2型糖尿病胰岛素抵抗大鼠模型证候演变与相关方药作用研究
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摘要
“方证相关”是中医辨证论治和方剂学中的重要逻辑命题。方剂的功用不仅与方药配伍有关,还与其所作用的病证有一定的适配性,不同的病证要求针对性的治法与方药,即“法随证立,方随证变”。方剂效用大小在相当程度上取决于所作用对象的病机与其方药配伍关系之间的关联程度,方与证之间存在有关联程度大小的问题。近些年有关方证研究主要是从静态或空间状态下证候分布的角度进行探讨,从时间纬度和疾病发展及证候动态演变角度进行研究的则很少。证候“动态时空”的特性决定从证候动态演变角度进行“方证相关”研究是一个值得实践的思路。
本课题以“方证相关”为逻辑基础,以2型糖尿病胰岛素抵抗的现代病理生理和中医关于本病病机认识、防治经验为背景,在复制2型糖尿病IR大鼠模型的过程中,通过观察大鼠外在行为表现和对实验室指标及其与中医证型相关的分析,探查其证候病机动态演变规律;在此基础上,选择与证候病机有不同关联程度的方药作用于模型发展过程中的不同阶段,运用关联排他即异方同证的研究方法,比较同一证候/阶段不同中医方药生物效用差异,探查方药效用与病证的关联程度,并探讨其生物学基础;最后选择与病证关联程度最高的中医药干预方药,从分子水平上探察有效方药对2型糖尿病胰岛素抵抗大鼠模型作用的部分机制。
论文分为文献综述和实验研究两大部分。文献综述主要包括中医方证关系研究进展;2型糖尿病胰岛素抵抗的现代研究进展及动物模型研究进展;2型糖尿病胰岛素抵抗的中医药研究进展三方面。实验研究主要包括2型糖尿病胰岛素抵抗大鼠模型中医证候病机动态演变规律的探究;基于2型糖尿病胰岛素抵抗大鼠模型中医证候演变的相关中医方药干预作用比较;有效中医方药对2型糖尿病胰岛素抵抗大鼠模型作用的机制研究三部分。
研究一2型糖尿病胰岛素抵抗大鼠模型中医证候病机动态演变规律的研究
方法:采用高脂饲料喂养加小剂量链脲佐菌素(STZ)腹腔注射的方法造模。大鼠分为正常组(50只)与造模组(60只)。前5w正常组基础饲料喂养,造模组高脂饲料喂养。第6w造模组给予小剂量STZ(30mg/kg)腹腔注射,检测选取符合标准(FPG≥11.1mmol/L,Fins,20-40uIU/ml)的大鼠正式纳入模型组。正常组、模型组继续分别给于基础饲料、高脂饲料喂养。分别于第0w、第6w末、8w末、10w末、12w末取材,生化法测定血清FPG、TC、TG、HDL-C、LDL-C;放免法测定血清Fins、TNF-α、Leptin、IL-6,血浆cAMP、cGMP;用血流变仪测定200/s、5/s切变率下的全血比粘度及血浆比粘度。
结果:1)外观行为学观察:在6w-8w阶段,模型组大鼠出现嗜睡、眯眼、倦怠懒动,被毛脱落,饮水量增加,大便干结,尾巴出汗潮湿等征象;在9w-10w阶段,再前一阶段征象的基础上,模型组大鼠出现形体肥胖、拱背扎堆、眯眼、精神萎靡、活动迟缓、背毛油腻等表现;在11w-12w阶段,大鼠又出现被毛减少,臀毛枯黄,尾巴尖部至根部出现不同程度的瘀斑。模型组大鼠体重从第4w开始明显增加,第9w出现下降但仍明显高于正常组。2)糖代谢指标:与正常组相比,模型组大鼠FPG、Fins及IRI于第6w末开始持续不断升高,至12w末达到高峰;IAI于6w末开始不断降低,至12w末降低最为显著。3)脂代谢指标:与正常组相比,模型组大鼠从8w末血清TC、LDL-C含量开始升高,至12w末升高最为显著;血清TG含量从第10w开始不断升高,至第12w末显著升高;血清HDL-C含量0-6w出现降低,第6-8w升高,于10w末有明显降低,至12w末降低最为显著。4)细胞因子:与正常组相比,模型组大鼠TNF-a、Leptin、IL-6、cAMP及cAMP/cC-MP比值于第6w末开始持续升高,至12w末达到高峰;cGMP于6w末开始下降,8w末显著下降,至12w末降低最为明显。5)血液流变学:正常组大鼠血液流变学指标无明显改变。与正常组相比,模型组大鼠200/s、5/s切变率下的全血粘度及血浆粘度从第10w末开始升高,至12w末显著升高。
结论:采用高脂饲料喂养+小剂量STZ腹腔注射的方法复制的2型糖尿病IR大鼠模型具有中医证候阶段性变化的特点,并有相应生理病理生物学指标的改变。该模型大鼠在造模较早出现IR及继IR后出现高血糖、高胰岛素血症、高胆固醇血症、高甘油三脂血症以及血液高凝状态;其中医证候病机阶段性演变规律表现为中医气阴两虚证→气阴两虚兼痰浊证→气阴两虚兼痰浊、兼血瘀证的变化。
研究二2型糖尿病胰岛素抵抗大鼠模型基于证候病机演变相关中医方药干预作用比较
方法:采用高脂饲料喂养加小剂量链脲佐菌素(STZ)腹腔注射的方法造模,分阶段治疗观察。大鼠分为正常组(30只)与造模组(170只)。正常组基础饲料喂养,造模组高脂饲料喂养,连续5w。第6w造模组给于一次性小剂量STZ(30mg/kg)腹腔注射。经筛选将造模成功的大鼠随机分为模型组1、模型组2、模型组3,西药组1、西药组2、西药组3,每组10只。中药干预组第一阶段30只,中药干预组第二阶段30只,中药干预组第三阶段30只。正常组分为正常组1、正常组2、正常组3。正常各组继续给予基础饲料喂养,其他组继续给予高脂饲料喂养。
第一阶段:从第7w开始,正常组1和模型组1灌服等量蒸馏水,西药组1给予吡咯列酮(1.35mg/kg/d),将第一阶段中药干预组30只分为A方组、B方组、C方组,三组分别给于A方(5.31g/kg/d)、B方(3.15g/kg/d)、C方(3.15g/kg/d)灌胃。连续2周。第二阶段:从第9W开始,正常组2和模型组2灌服等量蒸馏水,西药组2给予吡咯列酮(1.35mg/kg/d),将第二阶段中药干预组30只分为A+B方组、A方组、B方组,三组分别给于A+B方(8.46g/kg/d)、A方(5.31g/kg/d)、B方(3.15g/kg/d)灌胃。连续2周。第三阶段:从第11w开始,正常组3和模型组3灌服等量蒸馏水,西药组3给予吡咯列酮(1.35mg/kg/d),将第三阶段中药干预组30只分为A+B+C方组、A+B方组、B+C方组,三组分别给于A+B+C方(11.61g/kg/d)、A+B方(8.46g/kg/d)、B+C方(6.30g/kg/d)灌胃。连续2周。上述各阶段各组大鼠分别给药2周后处死,采样做相关检测。
结果:第一阶段:与正常组比较,模型组大鼠血FPG、Fins、IRI明显升高,IAI明显降低;FFA、Leptin、TNF-α、IL-6明显升高;cAMP、cAMP/cGMP明显升高;ET含量明显升高。与模型组比较,A方组、B方组、C方组大鼠血FPG、Fins、IRI和IAI;TG、TC、HDL-c、LDL-c均无明显变化。A方组大鼠血Leptin、TNF-α和cAMP、cAMP/cGMP明显降低,B方组、C方组大鼠血Leptin、TNF-α和cAMP、cAMP/cGMP无明显变化。三方各组大鼠高切、低切下的全血比粘度与血浆比粘度无明显变化,A方组、B方组大鼠内皮素含量无明显变化,C方组大鼠血内皮素含量显著降低。A方组、B方组、C方组大鼠胰腺病理损伤均无明显改善。第二阶段:与正常组比较,模型组大鼠血FPG、Fins、IRI明显升高,IAI明显降低;TC、LDL-c明显升高;FFA、Leptin、TNF-α、IL-6明显升高,cAMP、cAMP/cGMP明显升高;ET含量明显升高。与模型组比较,A+B方组大鼠血FPG、Fins、IRI明显降低,IAI明显升高;TC、LDL-c明显降低;FFA、Leptin、TNF-α水平明显降低,cAMP含量、cAMP/cGMP比值明显降低;内皮素含量明显降低。A方组大鼠血Fins明显降低,Leptin、TNF-α明显降低,cAMP含量、cAMP/cGMP比值明显降低。B方组大鼠血Fins降低,TC、FFA含量明显降低。A+B方组、A方组、B方组三组大鼠胰腺病理损伤均无明显改善。
