胰岛素受体后信号通路与妊娠期糖尿病发病机制的研究
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摘要
第一部分GLUT-4的表达及转位与GDM胰岛素抵抗的关系
目的研究GDM患者骨骼肌组织中GLUT-4的表达及转位变化，分析GLUT-4的表达及转位变化与GDM糖代谢异常和胰岛素抵抗的关系。
方法选取GDM患者26例(GDM组)及同期糖耐量正常的孕妇26例(对照组)，收集空腹血，并提取完整的腹直肌组织样本。(1)采用放射免疫法及葡萄糖氧化酶法检测各组空腹胰岛素(FINS)及空腹葡萄糖(FPG)水平；应用稳态模型法计算胰岛素抵抗指数(HOMA-IR)；(2)采用RT-PCR法和western blot法检测骨骼肌组织中GLUT-4的表达和转位的变化；(3)免疫组化法检测GLUT-4在肌肉组织中的分布。
结果(1) GDM组中FPG、FINS、HOMA-IR水平均显著高于对照组，各指标分别比较，差异均有统计学意义(P＜0.05)；(2) GDM组和对照组之间骨骼肌中GLUT-4总量没有明显差异(P＞0.05)；(3) GDM组从骨骼肌细胞内膜转位到外膜的GLUT-4数量较对照组明显减少(P＜0.05)，相关分析显示GLUT-4转位的数量与FPG、FINS、HOMA-IR指数呈负相关(r=-0.42，-0.46，-0.51，P＜0.05)。
结论GDM患者骨骼肌组织中出现了GLUT-4的转位异常，可能是导致GDM葡萄糖的摄取障碍和胰岛素抵抗的分子机制之一。
第二部分GDM骨骼肌组织中PI3-K、PKB和GSK-3β表达和活性的变化
目的研究胰岛素受体后信号转导过程中的关键分子PI3Kp85、PKB、GSK-3β在GDM患者骨骼肌组织中的表达和活性变化。
方法选取GDM患者26例(GDM组)，同期糖耐量正常的孕妇26例(对照组)，提取完整的腹直肌活组织样本。(1)采用免疫组化法检测PI3Kp85、PKB、GSK-3β的表达；(2)应用Western blot方法检测GDM骨骼肌PKB、GSK-3β蛋白质磷酸化情况；(3) ELISA法测定肌肉组织中PI3-K的活性。
结果(1)与对照组相比GDM组中的信号转导分子PKB、GSK-3β蛋白的表达未发现数量上的不同(P＞0.05)；(2) GDM组中的PI3Kp85的蛋白较对照组水平高(P＜0.05)；(3) GDM组中的PKB、GSK-3β磷酸化水平及PI3-K的活性较对照组明显降低，差异有显著性(P＜0.05)。
结论在GDM骨骼肌中胰岛素受体后信号蛋白表达在GDM组和对照组中无显著变化，但出现了PI3-K及PKB、GSK-3β活性的下调，是导致GDM胰岛素抵抗和GLUT-4的转位下降的受体后原因。
第三部分钒酸钠调节IRS-1酪氨酸磷酸化对GDM胰岛素受体后信号通路的影响
目的研究酪氨酸磷酸化促进剂钒酸钠调节IRS-1酪氨酸磷酸化对GDM骨骼肌中胰岛素信号传导通路中的PI-3K、PKB的活性及GLUT-4的转位影响，探讨促进IRS-1酪氨酸磷酸化对GDM胰岛素受体后信号通路的影响。
方法选取GDM患者26例(GDM组)，同期糖耐量正常的孕妇26例(对照组)，提取完整的骨骼肌组织样本，用钒酸钠孵育后，蔗糖梯度离心法分离细胞内外膜提取总蛋白。(1)应用免疫沉淀法检测IRS-1的酪氨酸磷酸化水平；(2) ELISA法测定肌肉组织中PI3-K的活性；(3) Western blot方法检测GDM骨骼肌PKB磷酸化和骨骼肌组织中GLUT-4转位的变化。
结果(1)钒酸钠作用于GDM骨骼肌组织后，IRS-1酪氨酸磷酸化介导的PI3-k活性显著升高，差异有显著性(p＜0.05)；(2)钒酸钠作用后骨骼肌中的GLUT-4跨膜易位也明显增加；(3)但钒酸钠作用后他们的水平仍低于对照组(p＜0.05)。
结论改善GDM的IRS-1酪氨酸磷酸化，能增加PI3-K活性和GLUT-4的转位，部分改善GDM胰岛素信号传导，促进IRS-1酪氨酸磷酸化可成为治疗胰岛素抵抗潜在的靶点。
Part 1 The relationship between GLUT-4 expression andtranslocation and insulin resistance in gestational diabetes mellitus
Objective To investigate the GLUT-4 expression and translocation in gestational diabetesmellitus, analysis the relationship between GLUT-4 and insulin resistance in gestationaldiabetes mellitus
Methods (1) Fasting insulin(FINS) and Fasting plasma glucose(FPG) was measured byoxidase assay and immunoradioassay .insulin resistance index was calculated usinghomeostasis model assessment (HOMA-IR) .intact skeletal muscle strips and biopsiesspecimen were obtained, Skeletal muscle plasma membranes and the intracellularmembranes were separated by sucrose gradient ultracentrifugation; (2) the GLUT-4translocation were measured by Western blot assay;(3)The distribution of GLUT-4 measuredby immunohistochemistry assay.
