苦丁茶的降血糖活性物质基础与作用机理研究
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摘要
苦丁茶（Ilex kudincha C. J. Tseng）是冬青科（Aquifoliaceae）冬青属乔木植物的干燥嫩叶，主产于湖南、湖北、广东、广西等省，历代本草均有记载，有长期的临床应用基础，已经成为治疗心血管相关疾病、降血脂、降血糖等的常用辅助治疗药物，是药用植物研究的热点。本课题以苦丁茶调节糖脂代谢紊乱为研究内容，以降血糖、降血脂药理活性为基础，以传统的植物化学分离模式指导并跟踪，直至发现并确定苦丁茶降血糖、降血脂的活性成分，并利用液质联用（LC-MS/MS）技术对活性成分进行结构鉴定，同时从分子生物学的角度对其调节糖脂代谢紊乱的作用机理进行了研究。
本课题首先从苦丁茶水煎液对二型糖尿病小鼠降血糖活性的研究开始，采用高脂饲料(10%蛋黄，10%猪油，1%胆固醇，0.2%胆盐，78.8%基础饲料)配合低剂量注射四氧嘧啶(90mg·kg-1)的方法建立二型糖尿病小鼠模型。以苦丁茶水煎液10g·kg-1·d-1（相当于苦丁茶生药材质量）的剂量灌胃治疗1个月，研究苦丁茶水煎液对二型糖尿病小鼠体重的影响以及对小鼠血清中血糖(GLU)、总胆固醇(TC)、甘油三酯(TG)、超氧化物歧化酶(SOD)、丙二醛(MDA)和游离脂肪酸(NEFA)的影响，证明其降血糖、降血脂的药理活性。
然后将苦丁茶水煎液提取物按照化合物极性分为3个不同部位（部位A：100%甲醇回流部位、B：50%甲醇回流部位、C：50%甲醇回流残渣部位），并对这3个部位同时进行降血糖、降血脂的药理活性比较，采用单次高剂量腹腔注射四氧嘧啶(200mg·kg-1)的方法建立一型高血糖模型小鼠模型。以苦丁茶水煎液不同部位相当于苦丁茶原药材15g·kg-1·d-1的剂量灌胃治疗1个月，观察苦丁茶水煎液三个部位对高血糖模型小鼠体重的影响以及对小鼠血清中各项生化指标的影响。研究苦丁茶水煎液的不同部位对一型高血糖模型小鼠体重的影响以及对一型高血糖模型小鼠血清中GLU、TC、TG、SOD、MDA和NEFA的影响，筛选苦丁茶的降血糖、降血脂的活性部位。
最后，对活性部位进行系统的研究，包括苦丁茶活性部位的动物药理实验、降血糖和降血脂的作用机理、活性部位的化学成分研究。采用高脂饲料配合低剂量两次注射四氧嘧啶(60mg·kg-1)的方法建立二型糖尿病小鼠模型。以苦丁茶活性部位A的高、中、低三个剂量组(1.27、2.54、3.81g部位A·kg-1·d-1，相当于苦丁茶生药材5、10、15g·kg-1·d-1)灌胃治疗四周，观察苦丁茶活性部位A的高、中、低三个剂量组对二型糖尿病小鼠体重、进食量、进水量、及血清中GLU、TC、TG、SOD、MDA和NEFA水平的影响。同时，利用高分辨率飞行时间液相串联层析质谱技术(HR-Q/TOF-LC-MS/MS)对苦丁茶降血糖活性部位的化学成分进行系统的研究；然后，以分子生物学理论为指导，采用实时定量RT-PCR的方法研究实验小鼠肝脏中与糖代谢、脂代谢相关的基因:羟甲基戊二酰辅酶A还原酶（Hmgcr）基因，脂肪酸合成酶（Fas）基因，葡萄糖-6-磷酸酶（G6pc）基因，葡萄糖激酶（Gck）基因的表达情况，初步阐述苦丁茶活性部位调节糖脂代谢紊乱的作用机理。
实验结果表明，（1）苦丁茶水煎液能够显著降低二型糖尿病小鼠血清中的GLU、NEFA、TC、TG和MDA水平(p＜0.05)，显著提升二型糖尿病小鼠血清中SOD值(p＜0.05)，验证了苦丁茶水煎液对二型糖尿病小鼠良好的治疗作用。（2）通过不同部位的降血糖药理实验比较发现，苦丁茶水煎液部位A能够显著降低一型高血糖模型小鼠血清的GLU，TC水平(p＜0.05)，显著升高一型高血糖模型小鼠血清的SOD水平(p＜0.05)，部位B和部位C没有显著的降糖活性，说明苦丁茶的降血糖活性成分主要存在于部位A中。（3）苦丁茶活性部位A的高、中、低三个剂量组能够显著降低二型糖尿病小鼠体重、进食量、进水量、及血清中GLU(p＜0.05)水平，其中高剂量组能够显著降低二型糖尿病小鼠血清TC、TG和NEFA水平(p＜0.05)，显著提高血清SOD活性(p＜0.05)，能缓解糖尿病中“三多一少”的典型症状。（4）通过实时定量RT-PCR技术对苦丁茶中糖脂代谢相关基因表达的研究发现，苦丁茶活性部位A能够显著上调二型糖尿病小鼠肝脏中Hmgcr和Gck基因的表达；显著下调二型糖尿病小鼠肝脏中Fas和G6pc基因的表达。初步阐明了苦丁茶活性部位A降血糖、降血脂的作用机理可能包括：通过上调Hmgcr基因表达，诱导肝脏中胆固醇的合成和摄取，进一步通过胆汁酸排泄，并下调Fas基因表达，来改善糖尿病小鼠的脂代谢紊乱；同时，通过下调G6pc基因表达，减少糖异生，上调Gck基因表达而加速糖代谢从而降低体内葡萄糖的水平。（5）通过LC-MS/MS技术对苦丁茶活性部位A化学成分的研究，共检测到苦丁茶部位A中的17个主要化合物，鉴定了其中16个成分，包括3个绿原酸异构体（新绿原酸、绿原酸、隐绿原酸）、3个二咖啡酰基奎宁酸异构体、4个黄酮以及6三萜皂苷类成分。