第三阶段:与正常组比较,模型组大鼠血FPG、Fins、IRI显著升高,IAI显著降低;TC、TG、LDL-c明显升高,HDL-c明显降低;FFA、Leptin、TNF-α、IL-6均显著升高;cAMP、cAMP/cGMP明显升高;高切、低切下的全血比黏度与血浆比粘度明显升高,ET含量显著升高。与模型组比较,A+B+C方组大鼠血FPG、Fins、IRI明显降低,IAI明显升高;TC、LDL-C明显降低;FFA、Leptin、TNF-α、IL-6明显降低;cAMP、cAMP/cGMP明显降低;高切、低切下的全血比黏度与血浆比粘度明显降低,ET-1含量明显降低。A+B方组大鼠血FPG、Fins、IRI明显降低,IAI升高;TC、LDL-C明显降低;FFA、Leptin、TNF-α明显降低;cAMP、cAMP/cGMP比值明显降低;ET-1含量明显降低。B+C方组大鼠血Fins明显降低,FFA明显降低;高切、低切下的全血比黏度与血浆比粘度明显降低,ET-1含量明显降低。A+B+C方对模型大鼠胰腺病理损伤有一定改善作用。
结论:不同阶段体现不同治法的中医方药对模型大鼠相应证候/病证有不同程度的干预作用。第一阶段,比较A方、B方、C方的整体干预效应,A方对模型大鼠的干预作用优于B方和C方,推断A方与模型此阶段证候的关联性最大。第二阶段,比较A+B方、A方、B方的整体干预效应,以A+B方对模型大鼠此阶段的治疗作用最优,其次是A方,B方的治疗作用较差。推断A+B方与模型此阶段的病证有更高的关联程度。第三阶段,比较A+B+C方、A+B方、B+C方的整体干预效应,以A+B+C方对模型大鼠此阶段的治疗作用最优,推断A+B+C方与大鼠模型此阶段的病证有更高的关联程度。
研究三有效中医方药对2型糖尿病胰岛素抵抗大鼠模型作用机制研究
方法:以疗效最好(即与病证关联程度最高)的方药——A+B+C方作用于模型大鼠,采用实时荧光定量PCR技术测定大鼠脂肪组织PPAR-r mRNA和InsR mRNA,从分子层面进行中医药作用机制探查研究。
结果:有效中医方药对模型大鼠脂肪组织PPAR-r mRNA和InsR mRNA表达的影响:与正常组相比,模型组大鼠脂肪组织PPAR-r mRNA和InsR mRNA表达量均明显降低(P＜0.05)。与模型组比较,西药组和A+B+C方组大鼠脂肪组织PPAR-r mRNA表达量都明显升高(P＜0.01),InsR mRNA表达量有不同程度增加,但差异无显著性意义(P=0.060或P=0.061)。与西药组比较,A+B+C方脂肪组织PPAR-r mRNA表达量显著降低(P＜0.05)。
结论:有效中医方药A+B+C方—“益气养阴、化痰活血方”治疗2型糖尿病的作用机制可能与噻唑烷二酮类药物(TZDs)的作用机制相同,涉及脂肪组织细胞核受体PPAR-r激活和增加Ins受体。
综合结果表明,中药益气养阴、化痰活血方能够显著降低模型大鼠的FPG、Fins,提高胰岛素敏感性,改善胰岛素抵抗,纠正脂质代谢紊乱,降低FFA、Leptin、TNF-α和IL-6水平,对血液流变学异常等也有明显改善效应,其整体疗效并不逊于西药,且在血管内皮细胞损伤的保护、脂代谢的调节、高凝状态的抑制等方面有一定优势,体现了中医复方的多环节作用特点。
创新及意义:1)本研究发现以高脂饲料喂养+小剂量STZ腹腔注射的方法复制的2型糖尿病IR大鼠模型具有中医证候阶段性变化及相应生理病理生物学指标改变的特点,为病证结合及动态研究方证关系提供了一个有价值的研究性模型;2)从同证异方的角度通过对2型糖尿病胰岛素抵抗大鼠模型形成过程不同阶段相关中医方药的生物学效用进行比较,发现不同治法方药干预作用特点及与相关证候/病证的不同程度的关联程度,为理解中医方证相关及其内涵提供了一定实验依据;3)从客观实证角度论证了中医临床因证立法组方的合理性;在分子机制研究中发现中医有效干预方药防治2型糖尿病IR的作用机制与噻唑烷二酮类药物(TZDs)的作用相同:通过激活脂肪细胞核受体PPAR-r,增强机体胰岛素的敏感性,调节某些细胞因子水平,改善糖脂代谢,改善胰岛素抵抗状态。本研究不仅为从证候演变角度开展“方证相关”研究进行了有益的方法学探索,而且为认识理解“方证相关”及其科学内涵提供了一定的客观依据。
"Correlation between Formula and Syndrome" is an important logic proposition in diagnosis and treatment based on symptoms differentiation and formula -ology.The function and usage of formula not only have correlation with medical compatibility but also compatible with the syndrome which it will have effect on, that is the main effect of the formula depends on a considerable extent on the pathology and the role of targets of medical compatibility.The different syndrome should correspond to different treatment principals and formulas,"the treatment principals based on syndromes,different formulas based on syndromes".There is a problem of extent of correlation between the formula and syndrome.In recent years, many researchs mainly probed "Correlation between Formula and Syndrome" from static or space condition of syndromes,There are few research carrying out it from dynamic evolutionary of syndromes or the development of disease along with time.It is a good thought that probed "Correlation between Formula and Syndrome" from dynamic evolutionary of syndromes along with time based on the dynamic evolutionary character of syndromes.
