宫内生长受限大鼠肝脏磷酸肌醇-3-激酶信号通路分子的变化

Perturbed hepatic phosphoinositol 3-kinase signaling pathway in the rat with intrauterine growth restriction

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。［中国当代儿科杂志，2009，11（3）：221-224］

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). ConclusionsThe 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.［Chin J Contemp Pediatr, 2009, 11 (3):221-224］