Results (1) The levels of FPG, FINS, and insulin resistance index in GDM group weresignificantly higher than those in normal pregnancy group. (2) No significant differentwas observed in total GLUT-4 amount in skeletal muscle between control group and GDMgroup. (3) the amount of GLUT-4 in plasma membranes from GDM group wassignificant decreased in skeletal muscle cell from GDM compared to control group(P＜0.05).The translocation of GLUT-4 positively correlated with the FINS、FBG、HOMA-IR andlevels (r=-0.42, -0.46, -0.51, P＜0.05).
Conclusions The GLUT-4 translocation from intracellular membranes to plasmamembranes was significant decreased in skeletal muscle cell from GDM, The decreasedGLUT-4 translocation correlated with GDM IR.
Part2 The expression and phosphorylation of PI3K、PKB andGSK-3 in the skeletal muscle from pregnant women with gestationaldiabetes mellitus
Objective To investigate the expression and phosphorylation of insulin signalingtransduction molecules in the skeletal muscle of patients with gestational diabetes mellitus,and explore molecular mechanisms of insulin resistance in gestational diabetes mellitus
Methods The skeletal muscle samples from patients with GDM (GDM group ,n=26) ,normal pregnant women (control group, n=26) ; (1) The expression of PI3K、PKB、GSK-3 measured by immunohistochemistry assay; (2) The activity of PI3K was measuredby ELLISA method; (3) The phosphorylation of PKB and GSK-βwere determined bywestern blot assay.
Results (1) The expression amount of PKB and GSK-3 protein in skeletal muscle cell wasnot found different among the control group and GDM group.(P＞0.05); (2) The amount ofPI3-Kp85 was significant higher than in control group (P＜0.05); (3) the phosphorylation ofPI3-K、PKB and GSK-3 activity of PI3-K decease in GDM group as compared with thecontrol group(P＜0.05).
Conclusion The present results indicated that the decease of phosphorylation of PI3K、PKBand GSK-3βin the skeletal muscle of gestational diabetes mellitus may be one of themolecule mechanisms postreceptor signal transduction obstacle and insulin resistance ofGDM.
Part 3 Sodium vandate improve IRS-1 tyrosine phosphorylationon insulin postreceptor signal transduction and GLUT-4translocation in skeletal muscle from pregnant women withgestational diabetes mellitus
Objective To investigate the effect IRS-1 tyrosine phosphorylation on insulin postreceptorsignal transduction in skeletal muscle from women with gestational diabetes mellitus
Methods The skeletal muscle samples from patients with GDM and normal pregnantwomen were incubated in medium containing sodium vandate; (1) The tyrosinephosphorylation of IRS-1 was measured by immunoprecipitation; (2) The activity of PI3-Kwas measured by ELLISA method; (3) the GLUT-4 translocations were measured byWestern blot.
Results (1) Sodium vandate increased the tyrosine phosphorylation of the IRS-1; (2) andPI3-kinase activity and the translocation of GLUT-4 in skeletal muscle from pregnant; (3)but the value was still less than control subjects
Conclusion Sodium vandate increase IRS-1 tyrosine phosphorylation and improve insulinsignal transduction Mediated GLUT-4 translocation in skeletal muscle from women withgestational diabetes mellitus. It was indicated as potential approach for insulin resistance.