The research takes"Correlation between Formula and Syndrome'as logic basis, is mainly based on the theory of etiology and pathology of Type 2 Diabetes Insulin Resistance in western medicine and features of etiology and pathology and treatment in Chinese medicine.During replicated the rats model of Type 2 Diabetes Insulin Resistance,by observing appearance and behavior of the rats model and analysing multiple indicators of experiment in biological system concomitantly corresponding TCM's syndromes,we explored the dynamic evolutionary progression of syndromes and pathology;On this basis,we selected some formulas which correlated with TCM's syndromes on some extent and influenced on the rats model in different phases.Compared the biological effects of different formulas by the research methods of correlation and exclusion,that is different formulas for one syndrome.To explore the relationship between the function and usage of formula and TCM's syndromes,and we also discussed the biological foundation of different formulas.Finally,we explored genes expression about PPAR-r mRNA and InsR mRNA in fattiness of the model and the effection of the best chinese medicine influencing the rats model by applying with Real Time quantitative PCR technology,and approached molecular mechanism of chinese medicines influencing the model.
The thesis is divided into two main parts:literature review and experimental research.Literature review is mainly focused on three aspects:The relationship between Formula and Syndrome in TCM;Review of the study about Insulin Resistance of Type 2 Diabetes in morden medicine and the study about experimental model of Type 2 Diabetes IR;Review of the study about Insulin Resistance of Type 2 Diabetes in traditional chinese medicine.Experiment study is mainly focused on three aspects:the study about the dynamic evolutionary progression of syndromes and pathology on the rats model of Type 2 Diabetes Insulin Resistance;Comparsion the biological effects of different formulas correlated TCM's syndromes pathology in different phase based on the progressive syndrome on the rats model of Type 2 Diabetes Insulin Resistance;the study of mechanism of the effective chinese medicine influence on the model.
Research 1:The study about the dynamic evolutionary progressive of syndromes and pathology on the rats model of Type 2 Diabetes Insulin Resistance
Methods:The research set on the rats model by feeding with high glucose and fat diet together with peritoneal injection of STZ.SD rats were randomly divided into the control group(50 rats) and model group(60 rats).During 1-5w,the control group were fed with normal food,the model group were fed with high glucose and high calories food.In the 6~(th) week,the model group were injected with STZ (30mg/kg) at abdomino.We selected model rats which measure up the standard (FPG≥11.1mmol/L,Fins 20-40uIU/ml)into the experiment.At the end of 0,6,8, 10,12 week,the rats were killed and taken blood and tissure.We used biological and chemical method to measure FPG,TC,TG,HDL-c,LDL-c,serumand plasma were measured by radioimmunoassay(RIA) to test the contents of Fins, TNF-α,Leptin,IL-6,cAMP,cGMP.Using DWN-90 blood liqid analyse apparatus to measure the whole blood viscosity at 200/s,5/s shear rate and plasma viscosity.
Results:
1) Appearance and behavior:During 6w-8w,the model rats appear lethargy, narrow their eyes,accidie,still,loss of hair,drinking increase,dejecta desiccation,sweatiness and wateriness at tail.During 9w-10w,the model rats appear fatness,extrados,gather together,narrow their eyes,accidie,action slow,fatness in hair which based on syndromes at first phase;During 11w-12w,the model rats appear continually loss of hair and turn into yellow color at stern,some petechias appear at the tail from top to root.Compared with the control group,the weight of the model group rises up obviously at 4~(th) week,and lowers continually from 9~(th) week,higher obviously than the control group.2)Glucose metabolism:Compared with the control group,the FPG,Fins,IRI level of the model group were increased continually from the end of 6~(th) week,reached its top at the end of 12~(th) week.the IAI level were decreased obviously from the end of 6~(th) week,reached its bottom at the end of 12~(th) week.3)Lipid metabolism:Compared with the control group,The TC,LDL-C level of the model group were increased continually from the end of 8~(th) week,reached its top at the end of 12~(th) week.The TG level were increased obviously from the end of 10~(th) week,reached its top at the end of 12~(th) week.The HDL-C level of the model group were decreased during 0-6w,were increased during 6-8w,were decreased obviously at the end of 10~(th) week,reach its bottom at the end of 12~(th) week.4)Adipokines:Compared with the control group,the TNF-a,Leptin,IL-6, cAMP,cAMP/cGMP level of the model group were increased continually from the end of 6~(th) week,reached their top at the end of 12~(th) week.The cGMP level of the model group were decreased from the end of 6~(th) week,reached its bottom at the end of 12~(th) week.6)Haematological change:The whole blood viscosity and plasma viscosity of the control group have no change.Compared with the control group,the whole blood viscosity and plasma viscosity of the model group at 200/s,5/s shear rate were increased continually from the end of 10~(th) week,reached it top at the end of 12~(th) week.
Conclusions:The rats model of T2DM IR which feeding high glucose and fat diet together with peritoneal injection of STZ appeared characters of dynamic evolutionary syndroms and corresponding biological items change during different phases.The model manifested hyperglycemia,hyper-insulinemia,high level cholesterin and triglyceride after IR.The dynamic evolutionary progression of syndromes and pathology in different phases are simultaneous deficiency of both qi and yin→simultaneous deficiency of both qi and yin concurrent phlegm turbidness→simultaneous deficiency of both qi and yin concurrent phlegm turbidness and blood stasis.
Research 2:Comparison of biological effects of different formulas correlated syndrome based on the progressive syndrome on the rats model of Type 2 Diabetes Insulin Resistance
Methods:The research set on the rats model by feeding with high glucose and fat diet together with peritoneal injection of STZ.SD rats were randomly divided into the control group(30 rats) and model group(170 rats).During 1-Sw,the control group were fed with normal food,the model group were fed with high glucose and high calories food.In the 6th week,the model group were injected with STZ(30mg/kg) at abdomino.We selected model rats which measure up the standard into the experiment.The rats were randomly divided into the model group 1,the model group 2,the model group 3,the xiyao group 1,the xiyao group 2,the xiyao group 3, 10 rats each group.the first phase intervention of chinese medicine 30 rats,the second phase intervention of chinese medicine 30 rats,the third phase intervention of Chinese Medicine 30 rats,The rats of the control group were divided into the control group 1,the control group 2,the control group 3.the control groups were fed with normal food continually,other groups were fed with high glucose and high calories food.
First phase:From the 7~(th) week,the control group 1 and the model group 1 were administrated the distilled water,the xiyao group 1 were administrated Pioglitazone(1.35mg/kg/d),The rats of first phase intervention of chinese medicine were divided into A formula group,B formula group,C formula group,they were administrated respectively with A formula(5.31g/kg/d),B formula(3.15g/kg/d),C formula(3.15g/kg/d) for two weeks.Second phase:From the 9~(th) week,the control group 2 and the model group 2 were administrated the distilled water,the xiyao group 2 were administrated Pioglitazone(1.35mg/kg/d),The rats of second phase intervention of chinese medicine were divided into A+B formula group,A formula group,B formula group,they were administrated respectively with A+B formula(8.46g/kg/d),A formula(5.31g/kg/d),B formula(3.15g/kg/d) for two weeks.Third phase:From the 11~(th) week,the control group 3 and the model group 3 were administrated the distilled water,the xiyao group 3 were administrated Pioglitazone(1.35mg/kg/d),the rats of third phase intervention of chinese medicine were divided into A+B+C formula group,A+B formula group,B+C formula group, they were administrated respectively with A+B+C formula(11.61g/kg/d),A+B formula(8.46g/kg/d),B+C formula(6.30g/kg/d )for two weeks.The rats were killed and taken blood and tissure to measure at different phases.
