肠道TLRs表达与胰岛素抵抗的机制研究

项目名称： 肠道TLRs表达与胰岛素抵抗的机制研究

项目编号： No.30801019

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 王宁

作者单位： 新疆医科大学

项目金额： 20万元

中文摘要： 胰岛素抵抗（IR）是2型糖尿病和代谢综合症发生的中心环节。高脂饮食、炎症因子都可引起IR，但起始通路仍未阐明。Toll样受体（TLR）不仅识别病原体模式受体，参与固有免疫应答，还可识别脂肪酸配体而激活炎症通路。因此我们提出了脂肪酸作为配体与肠壁TLRs 结合并激活下游的NF-κ#20449;号通路、释放炎症因子而引起胰岛素抵抗的假说。据此，我们采用高脂喂养小鼠模型，观察了喂养后不同时点肠壁TLR2、TLR4、 NF-κ#12289;TNF-а#12289;IL-6的表达及胰岛素受体底物蛋白水平的变化；以及脂肪、胰腺、肝脏、骨骼肌的上述指标。高脂喂养1天后，肠上皮TLR4/NF-κ#20449;号通路被激活，TNF-а#12289;IL-6阳性高表达，其表达高峰在第7天，此后减弱；长期高脂喂养未引起肠上皮大量单核/巨噬细胞、中性粒细胞等细胞的趋化。肠上皮细胞的胰岛素抵抗，发生在喂养后第12天及以后。脂肪组织、胰腺分别在高脂喂养后第3、21天出现TLR4/NF-κ#20449;号通路激活及炎症表达。研究提示FFA对肠道TLR4 /NF-κ#20449;号通路的激活可能起到"triger"的作用，激活体内多部位低度炎症的表达，进而引起胰岛素抵抗，并出现肠细胞IR。

中文关键词： 肠道;Toll 样受体;胰岛素抵抗;炎症

英文摘要： Insulin resistance (IR) is center component in development of type 2 diabetes mellitus and metabolism syndrome. High fat diet and inflammatory factor both can cause IR, but the original passageway is unclear. Toll like receptor (TLR) not only can recognize pathogen pattern acceptor and participate inherent immunity response, but also identify ligands for example fatty acids to activate inflammatory access. Therefore we assume that fatty acids as a ligand can bind with TLR4 that distributing on intestines, then enable the downstream NF-κsignaling passageway,release inflammatory factors to cause IR. Accordingly, we adopted mouse model that fed by high fat diet, observing expression of TLR2、TLR4、 NF-κ#12289;TNF-а#12289;IL-6 and diversity of insulin receptor substrate protein level which distributed on intestine，fat，pancreas，liver and skeletalmuscle in different time。After 1 day fed by high fat，intestinal TLR4/NF-κsignaling activated and reached peak on 7 days then decreased，positive expression of TNF-а#12289;IL-6 was obviously；after long-term high fat feeding，there were no mass monocaryon/macrophages cell，neutrophilic granulocyte and so on . After 12 days, IR of intestinal epithelial cells was found. Respectively，TLR4/NF-κsignal passageway of fat tissue and pancreas activated in 3 and 21days kept according with inflammation expression。Research indicated that FFA may play a part in activation of TLR4 /NF-κas trigger，enabled expression of low grade inflammation in some locations，and then induced IR including intestinal IR.

英文关键词： intestinal tract; Toll like receptors; insulin resistance; inflammation