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Chronic Hyperinsulinism Induced Down-regulation of Insulin Post-Receptor Signaling Transduction in Hep G2 Cells 被引量:1
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作者 袁莉 Reinhard Ziegler andreas hamann 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2002年第4期313-316,共4页
To study the regulatory effect of acute and chronic insulin treatmenton insulin post- re- ceptor signaling transduction pathway in a human hepatom a cell line (Hep G2 ) ,Hep G2 cells were incubated in the presence o... To study the regulatory effect of acute and chronic insulin treatmenton insulin post- re- ceptor signaling transduction pathway in a human hepatom a cell line (Hep G2 ) ,Hep G2 cells were incubated in the presence or absence of insulin with different concentrations in serum free m edia for16 h and then stim ulated with10 0 nmol/ L insulin for1m in.Protein levels of insulin receptor β- subunit(IRβ) ,insulin receptor substrate- 1(IRS- 1) and p85 subunit of phosphatidylinositol3- kinase(PI3- kinase) were determined in total cell lysates by Western- im munoblot.Phosphorylat- ed proteins IRβ,IRS- 1and interaction of PI3- kinase with IRS- 1were determ ined by im munopre- cipitation.Results showed that 1- min insulin stimulation rapidly induced tyrosine phosphorylation of IRβ and IRS- 1,which in turn,resulting in association of PI 3- kinase with IRS- 1.1- 10 0 nm ol/ L chronic insulin treatment induced a dose- dependent decrease in the protein level of IRβ and a slight decrease in the protein level of IRS- 1.There was a m ore marked reduction in the phospho- rylation of IRβ,IRS- 1,reaching a nadir of2 2 % (P<0 .0 1) and15 % (P<0 .0 1) of control lev- els,respectively,after16 h treatment with 10 0 nm ol/ L insulin.The association between IRS- 1 and PI3- kinase was decreased by6 6 % (P<0 .0 1) .There was no significant change in PI3- ki- nase protein levels. These data suggest that chronic insulin treatm ent can induce alterations of IRβ,IRS- 1and PI 3- kinase three early steps in insulin action,which contributes significantly to insulin resistance,and may account for desensitization of insulin action. 展开更多
关键词 INSULIN insulin signaling transduction insulin resistance
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慢性胰岛素刺激对胰岛素受体后不同信号转导途径的下降调节 被引量:5
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作者 袁莉 Reinhard ZIEGLER andreas hamann 《中华内分泌代谢杂志》 CAS CSCD 北大核心 2003年第4期308-312,共5页
目的 研究胰岛素慢性刺激对人肝癌细胞株 (HepG2 )胰岛素受体后不同信号转导途径的影响。方法 HepG2 细胞在无血清条件下与不同浓度的胰岛素 ( 0~ 10 0nmol/L)温育 16h ,然后用 10 0nmol/L胰岛素急性刺激 1min。这些细胞的溶解物中... 目的 研究胰岛素慢性刺激对人肝癌细胞株 (HepG2 )胰岛素受体后不同信号转导途径的影响。方法 HepG2 细胞在无血清条件下与不同浓度的胰岛素 ( 0~ 10 0nmol/L)温育 16h ,然后用 10 0nmol/L胰岛素急性刺激 1min。这些细胞的溶解物中的胰岛素受体 β亚单位 (IRβ) ,胰岛素受体底物 (IRS) 1,IRS 2 ,磷酯酰肌醇 3激酶 (PI3K)的调节亚单位P85 ,有丝分裂原激活蛋白激酶 (MAPK)的蛋白表达水平和MAPK的磷酸化水平通过Western免疫印迹法测定 ,IRβ、IRS 1/ 2的蛋白磷酸化水平以及IRS 1/ 2与P85的结合反应用特异性抗体的免疫沉淀法。结果 胰岛素 1min急性刺激能迅速导致IRβ、IRS 1、IRS 2的酪氨酸磷酸化和MAPK的磷酸化 ,以及IRS 1( 2 )与P85的相互作用而激活PI3K。高浓度胰岛素慢性刺激显著降低了IRβ、IRS 1和IRS 2的酪氨酸磷酸化。细胞用 10 0nmol/L胰岛素预温育 16h后 ,IRβ、IRS 1和IRS 2的磷酸化水平降至最低值 ,分别为对照水平的 2 2 .2 % (P <0 .0 1)、10 .9% (P <0 .0 1)和 2 2 .0 % (P<0 .0 1) ,与IRS的磷酸化变化相平行 ,IRS 1和IRS 2与PI3K的相互作用分别降低至对照水平的 3 4.3 %(P <0 .0 1)和 3 0 .0 % (P <0 .0 1) ,MAPK的磷酸化水平降低至对照水平的 16.4% (P <0 .0 1)。 展开更多