Results:
First phase:Compared with the control group,the FPG,Fins,IRI level of the model group were increased obviously,the IAI level were decreased obviously,the FFA,Leptin,TNF-a,IL-6,cAMP,cAMP/cGMP level were increased obviously,the ET level were increased obviously.Compared with the model group,the FPG,Fins,IRI,IAI,and TG,TC,HDL-c,LDL-c level of A formula group,B formula group and C formula group have no change.The Leptin,TNF-αand cAMP,cAMP/cGMP level of the A formula group was decreased obviously,B formula group and C formula group have no change on these.A formula group,B formula group and C formula group have no effect on the whole blood viscosity at the 200/s,5/s shear rate and plasma viscosity of the model group.A formula group,B formula group have no effect on the ET-1 of the model group.The ET-1 level of the C formula group was decreased significantly.The A formula group,B formula group and C formula group have no effect on Pancreas pathomorpholgoy.
Second phase:Compared with the control group,the FPG,Fins,IRI level of the model group were increased obviously,the IAI level were decreased obviously,the TC,LDL-c level were increased obviously,the FFA,Leptin,TNF-a,IL-6,cAMP, cAMP/cGMP level were increased obviously,the ET level were increased obviously. Compared with the model group,the FPG、Fins、IRI level of the A+B formula group were decreased obviously,the IAI level were increased obviously.The TC,LDL-C level of the A+B formula group were decreased.The FFA、Leptin、TNF-α、cAMP、cAMP/cGMP were decreased.The ET level were also decreased.The Fins level of the A formula group was decreased,the Leptin,TNF-α、cAMP、cAMP/cGMP level of the A formula group was decreased.The Fins level of the B formula group was decreased,the TC,FFA level of the B formula group was decreased obviously.The A+B formula group,A formula group and B formula group have no effect on Pancreas pathomorpholgoy.
Third phase:Compared with the control group,the FPG,Fins,IRI level of the model group were increased significantly,the IAI level were decreased significantly,the TC,TG,LDL-c level were increased obviously,the HDL-c level was decreased obviously,the FFA,Leptin,TNF-a,IL-6,cAMP,cAMP/cGMP level were increased obviously,the level of the whole blood viscosity at the 200/s,5/s shear rate and plasma viscosity were increased obviously,the ET level were increased obviously.Compared with the model group,the FPG,Fins,IRI level of the A+B+C formula group were decreased obviously,the IAI level was increased obviously.The TC、LDL-C level of the A+B+C formula group were decreased.The FFA,Leptin, TNF-α、IL-6、cAMP、cAMP/cGMP level were decreased obviously.The level of the whole blood viscosity at the 200/s,5/s shear rate and plasma viscosity of A+B+C formula group were decreased.The ET level of A+B+C formula group was decreased obviously.The FPG、Fins、IRI level of the A+B formula group were decreased,the IAI level was increased.The TC、LDL-C level of the A+B formula group were decreased.The FFA、Leptin、TNF-α、cAMP、cAMP/cGMP level of the A+B formula group were decreased.The ET level of A+B formula group was decreased.The Fins,FFA level of the B+C formula group were decreased,The level of the whole blood viscosity at the 200/s,5/s shear rate and plasma viscosity of B+C formula group were decreased.The ET level of the B+C formula group was decreased obviously.The A+B+C formula group have good effect on some extent to Pancreas pathomorpholgoy.
Conclusions:In different phases,the different formulas which representated different treatment principals have many effects on some extent to corresponding TCM's syndromes/disease.In the first phase,compared the whole effection of A formula,B formula,C formula,we found that the intervention of A formula are better than B formula and C formula,and we concluded A formula have the close correlation with syndromes in this phase.In the second phase,compared the whole effection of A+B formula,A formula,B formula,we found that the intervention of A+B formula were the best in three groups,the next was A formula,the intervention of B formula were not good.we concluded A+B formula have the close correlation with syndromes in this phase.In the third phase,compared the whole effection of A+B+C formula,A+B formula,B+C formula,we found that the intervention of A+B+C formula are the best in three groups,we concluded A+B+C formula have the close correlation with syndromes in this phase.
Research 3:the mechanism study of the effective chinese medicine influence on the rats model of Type 2 Diabetes Insulin Resistance
Methods:According to results of the former study,we selected the best effective formula—A+B+C formula,which has the closest correlation with disease and syndrome,we took it as the chinese medicine intervention group,and measured the expression of PPAR-γmRNA and InsR mRNA in fat by using the Real-time quantitative PCR.To explore mechanism of A+B+C formula influenceing on the rats model of Type 2 Diabetes Insulin Resistance.
Results:The effects on the expression of PPAR-γmRNA and InsR mRNA in fat of A+B+C formula:Compared with the control group,the expression of PPAR-γmRNA and InsR mRNA in fat of the model group were significantly decreased(P＜0.05).Compared with the model group,the expression of PPAR-γmRNA in fat of the xiyao group and A+B+C formula group were significantly increased(P＜0.01),the expression of InsR mRNA in fat were increased on some extent,but there was no distinct difference(P=0.060或P=0.061).Compared with the xiyao group,the expression of PPAR-γmRNA in fat of A+B+C formula were significantly decreased(P＜0.05).
Conclusions:We concluded that treatment mechanism of A+B+C formula (yiqiyangyin huatanhuoxue fang)to treat Type 2 Diabetes may act as a similar way of Thiazolidinediones(TZD),involving to activate PPAR-γand increased InsR.
To sum up,the findings indicated that the yiqiyangyin huatanhuoxue fang have effect on decreasing FPG、Fins level,enhancing the sensitivity of skeletal muscle and liver to insulin,ameliorating IR,correcting lipid metabolism turbulence,slowing the release of FFA,Leptin,TNF-a,IL-6,ameliorating haematological abnormity,the whole effection are same as Pioglitazone.the chinese medicine have other superority in treatment,for exemple,protecting endothelium cell of blood vessel,accommodating lipid metabolism,preventing blood coagulation,this showed the character that interventiong many aspect of chinese medicine compounds.
Innovation and Meaning:1)the research found that the rats model of T2DM IR which feeding high glucose and fat diet together with peritoneal injection of STZ appeared characters of dynamic evolutionary syndroms and corresponding biological items change during different phases.It offers a worth model for the study of"Correlation between Formula and Syndrome"from dynamic evolutionary progressive of disease and syndrome.2)Comparison of biological effects of different formulas correlated syndrome based on the progressive syndrome on the rats model of Type 2 Diabetes Insulin Resistance with the research methods of correlation and exclusion and different formulas for one syndrome.The research found the different formulas have different function characteristics,they have have correlation on some extent to corresponding TCM's syndromes/disease.3)It demonstrated the rationality about making out treatment methods based on different syndromes.The study of mechanism found that treatment mechanism of A+B+C formula to treat Type 2 Diabetes may act as a similar way with Thiazolidinediones(TZD).they are both activating PPAR-γ,enhancing the sensitivity of skeletal muscle and liver to insulin, accommodating some adipokines level,improving glucose and liquid metabolism ameliorating IR.The research not only carried out beneficial technology exploration for revealing the important logic proposition of"Correlation between Formula and Syndrome",but also provided objective evidence for recognizing "Correlation between Formula and Syndrome"and its scientific connotation.