课题研究以传统中医药理论为指导，以苦丁茶水煎液为初始研究对象，更符合苦丁茶的临床应用经验。同时将现代先进的LC-MS/MS技术成功应用于中药苦丁茶调节糖脂代谢的物质基础研究，鉴定了苦丁茶活性部位中的主要活性成分，表明了苦丁茶调节糖脂代谢紊乱的物质基础。然后以实时定量RT-PCR技术初步阐明了苦丁茶调节糖脂代谢的作用机理。本课题的研究成果为苦丁茶的开发利用奠定了坚实的基础。
Ilex kudincha C. J. Tseng is belongs to the Aquifoliaceae family, whichmainly grown in Hainan, Hubei, Guangdong and Guangxi area of China.The leaves of Ilex kudingcha are used as an ethnomedicine in the treatment ofsymptoms related with diabetes mellitus and obesity throughout the centuriesin China. Nowadays it becomes the research topic in the study of medicinalplants for the treatment ofcardiovascular-related diseases, diabetes mellitusand obesity. The present study investigated the anti-diabetic activities of anactive components group obtained from Ilex kudingcha in alloxan-inducedtype II diabetic mice. The project was based on the anti-diabetic activitiestogether with the method of bioassay-guided fractionation. The chemicalcomposition of active components group of Ilex kudincha was analyzed andidentification with LC-MS/MS. Meanwhile, the mechanism of theanti-diabetic activities of lex kudincha was study by the method of real timeRT-PCR from the perspective of molecular biology.
The project was first to study the hypoglycemic effect of Ilex kudincha ontype II diabetic mice. Type II diabetes were induced by a high-fat diet andalloxan. A high-fat diet contained basic diet (78.8%), egg yolk (10%), lard oil(10%), cholesterol (1%), and cholate (0.2%). The mice were fed this diet forone month, then combined with a once low-dose fresh alloxan (90mg·Kg1). The levels of serum total cholesterol (TC), serum glucose (GLU), triglyceride(TG), superoxide dismutase (SOD), malondialdehyde (MDA) andnonesterified fatty acid (NEFA) were investigated in type II diabetic mice afterone month of treatment of10g·kg-1·d-1Ilex kudincha. The study wasperformed to prove the hypoglycemic effect of Ilex kudincha.