目的研究GDM患者骨骼肌组织中GLUT-4的表达及转位变化，分析GLUT-4的表达及转位变化与GDM糖代谢异常和胰岛素抵抗的关系。
方法选取GDM患者26例(GDM组)及同期糖耐量正常的孕妇26例(对照组)，收集空腹血，并提取完整的腹直肌组织样本。(1)采用放射免疫法及葡萄糖氧化酶法检测各组空腹胰岛素(FINS)及空腹葡萄糖(FPG)水平；应用稳态模型法计算胰岛素抵抗指数(HOMA-IR)；(2)采用RT-PCR法和western blot法检测骨骼肌组织中GLUT-4的表达和转位的变化；(3)免疫组化法检测GLUT-4在肌肉组织中的分布。
结果(1) GDM组中FPG、FINS、HOMA-IR水平均显著高于对照组，各指标分别比较，差异均有统计学意义(P＜0.05)；(2) GDM组和对照组之间骨骼肌中GLUT-4总量没有明显差异(P＞0.05)；(3) GDM组从骨骼肌细胞内膜转位到外膜的GLUT-4数量较对照组明显减少(P＜0.05)，相关分析显示GLUT-4转位的数量与FPG、FINS、HOMA-IR指数呈负相关(r=-0.42，-0.46，-0.51，P＜0.05)。
结论GDM患者骨骼肌组织中出现了GLUT-4的转位异常，可能是导致GDM葡萄糖的摄取障碍和胰岛素抵抗的分子机制之一。
第二部分GDM骨骼肌组织中PI3-K、PKB和GSK-3β表达和活性的变化
目的研究胰岛素受体后信号转导过程中的关键分子PI3Kp85、PKB、GSK-3β在GDM患者骨骼肌组织中的表达和活性变化。
方法选取GDM患者26例(GDM组)，同期糖耐量正常的孕妇26例(对照组)，提取完整的腹直肌活组织样本。(1)采用免疫组化法检测PI3Kp85、PKB、GSK-3β的表达；(2)应用Western blot方法检测GDM骨骼肌PKB、GSK-3β蛋白质磷酸化情况；(3) ELISA法测定肌肉组织中PI3-K的活性。
结果(1)与对照组相比GDM组中的信号转导分子PKB、GSK-3β蛋白的表达未发现数量上的不同(P＞0.05)；(2) GDM组中的PI3Kp85的蛋白较对照组水平高(P＜0.05)；(3) GDM组中的PKB、GSK-3β磷酸化水平及PI3-K的活性较对照组明显降低，差异有显著性(P＜0.05)。
结论在GDM骨骼肌中胰岛素受体后信号蛋白表达在GDM组和对照组中无显著变化，但出现了PI3-K及PKB、GSK-3β活性的下调，是导致GDM胰岛素抵抗和GLUT-4的转位下降的受体后原因。
第三部分钒酸钠调节IRS-1酪氨酸磷酸化对GDM胰岛素受体后信号通路的影响
目的研究酪氨酸磷酸化促进剂钒酸钠调节IRS-1酪氨酸磷酸化对GDM骨骼肌中胰岛素信号传导通路中的PI-3K、PKB的活性及GLUT-4的转位影响，探讨促进IRS-1酪氨酸磷酸化对GDM胰岛素受体后信号通路的影响。
方法选取GDM患者26例(GDM组)，同期糖耐量正常的孕妇26例(对照组)，提取完整的骨骼肌组织样本，用钒酸钠孵育后，蔗糖梯度离心法分离细胞内外膜提取总蛋白。(1)应用免疫沉淀法检测IRS-1的酪氨酸磷酸化水平；(2) ELISA法测定肌肉组织中PI3-K的活性；(3) Western blot方法检测GDM骨骼肌PKB磷酸化和骨骼肌组织中GLUT-4转位的变化。
结果(1)钒酸钠作用于GDM骨骼肌组织后，IRS-1酪氨酸磷酸化介导的PI3-k活性显著升高，差异有显著性(p＜0.05)；(2)钒酸钠作用后骨骼肌中的GLUT-4跨膜易位也明显增加；(3)但钒酸钠作用后他们的水平仍低于对照组(p＜0.05)。
结论改善GDM的IRS-1酪氨酸磷酸化，能增加PI3-K活性和GLUT-4的转位，部分改善GDM胰岛素信号传导，促进IRS-1酪氨酸磷酸化可成为治疗胰岛素抵抗潜在的靶点。
Part 1 The relationship between GLUT-4 expression andtranslocation and insulin resistance in gestational diabetes mellitus
Objective To investigate the GLUT-4 expression and translocation in gestational diabetesmellitus, analysis the relationship between GLUT-4 and insulin resistance in gestationaldiabetes mellitus
Methods (1) Fasting insulin(FINS) and Fasting plasma glucose(FPG) was measured byoxidase assay and immunoradioassay .insulin resistance index was calculated usinghomeostasis model assessment (HOMA-IR) .intact skeletal muscle strips and biopsiesspecimen were obtained, Skeletal muscle plasma membranes and the intracellularmembranes were separated by sucrose gradient ultracentrifugation; (2) the GLUT-4translocation were measured by Western blot assay;(3)The distribution of GLUT-4 measuredby immunohistochemistry assay.