本课题以“方证相关”为逻辑基础,以2型糖尿病胰岛素抵抗的现代病理生理和中医关于本病病机认识、防治经验为背景,在复制2型糖尿病IR大鼠模型的过程中,通过观察大鼠外在行为表现和对实验室指标及其与中医证型相关的分析,探查其证候病机动态演变规律;在此基础上,选择与证候病机有不同关联程度的方药作用于模型发展过程中的不同阶段,运用关联排他即异方同证的研究方法,比较同一证候/阶段不同中医方药生物效用差异,探查方药效用与病证的关联程度,并探讨其生物学基础;最后选择与病证关联程度最高的中医药干预方药,从分子水平上探察有效方药对2型糖尿病胰岛素抵抗大鼠模型作用的部分机制。
论文分为文献综述和实验研究两大部分。文献综述主要包括中医方证关系研究进展;2型糖尿病胰岛素抵抗的现代研究进展及动物模型研究进展;2型糖尿病胰岛素抵抗的中医药研究进展三方面。实验研究主要包括2型糖尿病胰岛素抵抗大鼠模型中医证候病机动态演变规律的探究;基于2型糖尿病胰岛素抵抗大鼠模型中医证候演变的相关中医方药干预作用比较;有效中医方药对2型糖尿病胰岛素抵抗大鼠模型作用的机制研究三部分。
研究一2型糖尿病胰岛素抵抗大鼠模型中医证候病机动态演变规律的研究
方法:采用高脂饲料喂养加小剂量链脲佐菌素(STZ)腹腔注射的方法造模。大鼠分为正常组(50只)与造模组(60只)。前5w正常组基础饲料喂养,造模组高脂饲料喂养。第6w造模组给予小剂量STZ(30mg/kg)腹腔注射,检测选取符合标准(FPG≥11.1mmol/L,Fins,20-40uIU/ml)的大鼠正式纳入模型组。正常组、模型组继续分别给于基础饲料、高脂饲料喂养。分别于第0w、第6w末、8w末、10w末、12w末取材,生化法测定血清FPG、TC、TG、HDL-C、LDL-C;放免法测定血清Fins、TNF-α、Leptin、IL-6,血浆cAMP、cGMP;用血流变仪测定200/s、5/s切变率下的全血比粘度及血浆比粘度。
结果:1)外观行为学观察:在6w-8w阶段,模型组大鼠出现嗜睡、眯眼、倦怠懒动,被毛脱落,饮水量增加,大便干结,尾巴出汗潮湿等征象;在9w-10w阶段,再前一阶段征象的基础上,模型组大鼠出现形体肥胖、拱背扎堆、眯眼、精神萎靡、活动迟缓、背毛油腻等表现;在11w-12w阶段,大鼠又出现被毛减少,臀毛枯黄,尾巴尖部至根部出现不同程度的瘀斑。模型组大鼠体重从第4w开始明显增加,第9w出现下降但仍明显高于正常组。2)糖代谢指标:与正常组相比,模型组大鼠FPG、Fins及IRI于第6w末开始持续不断升高,至12w末达到高峰;IAI于6w末开始不断降低,至12w末降低最为显著。3)脂代谢指标:与正常组相比,模型组大鼠从8w末血清TC、LDL-C含量开始升高,至12w末升高最为显著;血清TG含量从第10w开始不断升高,至第12w末显著升高;血清HDL-C含量0-6w出现降低,第6-8w升高,于10w末有明显降低,至12w末降低最为显著。4)细胞因子:与正常组相比,模型组大鼠TNF-a、Leptin、IL-6、cAMP及cAMP/cC-MP比值于第6w末开始持续升高,至12w末达到高峰;cGMP于6w末开始下降,8w末显著下降,至12w末降低最为明显。5)血液流变学:正常组大鼠血液流变学指标无明显改变。与正常组相比,模型组大鼠200/s、5/s切变率下的全血粘度及血浆粘度从第10w末开始升高,至12w末显著升高。
结论:采用高脂饲料喂养+小剂量STZ腹腔注射的方法复制的2型糖尿病IR大鼠模型具有中医证候阶段性变化的特点,并有相应生理病理生物学指标的改变。该模型大鼠在造模较早出现IR及继IR后出现高血糖、高胰岛素血症、高胆固醇血症、高甘油三脂血症以及血液高凝状态;其中医证候病机阶段性演变规律表现为中医气阴两虚证→气阴两虚兼痰浊证→气阴两虚兼痰浊、兼血瘀证的变化。
研究二2型糖尿病胰岛素抵抗大鼠模型基于证候病机演变相关中医方药干预作用比较
方法:采用高脂饲料喂养加小剂量链脲佐菌素(STZ)腹腔注射的方法造模,分阶段治疗观察。大鼠分为正常组(30只)与造模组(170只)。正常组基础饲料喂养,造模组高脂饲料喂养,连续5w。第6w造模组给于一次性小剂量STZ(30mg/kg)腹腔注射。经筛选将造模成功的大鼠随机分为模型组1、模型组2、模型组3,西药组1、西药组2、西药组3,每组10只。中药干预组第一阶段30只,中药干预组第二阶段30只,中药干预组第三阶段30只。正常组分为正常组1、正常组2、正常组3。正常各组继续给予基础饲料喂养,其他组继续给予高脂饲料喂养。
第一阶段:从第7w开始,正常组1和模型组1灌服等量蒸馏水,西药组1给予吡咯列酮(1.35mg/kg/d),将第一阶段中药干预组30只分为A方组、B方组、C方组,三组分别给于A方(5.31g/kg/d)、B方(3.15g/kg/d)、C方(3.15g/kg/d)灌胃。连续2周。第二阶段:从第9W开始,正常组2和模型组2灌服等量蒸馏水,西药组2给予吡咯列酮(1.35mg/kg/d),将第二阶段中药干预组30只分为A+B方组、A方组、B方组,三组分别给于A+B方(8.46g/kg/d)、A方(5.31g/kg/d)、B方(3.15g/kg/d)灌胃。连续2周。第三阶段:从第11w开始,正常组3和模型组3灌服等量蒸馏水,西药组3给予吡咯列酮(1.35mg/kg/d),将第三阶段中药干预组30只分为A+B+C方组、A+B方组、B+C方组,三组分别给于A+B+C方(11.61g/kg/d)、A+B方(8.46g/kg/d)、B+C方(6.30g/kg/d)灌胃。连续2周。上述各阶段各组大鼠分别给药2周后处死,采样做相关检测。
结果:第一阶段:与正常组比较,模型组大鼠血FPG、Fins、IRI明显升高,IAI明显降低;FFA、Leptin、TNF-α、IL-6明显升高;cAMP、cAMP/cGMP明显升高;ET含量明显升高。与模型组比较,A方组、B方组、C方组大鼠血FPG、Fins、IRI和IAI;TG、TC、HDL-c、LDL-c均无明显变化。A方组大鼠血Leptin、TNF-α和cAMP、cAMP/cGMP明显降低,B方组、C方组大鼠血Leptin、TNF-α和cAMP、cAMP/cGMP无明显变化。三方各组大鼠高切、低切下的全血比粘度与血浆比粘度无明显变化,A方组、B方组大鼠内皮素含量无明显变化,C方组大鼠血内皮素含量显著降低。A方组、B方组、C方组大鼠胰腺病理损伤均无明显改善。第二阶段:与正常组比较,模型组大鼠血FPG、Fins、IRI明显升高,IAI明显降低;TC、LDL-c明显升高;FFA、Leptin、TNF-α、IL-6明显升高,cAMP、cAMP/cGMP明显升高;ET含量明显升高。与模型组比较,A+B方组大鼠血FPG、Fins、IRI明显降低,IAI明显升高;TC、LDL-c明显降低;FFA、Leptin、TNF-α水平明显降低,cAMP含量、cAMP/cGMP比值明显降低;内皮素含量明显降低。A方组大鼠血Fins明显降低,Leptin、TNF-α明显降低,cAMP含量、cAMP/cGMP比值明显降低。B方组大鼠血Fins降低,TC、FFA含量明显降低。A+B方组、A方组、B方组三组大鼠胰腺病理损伤均无明显改善。