Second, the Ilex kudincha decoction was separated into three fractions (A,B and C) in order to investigate the effects of different fractions of Ilexkudincha decoction on the levels of serum TC, GLU, TG, SOD, MDA andNEFA in type I hyperglycemic mice. The hyperglycemic mice were inducedby a single high dose intraperitoeal injection of200mg·Kg1body weightfresh alloxan solution. Twenty-four hours after the alloxan administration,fasting blood was collected from caudal vein of all the animals to determinethe glucose concentration. The hypoglycemic effects were evaluated by thelevels of several diabetes-related serum parameters including GLU、TC、TG、SOD、MDA and NEFA after one month treatments of fractions A, B and C of15g·kg-1·d-1Ilex kudincha.
Then the hypoglycemic effects of the active components group from Ilexkudincha on type II diabetic mice was investigated including the animalexperiments, the mechanism of its anti-diabetic activities and the chemicalcomposition of the active components group from Ilex kudingcha. Mouse wasfed a high-fat diet for4weeks to prepare the hyperlipidemia mouse. Thehyperlipidemia mouse was treated with a twice low-dose intraperitonealinjection of fresh alloxan (60mg·kg1×2of body weight) for establishment oftype II diabetic mouse. The active components group of low, medium and highdose groups were treated with1.27g,2.54g and3.81g powder·Kg1bodyweight. The1.27g,2.54g and3.81g active components group powder wereequivalent to5g,10g, and15g Ilex kudingcha. Food and water intake werechecked every4days. And other serum biochemical parameters including GLU、TC、TG、SOD、MDA and NEFA were investigated after4weeks oftreatments. For the chemical composition study, the active components group(fraction A) was thawed at room temperature, dissolved in80%aqueousmethanol (10mg·mL1of methanol), and used directly forLC-DAD/HR-ESI-TOF-MS analysis. The study of the mechanism ofanti-diabetic activities was based on the principles of molecular biology andusing the technology of quantitative Real-Time RT-PCR. Four genes wereexamined by real-time RT-PCR. The representative genes were selectedaccording to metabolic functions in terms of gluconeogenesis (G6pc),glycolysis (Gck), lipid metabolism (Fas), and cholesterol synthesis (Hmgcr).
The results were:(1) Ilex kudincha decoction can significantly reduceserum GLU, NEFA, TC, TG and MDA levels. Also, the serum SOD activity issignificantly increased in type II diabetic mice treated with Ilex kudinchadecoction for one month. The therapeutic effect of Ilex kudincha was proved.
(2) The fraction A of Ilex kudincha decoction can significantly decreaseserum GLU and TC levels, and increase serum SOD activity in type Ihyperglycemic mice. The fractions B and C do not possessed significantanti-diabetic activity.
(3) The active components group (fraction A) of low, medium and highdose groups could significantly reduce the body weight, food and water intakeand serum GLU levels in type II diabetic mice. Especially, the high dose groupcould significantly decrease serum TC, TG and NEFA levels and increaseserum SOD activity in type II diabetic mice.
(4) The3-Hydroxy-3-methylglutaryl coenzyme A reductase andglucokinase were upregulated significantly, while fatty acid synthetase,glucose-6-phosphatase catalytic enzyme was downregulated in diabetic miceafter treatment of the active components group from Ilex kudingcha. Themechanism of the hypoglycemic and hypolipidemic effects of the active components group from Ilex kudingcha including the increased excretion ofbile acid and cholesterol induced a deficiency in hepatic cholesterol and itsderivatives, leading to the potent induction of cholesterol synthesis andcholesterol uptake and the activation of glycolysis and inactivation ofgluconeogenesis in liver.
(5) In the study, sixteen components including three chlorogenic acidsisomers (neochlorogenic acid, chlorogenic acid, and cryptochlorogenic acid),three dicaffeoylquinic acids isomers, four flavonoids, and six triterpenoidsaponins were identified or characterized by their MS/MS spectra and LCretention time.
