
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
刘晓梅, 焦伊胜, 潘莉莉, 卢岩, 李书琴
中国当代儿科杂志 ›› 2009, Vol. 11 ›› Issue (03) : 221-224.
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
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]
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]
宫内生长受限 / 胰岛素抵抗 / 信号传导 / 磷酸肌醇-3-激酶 / 大鼠
Intrauterine growth restriction / Insulin resistance / Signal transduction / Phosphoinositol 3-kinase / Rats
[1]李静,华琦.胰岛素抵抗[M].//张建,华琦,李静.代谢综合征. 北京:人民卫生出版社,2003,64-72.
[2]Cantley LC. The phosphoinositide 3-kinase pathway[J]. Science, 2002, 296: (5573): 1655-1657.
[3]Desai M, Gayle D, Babu J, Ross MG. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition[J].Am J Physiol Regul Integr Comp Physiol, 2005, 288(1):R91-96.
[4]Ibáňez L, Ong K, Dunger DB, de Zegher F. Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational-age children[J].J Clin Endocrinol Metab, 2006, 91(6): 2153-2158.
[5]Matharu K, Ozanne SE.The fetal origins of disease and associations with low birthweight[J].NeoReviews, 2004, 5(12): 522-526.
[6]刘军,丘小汕,张怡坚,杜敏联,郑树森.高蛋白质喂养对生后早期营养不良的宫内生长迟缓大鼠糖代谢的远期影响[J].中国当代儿科杂志, 2002, 4(4):294-296.
[7]刘晓梅,卢岩,潘莉莉,李书琴.宫内生长受限大鼠肝脏糖异生酶的表达增加与胰岛素抵抗[J].中国当代儿科杂志, 2008, 10(2):216-220.
[8]Kido Y, Nakae J, Accili D. Clinical review 125: The insulin receptor and its cellular targets[J]. J Clin Endocrinol Metab, 2001, 86 (3):972-979.
[9]Brazil DP, Hemmings BA. Ten years of protein kinase B signalling: a hard Akt to follow[J]. Trends Biochem Sci, 2001, 26 (11):657-664.
[10]Suzuki R, Tobe K, Aoyama M, Inoue A, Sakamoto K, Yamauchi T, et al . Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2(-/-) mice[J]. J Biol Chem, 2004, 279(24):25039-25049.
[11]White MF. IRS proteins and the common path to diabetes[J]. Am J Physiol Endocrinol Metab, 2002, 283(3):413-422.
[12]Kaidanovich O, Eldar-Finkelman H.The role of glycogensynthase kinase-3 in insulin resistance and type 2 diabetes[J].Export Opin Ther Targets, 2002, 6(5): 555-561.
[13]Lochhead PA, Coghlan M, Rice SQJ, Sutherland C. Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression[J]. Diabetes, 2001, 50(5):937-946.
[14]Kaidanovich-Beilin O, Eldar-Finkelman H. Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle [J]. J Pharmacol Exp Ther, 2006, 316(1):17-24.
[15]Plotkin B, Kaidanovich O, Talior I, Finkelman HE. Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3[J]. J Pharmacol Exp Ther, 2003, 305(3):974-980.