第三阶段:与正常组比较,模型组大鼠血FPG、Fins、IRI显著升高,IAI显著降低;TC、TG、LDL-c明显升高,HDL-c明显降低;FFA、Leptin、TNF-α、IL-6均显著升高;cAMP、cAMP/cGMP明显升高;高切、低切下的全血比黏度与血浆比粘度明显升高,ET含量显著升高。与模型组比较,A+B+C方组大鼠血FPG、Fins、IRI明显降低,IAI明显升高;TC、LDL-C明显降低;FFA、Leptin、TNF-α、IL-6明显降低;cAMP、cAMP/cGMP明显降低;高切、低切下的全血比黏度与血浆比粘度明显降低,ET-1含量明显降低。A+B方组大鼠血FPG、Fins、IRI明显降低,IAI升高;TC、LDL-C明显降低;FFA、Leptin、TNF-α明显降低;cAMP、cAMP/cGMP比值明显降低;ET-1含量明显降低。B+C方组大鼠血Fins明显降低,FFA明显降低;高切、低切下的全血比黏度与血浆比粘度明显降低,ET-1含量明显降低。A+B+C方对模型大鼠胰腺病理损伤有一定改善作用。
结论:不同阶段体现不同治法的中医方药对模型大鼠相应证候/病证有不同程度的干预作用。第一阶段,比较A方、B方、C方的整体干预效应,A方对模型大鼠的干预作用优于B方和C方,推断A方与模型此阶段证候的关联性最大。第二阶段,比较A+B方、A方、B方的整体干预效应,以A+B方对模型大鼠此阶段的治疗作用最优,其次是A方,B方的治疗作用较差。推断A+B方与模型此阶段的病证有更高的关联程度。第三阶段,比较A+B+C方、A+B方、B+C方的整体干预效应,以A+B+C方对模型大鼠此阶段的治疗作用最优,推断A+B+C方与大鼠模型此阶段的病证有更高的关联程度。
研究三有效中医方药对2型糖尿病胰岛素抵抗大鼠模型作用机制研究
方法:以疗效最好(即与病证关联程度最高)的方药——A+B+C方作用于模型大鼠,采用实时荧光定量PCR技术测定大鼠脂肪组织PPAR-r mRNA和InsR mRNA,从分子层面进行中医药作用机制探查研究。
结果:有效中医方药对模型大鼠脂肪组织PPAR-r mRNA和InsR mRNA表达的影响:与正常组相比,模型组大鼠脂肪组织PPAR-r mRNA和InsR mRNA表达量均明显降低(P＜0.05)。与模型组比较,西药组和A+B+C方组大鼠脂肪组织PPAR-r mRNA表达量都明显升高(P＜0.01),InsR mRNA表达量有不同程度增加,但差异无显著性意义(P=0.060或P=0.061)。与西药组比较,A+B+C方脂肪组织PPAR-r mRNA表达量显著降低(P＜0.05)。
结论:有效中医方药A+B+C方—“益气养阴、化痰活血方”治疗2型糖尿病的作用机制可能与噻唑烷二酮类药物(TZDs)的作用机制相同,涉及脂肪组织细胞核受体PPAR-r激活和增加Ins受体。
综合结果表明,中药益气养阴、化痰活血方能够显著降低模型大鼠的FPG、Fins,提高胰岛素敏感性,改善胰岛素抵抗,纠正脂质代谢紊乱,降低FFA、Leptin、TNF-α和IL-6水平,对血液流变学异常等也有明显改善效应,其整体疗效并不逊于西药,且在血管内皮细胞损伤的保护、脂代谢的调节、高凝状态的抑制等方面有一定优势,体现了中医复方的多环节作用特点。
创新及意义:1)本研究发现以高脂饲料喂养+小剂量STZ腹腔注射的方法复制的2型糖尿病IR大鼠模型具有中医证候阶段性变化及相应生理病理生物学指标改变的特点,为病证结合及动态研究方证关系提供了一个有价值的研究性模型;2)从同证异方的角度通过对2型糖尿病胰岛素抵抗大鼠模型形成过程不同阶段相关中医方药的生物学效用进行比较,发现不同治法方药干预作用特点及与相关证候/病证的不同程度的关联程度,为理解中医方证相关及其内涵提供了一定实验依据;3)从客观实证角度论证了中医临床因证立法组方的合理性;在分子机制研究中发现中医有效干预方药防治2型糖尿病IR的作用机制与噻唑烷二酮类药物(TZDs)的作用相同:通过激活脂肪细胞核受体PPAR-r,增强机体胰岛素的敏感性,调节某些细胞因子水平,改善糖脂代谢,改善胰岛素抵抗状态。本研究不仅为从证候演变角度开展“方证相关”研究进行了有益的方法学探索,而且为认识理解“方证相关”及其科学内涵提供了一定的客观依据。
"Correlation between Formula and Syndrome" is an important logic proposition in diagnosis and treatment based on symptoms differentiation and formula -ology.The function and usage of formula not only have correlation with medical compatibility but also compatible with the syndrome which it will have effect on, that is the main effect of the formula depends on a considerable extent on the pathology and the role of targets of medical compatibility.The different syndrome should correspond to different treatment principals and formulas,"the treatment principals based on syndromes,different formulas based on syndromes".There is a problem of extent of correlation between the formula and syndrome.In recent years, many researchs mainly probed "Correlation between Formula and Syndrome" from static or space condition of syndromes,There are few research carrying out it from dynamic evolutionary of syndromes or the development of disease along with time.It is a good thought that probed "Correlation between Formula and Syndrome" from dynamic evolutionary of syndromes along with time based on the dynamic evolutionary character of syndromes.
