葛根素与葡萄糖耐量因子现代复方制剂降糖降脂作用机制初探

【作者】 刘亚明；

【导师】 牛欣； 冯前进；

【作者基本信息】 北京中医药大学 ， 中西医结合基础， 2003， 博士

【摘要】 目前随着经济的全球化发展和人民生活方式的改变以及人口老龄化出现，糖尿(消渴)病患者(主要是Ⅱ型糖尿病)的数量迅速增加，其发病率在全球范围内呈逐渐增高的趋势，尤其在发展中国家，增加的速度更快，呈现流行势态。糖尿病已成为全世界许多国家的常见病和多发病，其死亡率已居肿瘤、心血管病之后的第三位，是工业发达国家中仅次于癌症、艾滋病和心血管病之后需优先考虑的疾病。据国际糖尿病联盟(IDF)调查；10年前全世界糖尿病人口约4000万人，而在2000年已达近1.6亿。从1987年至1997年，我国也多次进行糖尿病普查，结果表明，糖尿病的总患病率呈快速增长之势。1987年的患病率仅6.09‰(标准化后为6.74‰)，1997年已经迅速增长至11.46‰(标准化后为10.67‰)；局部地区患病率最高达19.46‰(标准化后为12.41‰)。按照国际卫生组织(WHO)规定标准进行的为期10年的前瞻性研究结果显示，糖尿病患病率标准化后为12.64‰，其中糖耐量减低患病率为7.688‰每年糖耐量减低转化为糖尿病的比例为7.7％，与发达国家相比，我国糖尿病患病率较低，但我国人口较多(约占全世界的1/4左右)，将成为糖尿病患病增长最快的国家之一，预计到2010年糖尿病患者总数将居世界各国之首位。从而为糖尿(消渴)病的发生机理和防治药物的研制和开发提供了广阔的前景。 中医认为消渴病的发病机致在脏腑方面，以肾为本，肝脾并重，与肺、胃密切相关，气阴两虚是消渴病中最常见的基本病机，消渴病贯串于上中下，其脏腑病位，上焦在肺，中焦在脾胃，下焦在肝肾，而以肾为本。当消渴病后期，由于阴损及阳，阴阳两虚，则转化成消渴重症。由于血瘀证在糖尿病中具有普遍性，因而一些中西医家如施今墨、祝湛予等倡导气阴两虚及血瘀学说，但真正在临床上能够按照上述方法进行治疗的却甚少，因此通过从临床特征、病理生理基础、治法及方药等方面揭示糖尿病血瘀证的实质，确定中西医结合方法对糖尿病血瘀证的合理应用(活血化瘀和它法并用)，在目前有着重要的意义。 葡萄糖耐量因子(GTF)与传统中医药的有机结合在防治糖尿病方面具有独特的优势：二十世纪五十年代，MertZW和Schwarz通过实验证明，铬缺乏大鼠出现糖耐量极度受损，流行病学研究结果也显示，在以精制食品为主的人群中，铬是唯一随着年龄增长而逐渐减少的微量元素，从而形成机体的铬缺乏状态。实验研究证明，GTF是一种以铬为活性中心的多种氨基酸的络合物。是机体糖、脂代谢的一个十分重4 现代复方制剂葛根素与葡萄糖耐量因子降糖、降脂作用机制初探要的调节因子；对于维持机体正常的糖耐量水平发挥重要作用。本研究结合国内外防治糖尿病和高血脂症研究的成果和临证实际应用经验，在合成目前已公认的用于糖尿病有效的葡萄糖耐量因子（GTF）的基础上，与治疗糖尿病的传统中药葛根的有效成分提取物葛根素形成一种新的物质—一复方葛根肢囊，在迄今完成的基础和临床研究表明，该物质已取得良好的降糖和恢复胰岛功能以及降血脂等作用。本课题的研究据查新检索表明：研究具有显著的实用性和一定的科学性。实验共分为五部分；主要实验内容与结果如下。1 复方葛根胶囊的制备 豆科植物野葛的块根葛根，在传统中医治疗消渴病方面有较好功效的记载，由葛根提取的葛根素在现代治疗糖尿病并发症方面也有显著效果；葡萄糖耐量因子 （GTF）在防治糖尿病方面的肯定疗效，国内外学者均已进行了大量的相关报道，因此我们在选方用药方面，在中西医结合和中医理论指导下，根据糖尿病本虚标实的证候特点，治疗时以扶正驱邪并举为法，采用益气养阴，健脾补肾，清热化瘀的原则，将中药葛根提取物葛根素和酵母提取物GTF制按一定比例酉己方，制剂成复方葛根胶囊。按照《药典》规定的野葛根1种作为提取原料，并对其进行了有关的显微结构鉴定，同时对复方葛根胶囊进行了相应的红外光谱测定和铬含量测定，结果显示，在本方中含铬量和红外测定区域与国外文献报告结果基本一致。本方具有益气健脾、养阴生津、养血活血化瘀之效。2复方葛根胶囊对实验性糖尿病小鼠空腹血糖及糖耐量的影g＠。 为探讨复方葛根胶囊对四氧啼唉性糖尿病小鼠血糖及糖耐量的影响，检测其降低高血糖作用，对复制糖尿病模型小鼠分别分为模型组，模型加复方葛根胶囊试验大、小剂量组（分别予以复方葛根胶囊0．34，0二7g／kg 厂模型加优降糖阳性药对照组（优降糖sing／kg），正常对照组和模型对照组灌胃以等体积（0．Zml／l og）蒸馏水，每日1次；连续10天。分别进行血糖和糖耐量的测定。结果表明，复方葛根胶囊能降低四氧啼唆糖尿病小鼠空腹血糖含量，与模型组比较其差异有显著性意义（P＜O刀1或P＜0刀01X 实验发现复方葛根胶囊的大、小剂量组对四氧啼唉所致糖尿病小鼠空腹高血糖含量均有明显的降低作用。同时复方葛根胶囊能显著提高糖尿病小鼠的糖耐量水平，与模型组比较有显著性差异（P＜0．01或P＜0．0of）。 中文摘要5 3复方葛根腔囊对高脂血症更多还原

