and food intake between the PBS and BTA groups. Intraperitoneal glucose tolerance test and insulin sensitivity test were performed to examine the effect of hypoglycemic effect after 4 weeks of BTA administration. As a result, it showed a clear hypoglycemic effect in the BTA administration group, and the sensitivity to insulin showed no change in the BTA administration group compared to the control group. Insulin staining of pancreatic tissues was performed after sacrifice to determine whether the insulin levels of the pancreatic beta cells were changed by BTA. As a result, in the PBS control group, the shape of islets was destroyed and insulin was not stained, but the BTA-administered group preserved insulin-stained beta cells well. It was also found that glucose-stimulated insulin secretion was increased in the BTA-administered group compared to the PBS-administered group.
본 발명은 1,2,3-Benzentricarboxylic acid를 C57BLKS/J-db/db 생쥐에 투여시 탁월한 혈당강하, 췌장 베타세포 보존, 포도당 자극 인슐린 분비 증가 효과를 나타냈다. In the present invention, when 1,2,3-Benzentricarboxylic acid was administered to C57BLKS / J-db / db mice, it showed an excellent effect on hypoglycemia, pancreatic beta cell preservation, and glucose-stimulated insulin secretion.
도 1은 BTA의 혈당강하 효과를 나타낸 그림으로, 1a는 PBS 대조군과 BTA 투여군의 체중 변화를 나타낸 그래프이고, 1b는 PBS 대조군과 BTA 투여군의 먹이 섭취량을 나타낸 그래프이며, 1c는 PBS 대조군과 BTA 투여군의 혈중 포도당 농도를 나타낸 그래프이고, 1d는 PBS 대조군과 BTA 투여군의 혈중 인슐린 농도를 나타낸 그래프를 나타낸다.
도 2는 BTA의 혈당강하 효능 및 인슐린저항성 회복 효과를 나타낸 그림으로, 2a는 PBS 대조군과 BTA 투여군의 복강 내 당부하검사를 나타낸 그래프이고, 2b는 PBS 대조군과 BTA 투여군의 인슐린 민감도를 나타낸 그래프이다.
도 3은 BTA의 췌장의 베타세포 보존 효과를 나타낸 그림으로, 3a는 PBS 대조군과 BTA 투여군의 췌장의 H&E 염색을 나타낸 그림이고, 3b는 PBS 대조군과 BTA 투여군의 췌장의 인슐린을 염색한 그림이다.
도 4는 BTA에 의한 포도당 자극 인슐린 분비 증가 효과를 나타낸 그림으로, PBS 대조군과 BTA 투여군 간의 포도당 자극 인슐린 분비량을 나타낸 그림이다.1 is a graph showing the hypoglycemic effect of BTA, 1a is a graph showing the change in body weight of the PBS control group and BTA group, 1b is a graph showing the food intake of the PBS control group and BTA group, 1c is a PBS control group and BTA group Is a graph showing the blood glucose concentration, 1d is a graph showing the blood insulin concentration of the PBS control group and the BTA administration group.
Figure 2 is a graph showing the hypoglycemic effect and the recovery of insulin resistance of BTA, 2a is a graph showing the intraperitoneal glucose tolerance test of the PBS control group and BTA group, 2b is a graph showing the insulin sensitivity of the PBS control group and BTA group. .
3 is a diagram showing the beta-cell preservation effect of the pancreas of BTA, 3a is a picture showing the H & E staining of the pancreas of the PBS control group and the BTA-administered group, 3b is a staining of the pancreas insulin of the PBS control group and the BTA-administered group.
4 is a diagram showing the effect of increasing glucose-stimulated insulin secretion by BTA, a diagram showing the glucose-stimulated insulin secretion between the PBS control group and the BTA administration group.
이하에서는 본 발명을 좀 더 자세히 실시 예를 들어 설명하고자 한다. 단 하기 실시예는 본 발명을 예시하기 위한 목적으로 기재된 것으로서 본 발명의 범위는 하기 실시예에 의하여 제한되는 것으로 해석되지 아니한다. Hereinafter, the present invention will be described with reference to Examples. However, the following examples are described for the purpose of illustrating the present invention and the scope of the present invention is not to be construed as limited by the following examples.
