从IRE1α/JNK传导通路研究解毒通络调肝方干预内质网应激治疗2型糖尿病双重效应的机制

There are two key links in the pathogenesis of Type 2 Diabetes Mellitus(T2DM), insulin resistance and the dysfunction of beta cell. Endoplasmic reticulum stress can both induce insulin resistance and lead to the dysfunction of pancreatic islet beta cell. IRE1A/JNK pathway is the specific molecular pathway of it. From microcosmic world, any generating of the basic components(such as poison sputum, stasis, wet, heat and other pathological products)belonging to the poison is inseparable with the cell activities, also the metabolic activities of the cell are the embodiments of the cell endoplasmic reticulum's functions. So it is visible that the forming of the poison can be due to the function changes of the cell's endoplasmic reticulum. According to what we said above, we can hypothesize that the endoplasmic reticulum stress may be the common pathway of insulin resistance and beta cell dysfunction. Jiedu Tongluo tiaogan fang may display double effects in the treatments of T2DM by the interventing of endoplasmic reticulum stress. On the basis of the prophase researches, this topic adopts spontaneously obese rat models with T2DM, and combining with clinical researches, by considering both the target organs' liver and fat that the pancreas insulin effects on and pancreas what is called insulin secretory organ as research objects, to study that Jiedu Tongluo tiaogan fang intervents on endoplasmic reticulum stress through the IRE1A/JNK pathway, to display double effects in the treatments of T2DM, also to enrich toxin damaging for the target of providing new ideas and methods for the treatments of diabetes by the Traditional Chinese Medicine.

2型糖尿病（T2DM）两个发病关键环节是胰岛素抵抗和胰岛β细胞功能减退。内质网应激既能引起胰岛素抵抗，又能导致胰岛β细胞功能减退，可能是胰岛素抵抗、胰岛β细胞功能减退的共同途径，而肌醇需要酶lα（IRE1α）/ c-Jun氨基末端激酶 (JNK）传导通路是其具体分子途径。从微观上讲任何一个毒的基本成分（如痰、湿、瘀、热等）的产生与机体的细胞活动密不可分，而细胞的代谢活动则是细胞内质网功能具体体现。可见毒的形成是由于细胞的内质网功能变化。针对T2DM毒损致病确立的解毒通络调肝方，可能是通过干预内质网应激发挥治疗作用。本课题在前期研究基础上，采用自发肥胖T2DM大鼠模型，并结合临床研究，通过对胰岛素作用靶器官肝脏、脂肪和胰岛素分泌器官胰腺为研究对象，从IRE1α/JNK传导通路研究解毒通络调肝方干预内质网应激,发挥治疗T2DM的双重效应，丰富毒损致病理论，为中医药治疗糖尿病提供新的思路与方法。

2型糖尿病（T2DM）两个发病关键环节是胰岛素抵抗和胰岛β细胞功能减退。内质网应激既能引起胰岛素抵抗，又能导致胰岛β细胞功能减退，可能是胰岛素抵抗、胰岛β细胞功能减退的共同途径，而肌醇需要酶lα（IRE1α）/ c-Jun氨基末端激酶 (JNK）传导通路是其具体分子途径。从微观上讲任何一个毒的基本成分（如痰、湿、瘀、热等）的产生与机体的细胞活动密不可分，而细胞的代谢活动则是细胞内质网功能具体体现。可见毒的形成是由于细胞的内质网功能变化。针对T2DM毒损致病确立的解毒通络调肝方，可能是通过干预内质网应激发挥治疗作用。本课题在前期研究基础上，采用自发肥胖T2DM大鼠模型、HepG2、3T3-L1、INS-1细胞，并结合临床研究，通过对胰岛素作用靶器官肝脏、脂肪和胰岛素分泌器官胰腺为研究对象，从IRE1α/JNK传导通路研究解毒通络调肝方干预内质网应激,发挥治疗T2DM的双重效应，丰富毒损致病理论，为中医药治疗糖尿病提供新的思路与方法。.体内实验证实，9周龄ZDF大鼠以Purina #5008饲养诱导11周，可以成功制备2型糖尿病动物模型，且具有高血糖、高胰岛素血症、高脂血症特征。解毒通络调肝方可显著改善肥胖2型糖尿病大鼠糖脂代谢水平。通过解毒通络调肝方干预，可降低肝脏、胰腺及脂肪IRE1、P-IRE1、JNK、P-JNK的基因及蛋白表达。.体外实验证实，解毒通络调肝方可有效抑制内质网应激状态下HepG2、3T3-L1、INS-1细胞中相关炎症因子的表达。并能降低细胞中IRE1、JNK、NF-κB的蛋白表达水平。.临床试验证实，解毒通络调肝方可显著降低肥胖2型糖尿病患者糖、脂代谢水平，具有较好的降糖、调脂和改善胰岛素抵抗的作用。同时能够降低患者血清中TNF-α、IL-6、CRP水平，降低外周血单个核细胞NF-κB 蛋白水平。.解毒通络调肝方治疗肥胖2型糖尿病的作用机理可能为，从IRE1α/JNK传导通路研究通过改善ERS，减轻炎症反应，改善2型糖尿病胰岛素抵抗和保护胰岛β细胞功能。