The project subject to the Traditional Chinese Medicine theory as a guideto investigate the anti-diabetic activity of Ilex kudingcha which was more inline with the experience of the clinical application of Ilex kudingcha. Thestudy successfully used the modern advanced technology and methods such asLC-MS/MS technology in basic research material of anti-diabetic activity ofIlex kudingcha. The active components was identified and the mechanism ofhypoglycemic and hypolipidemic effects of Ilex kudingcha were clarified bythe quantitative real-time RT-PCR technique which laid a solid foundation forthe development and utilization of Ilex kudingcha.
本课题首先从苦丁茶水煎液对二型糖尿病小鼠降血糖活性的研究开始，采用高脂饲料(10%蛋黄，10%猪油，1%胆固醇，0.2%胆盐，78.8%基础饲料)配合低剂量注射四氧嘧啶(90mg·kg-1)的方法建立二型糖尿病小鼠模型。以苦丁茶水煎液10g·kg-1·d-1（相当于苦丁茶生药材质量）的剂量灌胃治疗1个月，研究苦丁茶水煎液对二型糖尿病小鼠体重的影响以及对小鼠血清中血糖(GLU)、总胆固醇(TC)、甘油三酯(TG)、超氧化物歧化酶(SOD)、丙二醛(MDA)和游离脂肪酸(NEFA)的影响，证明其降血糖、降血脂的药理活性。
然后将苦丁茶水煎液提取物按照化合物极性分为3个不同部位（部位A：100%甲醇回流部位、B：50%甲醇回流部位、C：50%甲醇回流残渣部位），并对这3个部位同时进行降血糖、降血脂的药理活性比较，采用单次高剂量腹腔注射四氧嘧啶(200mg·kg-1)的方法建立一型高血糖模型小鼠模型。以苦丁茶水煎液不同部位相当于苦丁茶原药材15g·kg-1·d-1的剂量灌胃治疗1个月，观察苦丁茶水煎液三个部位对高血糖模型小鼠体重的影响以及对小鼠血清中各项生化指标的影响。研究苦丁茶水煎液的不同部位对一型高血糖模型小鼠体重的影响以及对一型高血糖模型小鼠血清中GLU、TC、TG、SOD、MDA和NEFA的影响，筛选苦丁茶的降血糖、降血脂的活性部位。
最后，对活性部位进行系统的研究，包括苦丁茶活性部位的动物药理实验、降血糖和降血脂的作用机理、活性部位的化学成分研究。采用高脂饲料配合低剂量两次注射四氧嘧啶(60mg·kg-1)的方法建立二型糖尿病小鼠模型。以苦丁茶活性部位A的高、中、低三个剂量组(1.27、2.54、3.81g部位A·kg-1·d-1，相当于苦丁茶生药材5、10、15g·kg-1·d-1)灌胃治疗四周，观察苦丁茶活性部位A的高、中、低三个剂量组对二型糖尿病小鼠体重、进食量、进水量、及血清中GLU、TC、TG、SOD、MDA和NEFA水平的影响。同时，利用高分辨率飞行时间液相串联层析质谱技术(HR-Q/TOF-LC-MS/MS)对苦丁茶降血糖活性部位的化学成分进行系统的研究；然后，以分子生物学理论为指导，采用实时定量RT-PCR的方法研究实验小鼠肝脏中与糖代谢、脂代谢相关的基因:羟甲基戊二酰辅酶A还原酶（Hmgcr）基因，脂肪酸合成酶（Fas）基因，葡萄糖-6-磷酸酶（G6pc）基因，葡萄糖激酶（Gck）基因的表达情况，初步阐述苦丁茶活性部位调节糖脂代谢紊乱的作用机理。
实验结果表明，（1）苦丁茶水煎液能够显著降低二型糖尿病小鼠血清中的GLU、NEFA、TC、TG和MDA水平(p＜0.05)，显著提升二型糖尿病小鼠血清中SOD值(p＜0.05)，验证了苦丁茶水煎液对二型糖尿病小鼠良好的治疗作用。（2）通过不同部位的降血糖药理实验比较发现，苦丁茶水煎液部位A能够显著降低一型高血糖模型小鼠血清的GLU，TC水平(p＜0.05)，显著升高一型高血糖模型小鼠血清的SOD水平(p＜0.05)，部位B和部位C没有显著的降糖活性，说明苦丁茶的降血糖活性成分主要存在于部位A中。（3）苦丁茶活性部位A的高、中、低三个剂量组能够显著降低二型糖尿病小鼠体重、进食量、进水量、及血清中GLU(p＜0.05)水平，其中高剂量组能够显著降低二型糖尿病小鼠血清TC、TG和NEFA水平(p＜0.05)，显著提高血清SOD活性(p＜0.05)，能缓解糖尿病中“三多一少”的典型症状。（4）通过实时定量RT-PCR技术对苦丁茶中糖脂代谢相关基因表达的研究发现，苦丁茶活性部位A能够显著上调二型糖尿病小鼠肝脏中Hmgcr和Gck基因的表达；显著下调二型糖尿病小鼠肝脏中Fas和G6pc基因的表达。初步阐明了苦丁茶活性部位A降血糖、降血脂的作用机理可能包括：通过上调Hmgcr基因表达，诱导肝脏中胆固醇的合成和摄取，进一步通过胆汁酸排泄，并下调Fas基因表达，来改善糖尿病小鼠的脂代谢紊乱；同时，通过下调G6pc基因表达，减少糖异生，上调Gck基因表达而加速糖代谢从而降低体内葡萄糖的水平。（5）通过LC-MS/MS技术对苦丁茶活性部位A化学成分的研究，共检测到苦丁茶部位A中的17个主要化合物，鉴定了其中16个成分，包括3个绿原酸异构体（新绿原酸、绿原酸、隐绿原酸）、3个二咖啡酰基奎宁酸异构体、4个黄酮以及6三萜皂苷类成分。