실시예1Example 1 : : BTABTA 의 혈당강하 효능 및 인슐린저항성 회복 효과Hypoglycemic effect and insulin resistance recovery effect
BTA를 C57BLKS/J-db/db mice에 4 주간 투여 후 체중, 인슐린량 및 먹이섭취량을 조사한 결과 대조군과 BTA 투여군 사이 유의적인 차이점은 없었다 (도 1a,b,d). 그러나 공복 혈당은 BTA 투여군과 대조군에서 유의적인 차이를 나타냈다 (도 1c). BTA의 항당뇨 효과를 자세히 알아보기 위해 각 군에서 복강 내 당부하 검사와 인슐린민감도 실험을 수행하였다. 복강 내 당부하 검사 결과 대조군의 경우 공복혈당이 519 mg/dl인 반면 복강 내로 2g/kg의 당을 투여시 60분 후 600 mg/dl으로 증가 하였으며 180분 후 혈당 또한 600 mg/dl 이었다. 반면에 BTA 투여군의 경우 공복혈당이 344 mg/dl 이었고 복강 내로 2g/kg의 당을 투여시 60분 후 444 mg/dl으로 증가하였으나 180분 후 혈당은 236 mg/dl으로 떨어져 대조군에 비해 현저한 혈당 강하 효과를 나타냈다 (도 2 a). 인슐린 민감도 검사 결과 대조군의 경우 공복혈당을 100%로 한 경우 복강 내로 1U/kg의 인슐린을 투여 60분후 혈당은 65%로 감소하였으며 120분 후 65%로 감소하였다. BTA 투여군의 인슐린 감수성은 공복혈당을 100%로 한 경우 복강 내로 1U/kg의 인슐린을 투여 60분 후 혈당은 62%로 감소하였으며 120분 후 혈당은 66%로 감소하였다 (도2b). 인슐린 투여 후 혈당은 60분 후 및 120분 후 대조군과 BTA 투여군에서 유의적인 차이는 없었다.After 4 weeks of administration of BTA to C57BLKS / J-db / db mice, body weight, insulin and food intake were not significantly different between the control group and the BTA-administered group (FIGS. 1A, B, and D). However, fasting blood glucose showed a significant difference between the BTA-administered group and the control group (FIG. 1C). To investigate the antidiabetic effect of BTA, intraperitoneal glucose tolerance test and insulin sensitivity test were performed in each group. Intraperitoneal glucose tolerance test showed that fasting blood glucose was 519 mg / dl in the control group, but increased to 600 mg / dl after 60 minutes with 2 g / kg of glucose intraperitoneally and 600 mg / dl after 180 minutes. On the other hand, in the BTA group, fasting glucose was 344 mg / dl, and when 2 g / kg of glucose was injected into the abdominal cavity, it increased to 444 mg / dl after 60 minutes, but after 180 minutes, blood glucose dropped to 236 mg / dl, which was significantly higher than that of the control group. A depressive effect was shown (FIG. 2 a). Insulin sensitivity test showed that the fasting blood glucose level in the control group was reduced to 65% after 60 minutes of 1 U / kg insulin intraperitoneally and to 65% after 120 minutes. Insulin susceptibility of the BTA-administered group was 100% fasting blood sugar, 60 minutes after 1U / kg of insulin intraperitoneally reduced blood sugar to 62% and after 120 minutes blood sugar was reduced to 66% (Fig. 2b). There was no significant difference between the control group and the BTA group after 60 minutes and 120 minutes after insulin administration.
1-1 동물 실험1-1 Animal Experiment
8주령의 웅성의 C57BLKS/J-db/db mice를 일본의 SLC에서 수입하였다. 이 동물을 아주대학교 의과대학 동물 실험실에서 우리당 2마리씩 분리하여 온도 22±0.5℃, 습도 55±5%에서 12시간 밤낮의 주기로 사육하였다. 9주령의 C57BLKS/J-db/db mice를 3개의 군으로 나누고 대조군으로는 PBS를 투여하였고 실험군으로는 BTA를 0.05g/kg, 0.1g/kg로 PBS에 녹여서 4주간 복강 투여하였다. 1주마다 몸무게, 먹이 섭취량을 측정하였고 4주 투여 후 복강 내 당부하 검사, 인슐린 내성검사를 수행하고 혈액에서 포도당 농도와 인슐린 량을 측정하였다. 또한 생쥐를 희생하고 islet을 분리하여 베타세포의 인슐린 보존정도를 확인하였다.Eight-week-old male C57BLKS / J-db / db mice were imported from SLC in Japan. Two animals per cage were isolated from the Ajou University School of Medicine animal breeding and reared at 12 ± day and night cycles at a temperature of 22 ± 0.5 ° C and a humidity of 55 ± 5%. Nine-week-old C57BLKS / J-db / db mice were divided into three groups, and PBS was administered as a control group. BTA was dissolved in PBS at 0.05g / kg and 0.1g / kg for 4 weeks. The body weight and food intake were measured every week. After 4 weeks of administration, intraperitoneal glucose tolerance test and insulin resistance test were performed, and glucose concentration and insulin level were measured in blood. We also sacrificed mice and isolated the islets to confirm the insulin preservation of beta cells.
