氯沙坦通过增加葡萄糖转运蛋白4膜转位改善2型糖尿病大鼠胰岛素抵抗

目的研究2型糖尿病（T2DM）sD大鼠血管紧张素Ⅱ受体拮抗剂（ARB）是否改善胰岛素抵抗及对IRSl磷酸化、P13K途径中Akt磷酸化及GLUT4转位的影响。方法42只sD大鼠分别给予高脂高糖饮食／链脲佐菌素（STZ）或普通饮食喂养，当空腹血糖（FPG）〉／7．8mmol／L且伴有胰岛素抵抗者为成模T2DM大鼠20只，正常组20只；分为正常不干预组（A组）、正常干预组（B组）、T2DM不干预组（C组）及T2DM干预组（D组），每组10只。B组及D组给予氯沙坦（4mg·k～·d“），干预6周后计算胰岛素敏感指数（ISI），取腓肠肌备用。通过免疫组织化学（IHC）及Westernbloting检测IRSl／P＇yr_IRSl、Akt／Pser473-Akt及GLUT4蛋白表达。结果（1）成功制备了T2DM大鼠模型。IHC结果示C、D组较A、B组P”-IRSl、P-Akt蛋白表达减少；Westernbloting结果示Ptyr。-IRSl、GLUT4膜蛋白表达减少（P〈0．05）。（2）氯沙坦干预后，D组FBG（mmol／L）、FINS（p~U／M1）（18．8±4．1，27±5）较c组（19．74-3．7，27±6）降低，IsI升高（D组一6．18±0．08，C组一6．18±0．08，P〈0．05）；IHC示Ptyr-IRSl蛋白表达升高（P〈0．05）；Westernbloting示GLUT4膜蛋白、P-IRSl上升（P〈0．05），P-Akt蛋白的表达无差异（P〉0．05）。结论氯沙坦通过增加骨骼肌组织中GLUT4的转位而改善T2DM大鼠的胰岛素抵抗。

Insulin resistance is improved by Iosartan in type 2 diabetic rats through glucose transporter protein4 pathway

Objective An animal model for type 2 diabetes mellitus （T2DM） was developed for studying improvment of anigotensin II receptor blocker on insulin resistance （IR） and influence on insulin receptor substrate 1 （IRS1）and Akt phosphorylation of phosphatidylinositol 3-kinase （PI3K）pathway and translocatiou of glucose transporter-4 （ GLUT4 ）. Methods Twenty of 42 male SD rats were randomly fed with high-fat/high-sugar diet and treated with Streptozotozin for type 2 diabetic model and other 20 for nol~nal control group fed with standard diet. Rats with FPG~〉7.8 mmol/L accompanied by IR were considered as T2DM models. Rats were randomly divided into control group A, control treated group B, T2DM control group C and T2DM treated group D（n = 10 in each group） , rats in group B and D were treated with losartan. Six weeks later, blood samples were measured to calculate ISI（ insulin-sensitivity index）. Skeletal muscles were removed from hind legs and stored. Expressions of IRS1/Ptyr-IRS1, Akt/P~47S-Akt and GLUT4 protein detected by Immunohistochemistry （IHC） and Western bloting. Results （ i ） Models of T2DM rats were successfully induced. Compared with group A and B, expressions of Ptyr-IRS1, p~rav3_Akt in group C and D by IHC and expressions of PtYr-IRS1 and membrane GLUT4 by Western bloting reduced significantly （ P 〈 0. 05）. （2）The value of FPG （retool/L） , FINS （p,U/M1） of T2DM rats decreased in Group D （18.8 ＋ 4. 1, 27 _＋5）compared with group C（19.7 ＋3.7,27 -＋6） , while ISI increased（D group -6. 18 -＋0. 08, C group -6. 18 -＋0. 08, P 〈0. 05）, the expression of P~Yr-IRS1 increased（P 〈0. 05） （IHC）, expression of membrane GLUT4 and p＇yr-IRS1 increased（ P 〈0. 05 ）（ Western bloting） , there was no difference of p~r473_Akt expression in both ways. Conclusion Losartan can increase the translocation of GLUT4 in muscle tissues to improve IR status of T2DM rats.