课题研究以传统中医药理论为指导，以苦丁茶水煎液为初始研究对象，更符合苦丁茶的临床应用经验。同时将现代先进的LC-MS/MS技术成功应用于中药苦丁茶调节糖脂代谢的物质基础研究，鉴定了苦丁茶活性部位中的主要活性成分，表明了苦丁茶调节糖脂代谢紊乱的物质基础。然后以实时定量RT-PCR技术初步阐明了苦丁茶调节糖脂代谢的作用机理。本课题的研究成果为苦丁茶的开发利用奠定了坚实的基础。
Ilex kudincha C. J. Tseng is belongs to the Aquifoliaceae family, whichmainly grown in Hainan, Hubei, Guangdong and Guangxi area of China.The leaves of Ilex kudingcha are used as an ethnomedicine in the treatment ofsymptoms related with diabetes mellitus and obesity throughout the centuriesin China. Nowadays it becomes the research topic in the study of medicinalplants for the treatment ofcardiovascular-related diseases, diabetes mellitusand obesity. The present study investigated the anti-diabetic activities of anactive components group obtained from Ilex kudingcha in alloxan-inducedtype II diabetic mice. The project was based on the anti-diabetic activitiestogether with the method of bioassay-guided fractionation. The chemicalcomposition of active components group of Ilex kudincha was analyzed andidentification with LC-MS/MS. Meanwhile, the mechanism of theanti-diabetic activities of lex kudincha was study by the method of real timeRT-PCR from the perspective of molecular biology.
The project was first to study the hypoglycemic effect of Ilex kudincha ontype II diabetic mice. Type II diabetes were induced by a high-fat diet andalloxan. A high-fat diet contained basic diet (78.8%), egg yolk (10%), lard oil(10%), cholesterol (1%), and cholate (0.2%). The mice were fed this diet forone month, then combined with a once low-dose fresh alloxan (90mg·Kg1). The levels of serum total cholesterol (TC), serum glucose (GLU), triglyceride(TG), superoxide dismutase (SOD), malondialdehyde (MDA) andnonesterified fatty acid (NEFA) were investigated in type II diabetic mice afterone month of treatment of10g·kg-1·d-1Ilex kudincha. The study wasperformed to prove the hypoglycemic effect of Ilex kudincha.