1-2 복강 내 1-2 intraperitoneal 당부하Party load 검사 ( Inspection ( IPGTTIPGTT ))
복강 내 당부하 검사는 13주령의 C57BLKS/J-db/db 생쥐를 10시간 금식시킨 후 복강 내로 2g/kg의 포도당을 투여하였다. 꼬리 정맥에서 혈액을 채취하여 0분, 60분, 180분 때 혈당을 측정하였다. 혈당 측정은 간이 혈당측정기 (Accucheck, Roche, Germany)을 이용하였다. Intraperitoneal glucose tolerance test was performed by fasting 13-week-old C57BLKS / J-db / db mice for 10 hours followed by 2 g / kg of glucose intraperitoneally. Blood was collected from the tail vein and blood glucose was measured at 0, 60, and 180 minutes. Blood glucose measurement was performed using a liver glucose meter (Accucheck, Roche, Germany).
1-3 인슐린 내성 검사(1-3 insulin resistance tests ( ITTITT ))
인슐린 내성 검사는 13주령의 C57BLKS/J-db/db 생쥐를 10시간 금식시킨 후 총량 1U/kg 인슐린 (Novolin R, Novodisk, Denmark)를 복강 내로 투여 하여 측정하였으며, 혈당은 주사 전과 주사 후 0분 60분 120분에 꼬리 정맥에서 간이 혈당측정기 (Accucheck, Roche, Germany)를 사용하여 측정하였다.The insulin resistance test was measured by fasting 10-week-old C57BLKS / J-db / db mice for 10 hours and then administering a total amount of 1U / kg insulin (Novolin R, Novodisk, Denmark) intraperitoneally. 60 minutes and 120 minutes in the tail vein was measured using a liver glucose meter (Accucheck, Roche, Germany).
1-4 인슐린 정량1-4 Insulin Quantitation
C57BLKS/J-db/db 생쥐를 10시간 금식시킨 후 꼬리의 정맥으로부터 채혈을 하고 혈장을 분리 후 인슐린 정량을 수행하였다. 인슐린 정량은 LINCO사의 Rat insulin assay kit (Linco Research, St. Charles, MO, USA)를 사용한 Radioimmunoassay법 이용하였다. 혈청을 125I로 표지된 인슐린과 인슐린 항체를 혼합시켜 4℃에서 18시간 방치하였다. Precipitating reagents를 넣고 4℃에서 20분 동안 방치 후 2000g 로 20분 동안 원심 분리하여 상등 액은 버리고 가라앉은 pellet을 취하여 방사성 동위원소의 활성을 gamma-counter (Perkin-Elmer, Fremont, CA, USA)를 이용하여 측정하였다. 인슐린의 양은 standard curve를 이용하여 계산하였다.C57BLKS / J-db / db mice were fasted for 10 hours, blood was collected from the veins of the tail, and plasma was separated and insulin quantified. Insulin quantification was performed using the Radioimmunoassay method using LINCO's Rat insulin assay kit (Linco Research, St. Charles, MO, USA). Serum was left at 4 ° C. for 18 hours by mixing 125 I labeled insulin and insulin antibody. Add precipitating reagents and leave at 4 ° C for 20 minutes, centrifuge at 2000g for 20 minutes, discard supernatant and take down the pellet to determine the activity of the radioisotope. Gamma-counter (Perkin-Elmer, Fremont, CA, USA) It measured using. The amount of insulin was calculated using a standard curve.