【Abstract】 The theory of Chinese Traditional medicine thinks that the incidence mechanism of diabetes lies in internal organs, regarding kidney as origin, laying equal stress on liver and spleen, relating closely with lung and stomach. Deficiency of energy and yin is the most familiar and basic mechanism of diabetes. Diabetes runs through top, intermediate and low internal organs, whose ill positions are top focus in lung, intermediate in spleen and stomach, low focus in liver and kidney. Kidney is thought as origin. In the late period of diabetes, as yin damages yang, leading insufficiency of yin and yang, diabetes turns to worse case. Though blood stasis symbol is general in diabetes, it is rare to cure diabetes by means of above methods in clinic. Therefore, nowadays it is meaningful to discover the essence of blood stasis in diabetes through clinical feature, basement of pathology and physiology, treatment methods and prescription, and to determine the reasonable application of Chinese-western medicine combination curing blood stasis in diabetes. The modern experimental researches indicate that glucose tolerance factor (GTF) is a kind of compound material of various amino acids centering with chrome and a vital adjusting factor for sugar and fat metabolism in organism, GTF also plays an important role in keeping normal level of glucose tolerant quantity. We integrated the achievement in and out of China to prevent and cure diabetes and high blood fat disease and practical clinical experiences to synthesize glucose tolerance factor (GTF) which has been generally known that is effective to diabetes. After that, we composed compound GEGEN capsule with GTF and valid composition, GENGEN element, from the traditional Chinese medicine GEGEN. This prescribe can benefit energy and spleen, living YIN and saliva, and raise blood and remove stasis. 1. SubjectThrough the research, we further explored the relation of diabetes (Dispelling Thirst) disease and blood stasis. According to the requests of pharmacy, i.e. " safe, effective, stable and control", and the theory of combining traditional Chinese and western medicine, we composed prescribes and used medicines to look for a kind of new medicine which has satisfied effect and is safer than chemistry synthesize medicine in preventing and curingdiabetes. We integrated biological pharmacy technique and traditional Chinese medicalpreparation effectively. The experiment is divided into totally five parts, of which maincontents and result as follows.2. Methods:2.1. Preparation of the compound GEGEN capsuleAt first, according to the requests of pharmacopoeia, we selected one kind of wild GEGEN, which is one of the seven medical GEGEN defined in. pharmacopoeia, as extract sample. And then, we determined the relative microstructure and relevant infrared and chrome content determination.2.2 The impact of compound GEGEN capsule to experimental diabetes small rats’ empty stomach blood sugar and glucose intolerant quantity.In order to inquiry into the impact of compound GEGEN capsule to Alloxan diabetes small rats’ empty stomach blood sugar and glucose intolerant quantity, to examine its effect on declining high blood sugar, the duplicated model young rats in diabetes are divided into model set, the sets that model sets fed the compound GEGEN capsule in big and small doses(fed the compound GEGEN capsule respectively 0.34,0.17 g/kg), the positive control set that model set fed Excellent Declining Sugar( fed Excellent Decline Sugar 5 mg/ kg), normal control set and model control set ig. Normal control set and model control set ig were given equal volume(0.2 ml/lOg) of distilled water once everyday for 10 days successively. Then we determined blood sugar and glucose tolerant quantity respectively.2.3. The impact of Compound GEGEN capsule to the blood fat level of big rat in high blood fat we took 50 Wistar big male rats and divided them into 5 sets randomly: normal control set(given normal foundation animal feed), High blood fat model se更多还原