糖脂平对高脂喂养胰岛素抵抗大鼠的影响及其部分作用机制研究

【作者】 刘桂芳；

【导师】 高彦彬；

【作者基本信息】 北京中医药大学 ， 中医内科学， 2009， 博士

【摘要】 目前,我国糖尿病患者人数正以惊人的速度增长,预计到2025年,20岁以上糖尿病患者可达4600万,糖尿病及其并发症的高致残率和致死率,严重影响着患者的生活质量及寿命。在我国,患病人群以2型糖尿病(T2DM)为主,胰岛素抵抗(insulinresistance,IR)是导致T2DM的中心环节,早在糖尿病发病之前就已经存在,因此早期干预IR对于防治IGT和T2DM有着重要的意义,而传统中医药在改善IR方面有着独特的优势。目的本研究基于中药复方糖脂平有效改善IR、干预糖耐量异常(IGT)的临床研究基础,采用高脂饲料喂养的方法复制出IR大鼠模型,探讨糖脂平有效改善IR的作用机制,为中医药改善IR、防治IGT和T2DM的理论和方法提供依据。方法1文献综述:查阅近年国内外2型糖尿病、胰岛素抵抗、脂联素、GLUT、PPARγ的相关文献资料。对目前现代医学和中医学关于IR的发病机理、治疗用药、评价方法、研究方法以及脂联素、GLUT、PPARγ的研究进展等进行了较为系统的论述和总结。2理论研究:在中医“治未病”思想的指导下,通过对相关文献的整理和研究,对早期IR的中医病机进行探讨,将其辨证为痰瘀互结,治以化痰活血法,采用中药复方糖脂平干预IR、防治IGT和T2DM。3实验研究:以高脂饲料喂养的方法制作IR大鼠模型,将PPARγ配体罗格列酮作为阳性对照药,采用正常血糖高胰岛素钳夹技术评价IR,观察糖脂平对实验性IR大鼠糖代谢、脂代谢、胰岛素敏感性、血清脂联素水平以及GLUT4 mRNA和PPARγ2 mRNA表达的影响。结果1 IR动物模型:复制出实验性IR大鼠模型,表现为体重增加、收缩压升高、空腹血糖升高、空腹胰岛素升高、脂代谢紊乱等特征,葡萄糖代谢率(M值)明显低于对照组,表现出明显的IR,且喂养周期适中,与人类IR的发病特点相近,是比较满意的动物模型。2作用研究:在成功复制实验性IR大鼠模型的基础上,观察糖脂平对大鼠糖脂代谢以及胰岛素敏感性的影响,并从细胞、分子生物学角度探讨其作用机制。实验结果表明糖脂平具有以下作用:可使葡萄糖代谢率(M值)显著升高(P＜0.05);有效抑制IR大鼠的体重增长(P＜0.01),较罗格列酮有明显的优势(P＜0.01);对IR大鼠的收缩压有降低趋势,但无显著作用(P＞0.05);降低IR大鼠空腹血糖(P＜0.05),与罗格列酮作用相近(P＞0.05);显著降低IR大鼠血浆TG和LDL-c的水平(P＜0.01,P＜0.05),而对TC和HDL-c的影响不大(P＞0.05);显著降低IR大鼠空腹胰岛素水平(P＜0.01),与罗格列酮作用相近(P＞0.05);升高IR大鼠血清脂联素水平(P＜0.05),与罗格列酮作用相近(P＞0.05);促进IR大鼠骨骼肌GLUT4 mRNA、脂肪组织PPARγ2 mRNA的表达(P＜0.05,P＜0.01)。结论综合以上研究结果,我们认为糖脂平具有改善糖脂代谢紊乱和胰岛素敏感性的作用,具有明显升高与胰岛素敏感性呈正相关的血清脂联素水平、葡萄糖转运蛋白GLUT4和促脂肪细胞分化因子PPARγ2基因表达的作用,这些作用在改善IR、促进胰岛素刺激下外周组织对葡萄糖的摄取和利用方面有重要的意义。更多还原

