2型糖尿病大鼠心肌IR、IRS-1的表达与罗格列酮及APP5肽类似物P165的干预效应

目的研究2型糖尿病大鼠心肌胰岛素信号转导通路蛋白胰岛素受体（IR）、胰岛素受体底物-1（IRS-1）的表达与正常SD大鼠的区别,并探讨进行罗格列酮及APP5肽类似物P165干预后对上述蛋白表达的影响。方法60只SD大鼠随机分为正常对照组（C组）、正常对照＋罗格列酮组（C＋RSG组）、2型糖尿病组（T2DM组）、2型糖尿病＋罗格列酮组（T2DM＋RSG组）、糖尿病给予P165小剂量组（T2DM＋P165小剂量组）、糖尿病给予P165大剂量组（T2DM＋P165大剂量组）,其中糖尿病动物采用高脂饮食后给予小剂量STZ腹腔注射的方法造模。后将各组SD大鼠处死,采用免疫组织化学染色和Western blot的方法检测心肌组织IR、IRS-1的表达。结果（1）2型糖尿病组（T2DM组）心肌组织IR、IRS-1的表达水平显著低于对照组（C组）;（2）2型糖尿病＋罗格列酮组（T2DM＋RSG组）心肌组织IR、IRS-1的表达水平显著高于T2DM组;（3）免疫组化染色发现2型糖尿病＋P165小/大剂量组（T2DM＋P165小/大剂量组）心肌组织IR、IRS-1免疫反应阳性颗粒沉着的累积光密度值显著高于T2DM组;Western blot结果显示T2DM＋P165小/大剂量组心肌组织IRS-1的表达水平显著高于T2DM组;而IR的表达水平与T2DM组相比无差别。结论（1）2型糖尿病大鼠心肌存在胰岛素抵抗或信号转导障碍;（2）罗格列酮干预后可以改善2型糖尿病心肌的胰岛素信号转导异常;（3）P165对2型糖尿病大鼠心肌胰岛素信号转导具有调节作用,其作用靶点可能为胰岛素受体底物。

Expression of Insulin Receptor and Insulin Receptor Substrate-1 in the Myocardium of Type 2 Diabetic Rats and the Interfering Effect of Rosiglitazone and APP 5-mer Peptide Analog P165

Objective To investigate the difference in expression of insulin signal transduction proteins insulin receptor （IR） and insulin receptor substrate-1 （IRS-1） in myocardium between type 2 diabetic and normal SD rats and to explore the interfering effect of rosiglitazone （RSG） and APP 5-mer peptide analog P165 （P165） on the expression of those proteins. Methods Sixty SD rats were randomized into six groups ： control （ C ）, control treated with rosiglitazone （ C ＋ RSG）, type 2 diabetesmellitus （T2DM）, T2DM treated with rosiglitazone （T2DM ＋ RSG）, T2DM treated with low-dose P165 （T2DM ＋ low-dose P165）, T2DM treated with high-dose P165 （T2DM ＋ high-dose P165）. Type 2 diabetes mellitus models were induced by high-fat diet with intraperitoneal injection of a low-dose streptozotocin. The SD rats were killed, and the myocardial expression of IR and IRS-1 was detected by immunohistochemistry and Western blot. Results （1） Compared with the control group, the myocardial expressions of IR and IRS-1 were significantly decreased in the T2DM group. （2） Compared with T2DM group, the myocardial expressions of IR and IRS-1 were significantly increased in the T2DM ＋ RSG group. （3） Compared with T2DM group, the integrated optical density of myocardial IR and IRS-1 immunoreactive positive granules was significantly increased in the T2DM ＋ low/high-dose P165 group. The results of Western blot indicated a significantly increased myocardial expression of IRS-1 in the T2DM ＋ low/high-dose P165 group, however, the expression of IR was not changed compared with that in the T2DM group. Conclusion （1） The myocardium of type 2 diabetic rats has insulin resistance or dysregulation of insulin signal transduction. （2） Rosiglitazone treatment may improve the dysregulation of insulin signal transduction in the myocardium of type 2 diabetic rats. （3） P165 may influence the regulation of insulin signal pathway in the myocardium of T2DM rats and its targets are insulin receptor substrates probably.