실시예Example 2: 2: BTABTA 의 췌장의 베타세포 보존 효과Beta-cell Preservation Effect of Pancreas
제 2형 당뇨병의 병인 중 한 요인은 인슐린 분비 이상 (Insulin deficiency) 및 베타세포의 양적 감소이다. 즉 인슐린 저항성을 극복 하려고 초기에는 인슐린 분비가 증가하지만 나중에 췌장의 인슐린 분비기능이 감소하는 인슐린 분비이상(Insulin deficiency) 및 베타세포의 양적인 감소가 동시에 일어나 인슐린 저항성을 극복하지 못해 혈당이 상승하게 된다. BTA를 투여한 군에서 인슐린을 분비하는 베타세포의 형태적 변화를 관찰하기 위하여 췌장의 조직을 Hematoxylin-Eosin (H&E) 염색과 인슐린 염색을 수행하였다. 대조군에서는 H&E 염색 결과 대조군에서는 췌장의 소도가 파괴되어 있는 양상을 보였고 인슐린 염색에서도 인슐린을 분비하는 베타세포의 염색이 감소되어 있었다. 그러나 BTA를 투여한 군에서는 췌장의 소도가 파괴가 일어나지 않았으며 (도 3 a), 인슐린 염색 역시 대조군에 비해 뚜렷하게 나타나 있었다. 이 결과로 BTA 투여 군에서는 인슐린을 보호하는 췌장의 베타세포가 잘 보존이 되어있음을 알 수 있었다 (도 3 b). One factor of the etiology of
2-1 췌장 소도 베타세포의 염색2-1 Staining of Pancreatic Islet Beta Cells
췌장의 형태 계측을 위해 14주령 때에 C57BLKS/J-db/db를 희생하여 췌장을 적출하고 4℃에서 4% paraformaldehyde로 24시간 고정 후 흐르는 물에 수세한 다음 파라핀으로 포매하여 조직을 5 μm 두께로 박절하였다. 박절한 조직을 코팅 슬라이드 위에 붙인 후 xylen으로 파라핀을 제거하고 계열 알콜순(100%, 95%, 90%, 80%, 70% EtOH)으로 함수 과정을 거친 후 면역 조직학적 염색을 시행하였다. For pancreatic morphology, the pancreas was harvested at the age of 14 weeks at the expense of C57BLKS / J-db / db, fixed at 4 ° C with 4% paraformaldehyde for 24 hours, washed with running water, embedded with paraffin, and tissues were 5 μm thick. I was cut off. After attaching the thin tissue to the coating slide, the paraffin was removed with xylen, followed by a water-based process (100%, 95%, 90%, 80%, 70% EtOH), followed by immunohistostaining.
2-2 2-2 HematoxylinHematoxylin -- EosinEosin (H&E) 염색 (H & E) dyeing
박절한 조직을 Harry's hematoxylin 염색액으로 5분간 염색 후 흐르는 물에 5분간 수세하고 1% HCl alcohol과 ammonia로 탈 염색하였다. 이후 흐르는 물에 10분간 수세한 후 다시 eosin 염색액으로 1분간 대조염색하고 함수의 역방향으로 탈수 과정을 거친 후 봉입하여 현미경 (Olympus, Tokyo, Japan)으로 관찰하였다.The thin tissue was stained with Harry's hematoxylin stain for 5 minutes, washed with running water for 5 minutes and destained with 1% HCl alcohol and ammonia. After washing with running water for 10 minutes, it was again counterstained with eosin stain for 1 minute, dehydrated in the reverse direction of hydration, and sealed and observed under a microscope (Olympus, Tokyo, Japan).
2-3 췌장 인슐린 염색2-3 Pancreatic Insulin Staining
박절한 조직을 PBS (pH7.4)으로 세척한 후 15분간 3% H2O2를 처리하여 세포내 과산화 효소 활성을 억제시켰으며, 항원성을 증가시키기 위해 0.01 M citrate buffer (pH 6.0)에 넣고 전자레인지로 10분간 가열하고 실온에서 식힌 후 PBS로 세척하였다. 세척한 각각의 조직위에 1 차 항체인 인슐린 (DAKO Co, CA. USA)을 항체 희석액 antibody diluent (DAKO. co, CA. USA)에 1: 1000으로 희석하여 4℃에서 하룻밤 동안 반응시키고 PBS로 세척하였고 2차 항체를 상온에서 30분간 반응시킨 후 PBS로 세척하였다. 0.05% 3,3‘-diamino-benzidine tetra-hydrochloride (DAB, DAKO Co, CA. USA) 발색시약을 조직에 떨어뜨려 2분간 발색시키고 흐르는 물에 염색 시약을 제거하였다. 물기를 제거한 후 여과시킨 harry's hematoxylin으로 2분간 대조염색을 시행하고 함수의 역방향으로 탈수과정을 거친 후 봉입하여 현미경 (Olympus, Tokyo, Japan)으로 관찰하였다.The washed tissue was washed with PBS (pH7.4) and treated with 3% H2O2 for 15 minutes to inhibit intracellular peroxidase activity.In order to increase antigenicity, it was placed in 0.01 M citrate buffer (pH 6.0) and microwaved. Heated for 10 minutes, cooled to room temperature, and washed with PBS. On each washed tissue, the primary antibody insulin (DAKO Co, CA. USA) was diluted 1: 1000 in antibody diluent antibody diluent (DAKO. Co, CA. USA), reacted overnight at 4 ° C. and washed with PBS. The secondary antibody was reacted at room temperature for 30 minutes and then washed with PBS. 0.05% 3,3′-diamino-benzidine tetra-hydrochloride (DAB, DAKO Co, CA. USA) coloring reagent was dropped on the tissue and developed for 2 minutes, and the staining reagent was removed in running water. After removal of water, contrast staining was performed with filtered harry's hematoxylin for 2 minutes, followed by dehydration in the reverse direction of hydration, and then sealed and observed under a microscope (Olympus, Tokyo, Japan).