The research takes"Correlation between Formula and Syndrome'as logic basis, is mainly based on the theory of etiology and pathology of Type 2 Diabetes Insulin Resistance in western medicine and features of etiology and pathology and treatment in Chinese medicine.During replicated the rats model of Type 2 Diabetes Insulin Resistance,by observing appearance and behavior of the rats model and analysing multiple indicators of experiment in biological system concomitantly corresponding TCM's syndromes,we explored the dynamic evolutionary progression of syndromes and pathology;On this basis,we selected some formulas which correlated with TCM's syndromes on some extent and influenced on the rats model in different phases.Compared the biological effects of different formulas by the research methods of correlation and exclusion,that is different formulas for one syndrome.To explore the relationship between the function and usage of formula and TCM's syndromes,and we also discussed the biological foundation of different formulas.Finally,we explored genes expression about PPAR-r mRNA and InsR mRNA in fattiness of the model and the effection of the best chinese medicine influencing the rats model by applying with Real Time quantitative PCR technology,and approached molecular mechanism of chinese medicines influencing the model.
The thesis is divided into two main parts:literature review and experimental research.Literature review is mainly focused on three aspects:The relationship between Formula and Syndrome in TCM;Review of the study about Insulin Resistance of Type 2 Diabetes in morden medicine and the study about experimental model of Type 2 Diabetes IR;Review of the study about Insulin Resistance of Type 2 Diabetes in traditional chinese medicine.Experiment study is mainly focused on three aspects:the study about the dynamic evolutionary progression of syndromes and pathology on the rats model of Type 2 Diabetes Insulin Resistance;Comparsion the biological effects of different formulas correlated TCM's syndromes pathology in different phase based on the progressive syndrome on the rats model of Type 2 Diabetes Insulin Resistance;the study of mechanism of the effective chinese medicine influence on the model.
Research 1:The study about the dynamic evolutionary progressive of syndromes and pathology on the rats model of Type 2 Diabetes Insulin Resistance
Methods:The research set on the rats model by feeding with high glucose and fat diet together with peritoneal injection of STZ.SD rats were randomly divided into the control group(50 rats) and model group(60 rats).During 1-5w,the control group were fed with normal food,the model group were fed with high glucose and high calories food.In the 6~(th) week,the model group were injected with STZ (30mg/kg) at abdomino.We selected model rats which measure up the standard (FPG≥11.1mmol/L,Fins 20-40uIU/ml)into the experiment.At the end of 0,6,8, 10,12 week,the rats were killed and taken blood and tissure.We used biological and chemical method to measure FPG,TC,TG,HDL-c,LDL-c,serumand plasma were measured by radioimmunoassay(RIA) to test the contents of Fins, TNF-α,Leptin,IL-6,cAMP,cGMP.Using DWN-90 blood liqid analyse apparatus to measure the whole blood viscosity at 200/s,5/s shear rate and plasma viscosity.
Results:
1) Appearance and behavior:During 6w-8w,the model rats appear lethargy, narrow their eyes,accidie,still,loss of hair,drinking increase,dejecta desiccation,sweatiness and wateriness at tail.During 9w-10w,the model rats appear fatness,extrados,gather together,narrow their eyes,accidie,action slow,fatness in hair which based on syndromes at first phase;During 11w-12w,the model rats appear continually loss of hair and turn into yellow color at stern,some petechias appear at the tail from top to root.Compared with the control group,the weight of the model group rises up obviously at 4~(th) week,and lowers continually from 9~(th) week,higher obviously than the control group.2)Glucose metabolism:Compared with the control group,the FPG,Fins,IRI level of the model group were increased continually from the end of 6~(th) week,reached its top at the end of 12~(th) week.the IAI level were decreased obviously from the end of 6~(th) week,reached its bottom at the end of 12~(th) week.3)Lipid metabolism:Compared with the control group,The TC,LDL-C level of the model group were increased continually from the end of 8~(th) week,reached its top at the end of 12~(th) week.The TG level were increased obviously from the end of 10~(th) week,reached its top at the end of 12~(th) week.The HDL-C level of the model group were decreased during 0-6w,were increased during 6-8w,were decreased obviously at the end of 10~(th) week,reach its bottom at the end of 12~(th) week.4)Adipokines:Compared with the control group,the TNF-a,Leptin,IL-6, cAMP,cAMP/cGMP level of the model group were increased continually from the end of 6~(th) week,reached their top at the end of 12~(th) week.The cGMP level of the model group were decreased from the end of 6~(th) week,reached its bottom at the end of 12~(th) week.6)Haematological change:The whole blood viscosity and plasma viscosity of the control group have no change.Compared with the control group,the whole blood viscosity and plasma viscosity of the model group at 200/s,5/s shear rate were increased continually from the end of 10~(th) week,reached it top at the end of 12~(th) week.
Conclusions:The rats model of T2DM IR which feeding high glucose and fat diet together with peritoneal injection of STZ appeared characters of dynamic evolutionary syndroms and corresponding biological items change during different phases.The model manifested hyperglycemia,hyper-insulinemia,high level cholesterin and triglyceride after IR.The dynamic evolutionary progression of syndromes and pathology in different phases are simultaneous deficiency of both qi and yin→simultaneous deficiency of both qi and yin concurrent phlegm turbidness→simultaneous deficiency of both qi and yin concurrent phlegm turbidness and blood stasis.
Research 2:Comparison of biological effects of different formulas correlated syndrome based on the progressive syndrome on the rats model of Type 2 Diabetes Insulin Resistance
Methods:The research set on the rats model by feeding with high glucose and fat diet together with peritoneal injection of STZ.SD rats were randomly divided into the control group(30 rats) and model group(170 rats).During 1-Sw,the control group were fed with normal food,the model group were fed with high glucose and high calories food.In the 6th week,the model group were injected with STZ(30mg/kg) at abdomino.We selected model rats which measure up the standard into the experiment.The rats were randomly divided into the model group 1,the model group 2,the model group 3,the xiyao group 1,the xiyao group 2,the xiyao group 3, 10 rats each group.the first phase intervention of chinese medicine 30 rats,the second phase intervention of chinese medicine 30 rats,the third phase intervention of Chinese Medicine 30 rats,The rats of the control group were divided into the control group 1,the control group 2,the control group 3.the control groups were fed with normal food continually,other groups were fed with high glucose and high calories food.
First phase:From the 7~(th) week,the control group 1 and the model group 1 were administrated the distilled water,the xiyao group 1 were administrated Pioglitazone(1.35mg/kg/d),The rats of first phase intervention of chinese medicine were divided into A formula group,B formula group,C formula group,they were administrated respectively with A formula(5.31g/kg/d),B formula(3.15g/kg/d),C formula(3.15g/kg/d) for two weeks.Second phase:From the 9~(th) week,the control group 2 and the model group 2 were administrated the distilled water,the xiyao group 2 were administrated Pioglitazone(1.35mg/kg/d),The rats of second phase intervention of chinese medicine were divided into A+B formula group,A formula group,B formula group,they were administrated respectively with A+B formula(8.46g/kg/d),A formula(5.31g/kg/d),B formula(3.15g/kg/d) for two weeks.Third phase:From the 11~(th) week,the control group 3 and the model group 3 were administrated the distilled water,the xiyao group 3 were administrated Pioglitazone(1.35mg/kg/d),the rats of third phase intervention of chinese medicine were divided into A+B+C formula group,A+B formula group,B+C formula group, they were administrated respectively with A+B+C formula(11.61g/kg/d),A+B formula(8.46g/kg/d),B+C formula(6.30g/kg/d )for two weeks.The rats were killed and taken blood and tissure to measure at different phases.
