【摘要】 目的研究宫内生长受限(IUGR)成年子鼠肝脏中受体后胰岛素信号传导通路分子的表达变化,探讨IUGR个体发生2型糖尿病的分子机制。方法通过低蛋白饮食法建立大鼠IUGR模型,采用Western blot检测雄性子鼠(8周)基础状态下肝脏中胰岛素受体底物(IRS)2、磷酸肌醇-3-激酶(PI-3K)、糖原合成酶激酶(GSK)3β的蛋白表达水平,以及胰岛素刺激后蛋白激酶B(PKB)的磷酸化水平变化。结果基础状态下,IUGR成年子鼠肝脏IRS-2的蛋白表达与正常对照差异无显著性,PI-3K的催化亚单位p110的蛋白表达比对照组明显降低;而GSK-3β蛋白含量比对照组明显增加,差异均有显著性(P<0.01)。基础状态和胰岛素刺激状态下,IUGR组肝脏PKB和磷酸化的PKB-Ser473表达水平都明显低于对照组(P<0.01),胰岛素刺激后,对照组肝脏磷酸化的PKB-Ser473表达明显增加,是基础状态的182%(P<0.01),而IUGR组肝脏磷酸化的PKB-Ser473的增加幅度较小,仅是基础状态的123%(P<0.05)。结论宫内蛋白营养不良造成的IUGR鼠机体胰岛素抵抗的发生可能与肝脏中PI-3K和其下游靶蛋白PKB的表达和活性降低,以及GSK-3β的表达增高有关。更多还原

【Abstract】 Objective To determine the molecular mechanisms linking intrauterine growth restriction(IUGR) to adult type 2 diabetes mellitus,the effect of IUGR on the hepatic post-receptor insulin-signaling pathway was investigated in the adult offspring.Methods The IUGR model was prepared by maternal protein-malnutrition.Western blotting analysis was undertaken to assess hepatic expression of insulin receptor substrate(IRS-2),phosphoinositol 3-kinase(PI-3K),protein kinase B(PKB),phosphorylated PKB-Ser473 and glycogen synthase kinase(GSK) 3 in 8-week-old male IUGR rats.Results The basal levels of PI-3K protein decreased in IUGR rats compared with normal controls(P<0.01),whereas GSK-3β protein level significantly increased in IUGR rats(P<0.01).Both PKB and phosphorylated PKB-Ser473 protein levels significantly decreased in the liver of IUGR rats compared with normal controls(P<0.01)).After insulin administration,phosphorylated PKB-Ser473 significantly increased to 182% of basal level in control rats(P<0.01);However,phosphorylation of PKB which responded to insulin was markedly blunted in IUGR rats compared with controls and only increased to 123% of basal level(P<0.05).Conclusions The level of PI-3K and PKB and phosphorylated PKB-Ser473 expression decreased in the liver of IUGR rats,whereas the levels of GSK-3β protein increased.It may contribute to the pathogenesis of insulin resistance in the IUGR rats.更多还原