选择性PI3K-Akt通路缺陷参与有生长追赶SGA大鼠胰岛素抵抗的发生机制  

Selective defect of PI3K-Akt pathway is involved in insulin resistance in small-for-gestational-age rats with catch-up growth

作　　者：邓红珠[1,2] 邓洪[3] 马华梅[2] 李燕虹[2] 苏喆[2] 杜敏联[2] 

机构地区：[1]中山大学附属第三医院儿科,广东广州510630 [2]中山大学附属第一医院儿科,广东广州510089 [3]中山大学附属第三医院感染科,广东广州510630

出　　处：《中国病理生理杂志》2012年第8期1471-1476,共6页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81100571);广东省自然科学基金资助项目(No.S2011020005224)

摘　　要：目的:研究有生长追赶的小于胎龄个体(SGA)骨骼肌组织胰岛素受体后信号分子的变化,探讨其胰岛素抵抗的发生机制。方法:应用孕鼠全程饮食限制法建立SGA大鼠模型。4周龄有生长追赶SGA(CUG-SGA)和无生长追赶SGA(NCUG-SGA)幼鼠随机分为对照组和胰岛素激发组,并设适于胎龄(AGA)组为对照。测定各组血糖和胰岛素(INS)浓度,计算胰岛素抵抗指数(HOMA-IR)和胰岛β细胞功能指数(HOMA-β)。应用Western blotting测定各组腓肠肌组织胰岛素受体后信号分子胰岛素受体底物1(IRS1)、蛋白激酶B(Akt)和细胞外信号调节激酶(ERK)的表达及其磷酸化情况。结果:(1)CUG-SGA和NCUG-SGA幼鼠INS和HOMA-IR较AGA组明显增高(均P<0.01),CUG-SGA幼鼠的INS和HOMA-IR显著高于NCUG-SGA组。(2)CUG-SGA幼鼠肌肉组织基础状态下已有p-IRS1表达,INS激发后p-IRS1的表达无显著增加;p-Akt的表达在基础状态和INS激发后均较AGA和NCUG-SGA组显著减低;CUG-SGA基础状态亦有p-ERK表达,INS激发后p-ERK表达显著下降。相关分析显示在基础状态和INS激发状态,SGA幼鼠p-Akt与p-ERK表达呈显著负相关(r=-0.737,P<0.05;r=-0.658,P<0.05)。结论:(1)无论追赶与否,SGA个体生后均呈现胰岛素抵抗,CUG-SGA胰岛素抵抗程度更重。(2)IRS1-PI3K-Akt通路受损是胰岛素抵抗发生的重要的受体后机制;该通路阻断的同时发生Ras-MAPK-ERK通路信号的慢性激活,这可能是胰岛素抵抗同时发生生长追赶的分子机制。To investigate the changes of insulin postreceptor signal pathway in the rats born small for gestational age （SGA） with catch -up growth （CUG） and to explore the possible mechanism of insulin resistance in CUG - SGA. METHODS： SGA rats born by pregnant rats with dietary restriction were randomly divided into insulin excitation group and control group. Blood glucose and serum insulin level were measured at the 4th week. Insulin resistance was eval- uated by the homeostasis model assessment of insulin resistance （ HOMA - IR）. The 13 - cell function was evaluated by HOMA - 13. The expression of insulin receptor substrate 1 （IRS1）, protein kinase B （Akt） and extracellular signal - regula- ted kinase （ERK）, and their phosphorylation in gastrocnemius muscle were analyzed by Western blotting using tubulin as an internal control. RESULTS： The levels of serum insulin and HOMA - IR in CUG - SGA group and non - catch - up growth（NCUG） -SGA group were significantly higher than those in appropriate for gestational age（AGA） group （all P 〈 0. 01 ）. The levels of serum insulin and HOMA - IR in CUG - SGA group were significantly higher than those in NCUG -SGA group （ both P 〈0. 01 ）. The expression of p - IRS1 in CUG - SGA animals under basal condition was not significantly increased after insulin excitation. The expression of p - Akt in SGA group was significantly lower than that in AGA group under the basal condition and insulin excitation state, and that in CUG - SGA group was reduced by 50% as compared with NCUG - SGA group. The expression of p - ERK in CUG - SGA group was significantly higher under the basal condition and was significantly decreased after insulin excitation. A negative correlation between the expression of p - ERK and p - Akt in SGA rats was observed （ r = - 0. 737, P 〈 0. 05 ; r = - 0. 658, P 〈 0. 05 ）. CONCLUSION ： SGA individuals all have insulin resistance, especially with CUG. The impairments of insulin receptor PI3K signal pathway in CUG - SGA i

关 键 词：小于胎龄儿 胰岛素抵抗 生长追赶 

分 类 号：R363[医药卫生—病理学]