Results:
First phase:Compared with the control group,the FPG,Fins,IRI level of the model group were increased obviously,the IAI level were decreased obviously,the FFA,Leptin,TNF-a,IL-6,cAMP,cAMP/cGMP level were increased obviously,the ET level were increased obviously.Compared with the model group,the FPG,Fins,IRI,IAI,and TG,TC,HDL-c,LDL-c level of A formula group,B formula group and C formula group have no change.The Leptin,TNF-αand cAMP,cAMP/cGMP level of the A formula group was decreased obviously,B formula group and C formula group have no change on these.A formula group,B formula group and C formula group have no effect on the whole blood viscosity at the 200/s,5/s shear rate and plasma viscosity of the model group.A formula group,B formula group have no effect on the ET-1 of the model group.The ET-1 level of the C formula group was decreased significantly.The A formula group,B formula group and C formula group have no effect on Pancreas pathomorpholgoy.
Second phase:Compared with the control group,the FPG,Fins,IRI level of the model group were increased obviously,the IAI level were decreased obviously,the TC,LDL-c level were increased obviously,the FFA,Leptin,TNF-a,IL-6,cAMP, cAMP/cGMP level were increased obviously,the ET level were increased obviously. Compared with the model group,the FPG、Fins、IRI level of the A+B formula group were decreased obviously,the IAI level were increased obviously.The TC,LDL-C level of the A+B formula group were decreased.The FFA、Leptin、TNF-α、cAMP、cAMP/cGMP were decreased.The ET level were also decreased.The Fins level of the A formula group was decreased,the Leptin,TNF-α、cAMP、cAMP/cGMP level of the A formula group was decreased.The Fins level of the B formula group was decreased,the TC,FFA level of the B formula group was decreased obviously.The A+B formula group,A formula group and B formula group have no effect on Pancreas pathomorpholgoy.
Third phase:Compared with the control group,the FPG,Fins,IRI level of the model group were increased significantly,the IAI level were decreased significantly,the TC,TG,LDL-c level were increased obviously,the HDL-c level was decreased obviously,the FFA,Leptin,TNF-a,IL-6,cAMP,cAMP/cGMP level were increased obviously,the level of the whole blood viscosity at the 200/s,5/s shear rate and plasma viscosity were increased obviously,the ET level were increased obviously.Compared with the model group,the FPG,Fins,IRI level of the A+B+C formula group were decreased obviously,the IAI level was increased obviously.The TC、LDL-C level of the A+B+C formula group were decreased.The FFA,Leptin, TNF-α、IL-6、cAMP、cAMP/cGMP level were decreased obviously.The level of the whole blood viscosity at the 200/s,5/s shear rate and plasma viscosity of A+B+C formula group were decreased.The ET level of A+B+C formula group was decreased obviously.The FPG、Fins、IRI level of the A+B formula group were decreased,the IAI level was increased.The TC、LDL-C level of the A+B formula group were decreased.The FFA、Leptin、TNF-α、cAMP、cAMP/cGMP level of the A+B formula group were decreased.The ET level of A+B formula group was decreased.The Fins,FFA level of the B+C formula group were decreased,The level of the whole blood viscosity at the 200/s,5/s shear rate and plasma viscosity of B+C formula group were decreased.The ET level of the B+C formula group was decreased obviously.The A+B+C formula group have good effect on some extent to Pancreas pathomorpholgoy.
Conclusions:In different phases,the different formulas which representated different treatment principals have many effects on some extent to corresponding TCM's syndromes/disease.In the first phase,compared the whole effection of A formula,B formula,C formula,we found that the intervention of A formula are better than B formula and C formula,and we concluded A formula have the close correlation with syndromes in this phase.In the second phase,compared the whole effection of A+B formula,A formula,B formula,we found that the intervention of A+B formula were the best in three groups,the next was A formula,the intervention of B formula were not good.we concluded A+B formula have the close correlation with syndromes in this phase.In the third phase,compared the whole effection of A+B+C formula,A+B formula,B+C formula,we found that the intervention of A+B+C formula are the best in three groups,we concluded A+B+C formula have the close correlation with syndromes in this phase.
Research 3:the mechanism study of the effective chinese medicine influence on the rats model of Type 2 Diabetes Insulin Resistance
Methods:According to results of the former study,we selected the best effective formula—A+B+C formula,which has the closest correlation with disease and syndrome,we took it as the chinese medicine intervention group,and measured the expression of PPAR-γmRNA and InsR mRNA in fat by using the Real-time quantitative PCR.To explore mechanism of A+B+C formula influenceing on the rats model of Type 2 Diabetes Insulin Resistance.
Results:The effects on the expression of PPAR-γmRNA and InsR mRNA in fat of A+B+C formula:Compared with the control group,the expression of PPAR-γmRNA and InsR mRNA in fat of the model group were significantly decreased(P＜0.05).Compared with the model group,the expression of PPAR-γmRNA in fat of the xiyao group and A+B+C formula group were significantly increased(P＜0.01),the expression of InsR mRNA in fat were increased on some extent,but there was no distinct difference(P=0.060或P=0.061).Compared with the xiyao group,the expression of PPAR-γmRNA in fat of A+B+C formula were significantly decreased(P＜0.05).
Conclusions:We concluded that treatment mechanism of A+B+C formula (yiqiyangyin huatanhuoxue fang)to treat Type 2 Diabetes may act as a similar way of Thiazolidinediones(TZD),involving to activate PPAR-γand increased InsR.
To sum up,the findings indicated that the yiqiyangyin huatanhuoxue fang have effect on decreasing FPG、Fins level,enhancing the sensitivity of skeletal muscle and liver to insulin,ameliorating IR,correcting lipid metabolism turbulence,slowing the release of FFA,Leptin,TNF-a,IL-6,ameliorating haematological abnormity,the whole effection are same as Pioglitazone.the chinese medicine have other superority in treatment,for exemple,protecting endothelium cell of blood vessel,accommodating lipid metabolism,preventing blood coagulation,this showed the character that interventiong many aspect of chinese medicine compounds.
Innovation and Meaning:1)the research found that the rats model of T2DM IR which feeding high glucose and fat diet together with peritoneal injection of STZ appeared characters of dynamic evolutionary syndroms and corresponding biological items change during different phases.It offers a worth model for the study of"Correlation between Formula and Syndrome"from dynamic evolutionary progressive of disease and syndrome.2)Comparison of biological effects of different formulas correlated syndrome based on the progressive syndrome on the rats model of Type 2 Diabetes Insulin Resistance with the research methods of correlation and exclusion and different formulas for one syndrome.The research found the different formulas have different function characteristics,they have have correlation on some extent to corresponding TCM's syndromes/disease.3)It demonstrated the rationality about making out treatment methods based on different syndromes.The study of mechanism found that treatment mechanism of A+B+C formula to treat Type 2 Diabetes may act as a similar way with Thiazolidinediones(TZD).they are both activating PPAR-γ,enhancing the sensitivity of skeletal muscle and liver to insulin, accommodating some adipokines level,improving glucose and liquid metabolism ameliorating IR.The research not only carried out beneficial technology exploration for revealing the important logic proposition of"Correlation between Formula and Syndrome",but also provided objective evidence for recognizing "Correlation between Formula and Syndrome"and its scientific connotation.
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