【Abstract】 At present,the number of diabetic patients in China are growing at an amazing rate,it is estimated that there will be 46 million diabetics over the age of 20 untill 2025,and it has seriously affected the life quality and expectancy of the patients.In China,patients with type 2 diabetes mellitus(T2DM)are the prevalence,insulin resistance(IR)is the main cause to type 2 diabetes and exists before diabetes onset,so it is significant to improve the status of IR for the prevention and treatment of IGT and T2DM,while Traditional Chinese Medicine(TCM)plays a distinct role in it.PurposeThis research is based on effective clinical treatment of IR and IGT,quoting the idea of "Zhiweibing" to IR theory and experiment research of TCM,inducing IR rats through high-fat-diet,to explore the function mechanisms,provide the basis for theories and methods of TCM treatment.Methods1 Literature Studies:Recent literature concerning type 2 diabetes,insulin resistance,adiponectin,GLUT and PPARγare documented.So this study has taken a full account of the pathogenesis mechanisms,medication,evaluation and research methods of IR into consideration both in TCM and allopathic medicine and made a systematic review of adiponectin,GLUT and PPARγadvancements.2 Theoretical Studies:To improve the status of IR with TCM under the guidance of "Zhiweibing" idea; research the Chinese medicine pathogenesis of early IR phase on the basis of existing achievements,the system type is differented into Tanyu retention,take advantage of Huatan Huoxue thrapy,and Tangzhiping is used to improve the status of IR for the prevention and treatment of IGT and T2DM.3 Laboratory Studies:The IR rats were induced by high-fat-diet and then treated them with Tangzhiping, comparing to the PPARγligand Rosiglitazone,performed the euglycemic hyperinsulin clamp technique to evaluate the insulin sensitivity,observed Tangzhiping’s influence on glucose metabolism,lipid metabolism,insulin sensitivity,serum adiponectin level,GLUT4 and PPARγ2 mRNA expression of IR rats. Results1 Evaluation of Animal Model:We induced laboratory IR rats by high-fat-diet,manifesting as increasing in weight, systolic blood pressure,FINS,disorder in lipid and glucose metabolism,significantly lower glucose metabolism rate(M)than that in control group,showing remarkable IR,adding to the moderate feeding cycle,just as the incidence of human IR features,which are relatively satisfied animal model.2 Effects Evaluation and Mechanisms Research:To investigate Tangzhiping’s influence on glucose,lipid metabolism as well as insulin sensitivity of IR rats,and to explore the function mechanisms from the perspective of cellular and molecular biology based on the success of experimental rat model of IR.The results show that Tangzhiping can increase glucose metabolism rate(M)(P＜0.05); decrease the weight of IR rats significantly(P＜0.01),better than that of Rosiglitazone (P＜0.01);both of Tangzhiping and Rosiglitazone can reduce systolic blood pressure,but not significantly(P＞0.05);lower fasting blood glucose in rats(P＜0.05),just as Rosiglitazone (P＞0.05);significantly reduce plasma TG and LDL-c levels(P＜0.01,P＜0.05),while TC and HDL-c little changed(P＞0.05);lower FINS(P＜0.01),just as Rosiglitazone(P＞0.05); enhance the level of serum adiponectin(P＜0.01),just as Rosiglitazone(P＞0.05);promote the expression of skeletal muscle GLUT4 mRNA and adipocyte PPARγ2 mRNA significantly (P＜0.05,P＜0.01).ConclusionBased on the above findings,we believe that Tangzhiping can improve glucose and lipid metabolism,increase insulin sensitivity,enhance serum adiponectin level,promote adipocyte differentiation factor-PPARγ2 and glucose transporter protein-GLUT4 mRNA expression significantly,which paly an important role in improving insulin sensitivity, enhancing the periphery tissue glucose uptake and utilization under insulin stimulation.更多还原