Second, the Ilex kudincha decoction was separated into three fractions (A,B and C) in order to investigate the effects of different fractions of Ilexkudincha decoction on the levels of serum TC, GLU, TG, SOD, MDA andNEFA in type I hyperglycemic mice. The hyperglycemic mice were inducedby a single high dose intraperitoeal injection of200mg·Kg1body weightfresh alloxan solution. Twenty-four hours after the alloxan administration,fasting blood was collected from caudal vein of all the animals to determinethe glucose concentration. The hypoglycemic effects were evaluated by thelevels of several diabetes-related serum parameters including GLU、TC、TG、SOD、MDA and NEFA after one month treatments of fractions A, B and C of15g·kg-1·d-1Ilex kudincha.
Then the hypoglycemic effects of the active components group from Ilexkudincha on type II diabetic mice was investigated including the animalexperiments, the mechanism of its anti-diabetic activities and the chemicalcomposition of the active components group from Ilex kudingcha. Mouse wasfed a high-fat diet for4weeks to prepare the hyperlipidemia mouse. Thehyperlipidemia mouse was treated with a twice low-dose intraperitonealinjection of fresh alloxan (60mg·kg1×2of body weight) for establishment oftype II diabetic mouse. The active components group of low, medium and highdose groups were treated with1.27g,2.54g and3.81g powder·Kg1bodyweight. The1.27g,2.54g and3.81g active components group powder wereequivalent to5g,10g, and15g Ilex kudingcha. Food and water intake werechecked every4days. And other serum biochemical parameters including GLU、TC、TG、SOD、MDA and NEFA were investigated after4weeks oftreatments. For the chemical composition study, the active components group(fraction A) was thawed at room temperature, dissolved in80%aqueousmethanol (10mg·mL1of methanol), and used directly forLC-DAD/HR-ESI-TOF-MS analysis. The study of the mechanism ofanti-diabetic activities was based on the principles of molecular biology andusing the technology of quantitative Real-Time RT-PCR. Four genes wereexamined by real-time RT-PCR. The representative genes were selectedaccording to metabolic functions in terms of gluconeogenesis (G6pc),glycolysis (Gck), lipid metabolism (Fas), and cholesterol synthesis (Hmgcr).
The results were:(1) Ilex kudincha decoction can significantly reduceserum GLU, NEFA, TC, TG and MDA levels. Also, the serum SOD activity issignificantly increased in type II diabetic mice treated with Ilex kudinchadecoction for one month. The therapeutic effect of Ilex kudincha was proved.
(2) The fraction A of Ilex kudincha decoction can significantly decreaseserum GLU and TC levels, and increase serum SOD activity in type Ihyperglycemic mice. The fractions B and C do not possessed significantanti-diabetic activity.
(3) The active components group (fraction A) of low, medium and highdose groups could significantly reduce the body weight, food and water intakeand serum GLU levels in type II diabetic mice. Especially, the high dose groupcould significantly decrease serum TC, TG and NEFA levels and increaseserum SOD activity in type II diabetic mice.
(4) The3-Hydroxy-3-methylglutaryl coenzyme A reductase andglucokinase were upregulated significantly, while fatty acid synthetase,glucose-6-phosphatase catalytic enzyme was downregulated in diabetic miceafter treatment of the active components group from Ilex kudingcha. Themechanism of the hypoglycemic and hypolipidemic effects of the active components group from Ilex kudingcha including the increased excretion ofbile acid and cholesterol induced a deficiency in hepatic cholesterol and itsderivatives, leading to the potent induction of cholesterol synthesis andcholesterol uptake and the activation of glycolysis and inactivation ofgluconeogenesis in liver.
(5) In the study, sixteen components including three chlorogenic acidsisomers (neochlorogenic acid, chlorogenic acid, and cryptochlorogenic acid),three dicaffeoylquinic acids isomers, four flavonoids, and six triterpenoidsaponins were identified or characterized by their MS/MS spectra and LCretention time.
The project subject to the Traditional Chinese Medicine theory as a guideto investigate the anti-diabetic activity of Ilex kudingcha which was more inline with the experience of the clinical application of Ilex kudingcha. Thestudy successfully used the modern advanced technology and methods such asLC-MS/MS technology in basic research material of anti-diabetic activity ofIlex kudingcha. The active components was identified and the mechanism ofhypoglycemic and hypolipidemic effects of Ilex kudingcha were clarified bythe quantitative real-time RT-PCR technique which laid a solid foundation forthe development and utilization of Ilex kudingcha.
引文
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