关键词 胰岛素受体 信号转导 调节 胰岛素抵抗 高胰岛素血症
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二甲双胍对磷酸烯醇丙酮酸羧激酶基因表达调节的研究 被引量:2
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作者 袁莉 Reinhard Ziegler andreas hamann 《中华内科杂志》 CAS CSCD 北大核心 2002年第10期663-666,共4页
目的 通过观察抗高血糖药物二甲双胍对肝糖异生中的关键限速酶磷酸烯醇丙酮酸羧激酶 (PEPCK)基因表达的调节以及胰岛素信号转导抑制剂的影响 ,探讨二甲双胍在肝细胞中作用的分子机制。方法 培养的小鼠肝癌细胞系 (H4IIE)用 0 1mmol/... 目的 通过观察抗高血糖药物二甲双胍对肝糖异生中的关键限速酶磷酸烯醇丙酮酸羧激酶 (PEPCK)基因表达的调节以及胰岛素信号转导抑制剂的影响 ,探讨二甲双胍在肝细胞中作用的分子机制。方法 培养的小鼠肝癌细胞系 (H4IIE)用 0 1mmol/L二甲双胍温育 16h ,并加用不同的调节因子 ,如胰岛素、环磷酸腺苷 (cAMP)、地塞米松、胰岛素信号转导抑制剂等。PEPCK的mRNA水平通过Northernblot分析。结果 治疗浓度 0 .1mmol/L二甲双胍显著降低了基础PEPCK的mRNA水平约 75 % (P <0 .0 1) ,对cAMP和地塞米松刺激的PEPCKmRNA表达 ,二甲双胍单独作用无显著性效果 ,但通过与胰岛素的联合作用可抑制cAMP和地塞米松刺激的PEPCK的基因表达。当培养液中加入 0 .1nmol/L低浓度胰岛素与二甲双胍共同温育时 ,cAMP和地塞米松引起的PEPCKmRNA表达显著降低了 94 % (P <0 .0 1)。胰岛素信号转导抑制剂如磷脂酰肌醇 3激酶 (PI3K)抑制剂渥蔓青霉素(wortmannin)和有丝分裂原激活蛋白激酶 (MAPK)抑制剂UO12 6对二甲双胍的作用无显著影响 ,但wortmannin显著阻止了胰岛素对PEPCK基因表达的调节作用。结论 二甲双胍可通过独立的非胰岛素信号转导途径或是与胰岛素的联合作用抑制PEPCK的基因表达 。 展开更多
关键词 二甲双胍 磷酸烯醇丙酮酸羧激酶 胰岛素 糖尿病
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Inhibition of phosphoenolpyruvate carboxykinase gene expression by metformin in cultured hepatocytes
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作者 袁莉 Reinhard Ziegler andreas hamann 《Chinese Medical Journal》 SCIE CAS CSCD 2002年第12期84-89,151-152,共6页
Objective To investigate the effect and mechanism of the antihyperglycemic agent metformin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) gene in hepatocytes and to determine whether the effects of me... Objective To investigate the effect and mechanism of the antihyperglycemic agent metformin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) gene in hepatocytes and to determine whether the effects of metformin in hepatocytes are transmitted throughout the known insulin signaling pathways Methods Confluent H4IIE rat heptoma cells were cultured for 16 h with 0 1 mmol/L metformin either in absence or presence of 0 1 nmol/L insulin, and then stimulated with various agents The expression of PEPCK gene was examined by Northern blot analysis Results Therapeutic concentrations of metformin significantly inhibited basal PEPCK mRNA expression and also decreased cAMP and dexamethasone induced PEPCK gene expression through interaction with insulin In the presence of insulin signaling pathway inhibitors wortmannin and UO126, metformin reduced PEPCK mRNA levels, but wortmannin blocked inhibitory regulation of insulin on PEPCK gene expression Conclusion Metformin inhibits PEPCK gene expression via either an insulin independent or an interacting with insulin manner The results suggest that a possible mechanism by which metformin reduces gluconeogenesis could be associated with the inhibition of PEPCK gene expression 展开更多
关键词 metformin· phosphoenolpyruvate carboxykinase ·gluconeogenesis·insulin· hepatocyte · signal transduction
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