실시예Example 3: 3: BTABTA 의 포도당 자극 인슐린 분비 증가 효과Increasing Glucose-stimulated Insulin Secretion
BTA를 투여한 군에서 포도당 자극 인슐린 분비가 증가 하는지를 알기 위해 포도당을 주입한 후 인슐린 분비량을 측정 하였다. 대조군의 경우 공복 인슐린 분비량이 1.1 ng/ml인 반면 복강 내로 2g/kg의 당을 투여한 다음 60분 때 0.6 ng/ml 으로 오히려 감소하였으며 2시간 후 1.3 ng/ml으로 증가 하였다. BTA 투여군의 경우 공복 인슐린 분비량은 1.1 ng/ml이었고 복강 내로 2g/kg의 당을 투여한 다음 60분 때 1.4 ng/ml으로 증가 하였으며 2시간 후 인슐린 분비량은 2 ng/ml으로 대조군에 비해 현저하게 포도당 자극 인슐린 분비량이 증가하였다 (도 4).Insulin secretion was measured after glucose infusion to determine if glucose-stimulated insulin secretion was increased in the BTA-administered group. In the control group, the fasting insulin secretion was 1.1 ng / ml, whereas the dose of 2 g / kg of sugar intraperitoneally decreased to 0.6 ng / ml at 60 minutes and increased to 1.3 ng / ml after 2 hours. In the BTA group, fasting insulin secretion was 1.1 ng / ml, and 2 g / kg of glucose was injected into the abdominal cavity and then increased to 1.4 ng / ml in 60 minutes. After 2 hours, insulin secretion was 2 ng / ml, which was significantly higher than that of the control group. Glucose stimulated insulin secretion was increased (FIG. 4).
3-1 인슐린 정량3-1 Insulin Quantitation
C57BLKS/J-db/db 생쥐를 10시간 금식시킨 후 복강 내로 2g/kg의 포도당을 투여한 다음 꼬리의 정맥으로부터 0분, 60분, 180분 때 혈액을 채취하여 혈장을 분리한 후 인슐린 정량을 수행하였다. 인슐린 정량은 LINCO사의 Rat insulin assay kit (Linco Research, St. Charles, MO, USA)를 사용한 radioimmunoassay법 이용하였다. 혈청을 125I로 표지된 인슐린과 인슐린 항체를 혼합시켜 4℃에서 18시간 방치하였다. Precipitating reagents를 넣고 4℃에서 20분 동안 방치 후 2000g 로 20분 동안 원심 분리하여 상등 액은 버리고 가라앉은 pellet을 취하여 방사성 동위원소의 활성을 gamma-counter(Perkin-Elmer, Fremont, CA, USA)를 이용하여 측정하였다. 인슐린의 양은 standard curve를 이용하여 계산하였다.After fasting C57BLKS / J-db / db mice for 10 hours, 2 g / kg glucose was injected into the abdominal cavity, and blood was collected at 0, 60, and 180 minutes from the vein of the tail to separate plasma, and then insulin quantification was performed. Was performed. Insulin quantification was performed using a radioimmunoassay method using LINCO's Rat insulin assay kit (Linco Research, St. Charles, MO, USA). Serum was left at 4 ° C. for 18 hours by mixing 125 I labeled insulin and insulin antibody. Add precipitating reagents and leave at 4 ° C for 20 minutes, centrifuge at 2000g for 20 minutes, discard supernatant and take down the pellet to reduce the activity of the radioisotope gamma-counter (Perkin-Elmer, Fremont, CA, USA). It measured using. The amount of insulin was calculated using a standard curve.
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