Results (1) The levels of FPG, FINS, and insulin resistance index in GDM group weresignificantly higher than those in normal pregnancy group. (2) No significant differentwas observed in total GLUT-4 amount in skeletal muscle between control group and GDMgroup. (3) the amount of GLUT-4 in plasma membranes from GDM group wassignificant decreased in skeletal muscle cell from GDM compared to control group(P＜0.05).The translocation of GLUT-4 positively correlated with the FINS、FBG、HOMA-IR andlevels (r=-0.42, -0.46, -0.51, P＜0.05).
Conclusions The GLUT-4 translocation from intracellular membranes to plasmamembranes was significant decreased in skeletal muscle cell from GDM, The decreasedGLUT-4 translocation correlated with GDM IR.
Part2 The expression and phosphorylation of PI3K、PKB andGSK-3 in the skeletal muscle from pregnant women with gestationaldiabetes mellitus
Objective To investigate the expression and phosphorylation of insulin signalingtransduction molecules in the skeletal muscle of patients with gestational diabetes mellitus,and explore molecular mechanisms of insulin resistance in gestational diabetes mellitus
Methods The skeletal muscle samples from patients with GDM (GDM group ,n=26) ,normal pregnant women (control group, n=26) ; (1) The expression of PI3K、PKB、GSK-3 measured by immunohistochemistry assay; (2) The activity of PI3K was measuredby ELLISA method; (3) The phosphorylation of PKB and GSK-βwere determined bywestern blot assay.
Results (1) The expression amount of PKB and GSK-3 protein in skeletal muscle cell wasnot found different among the control group and GDM group.(P＞0.05); (2) The amount ofPI3-Kp85 was significant higher than in control group (P＜0.05); (3) the phosphorylation ofPI3-K、PKB and GSK-3 activity of PI3-K decease in GDM group as compared with thecontrol group(P＜0.05).
Conclusion The present results indicated that the decease of phosphorylation of PI3K、PKBand GSK-3βin the skeletal muscle of gestational diabetes mellitus may be one of themolecule mechanisms postreceptor signal transduction obstacle and insulin resistance ofGDM.
Part 3 Sodium vandate improve IRS-1 tyrosine phosphorylationon insulin postreceptor signal transduction and GLUT-4translocation in skeletal muscle from pregnant women withgestational diabetes mellitus
Objective To investigate the effect IRS-1 tyrosine phosphorylation on insulin postreceptorsignal transduction in skeletal muscle from women with gestational diabetes mellitus
Methods The skeletal muscle samples from patients with GDM and normal pregnantwomen were incubated in medium containing sodium vandate; (1) The tyrosinephosphorylation of IRS-1 was measured by immunoprecipitation; (2) The activity of PI3-Kwas measured by ELLISA method; (3) the GLUT-4 translocations were measured byWestern blot.
Results (1) Sodium vandate increased the tyrosine phosphorylation of the IRS-1; (2) andPI3-kinase activity and the translocation of GLUT-4 in skeletal muscle from pregnant; (3)but the value was still less than control subjects
Conclusion Sodium vandate increase IRS-1 tyrosine phosphorylation and improve insulinsignal transduction Mediated GLUT-4 translocation in skeletal muscle from women withgestational diabetes mellitus. It was indicated as potential approach for insulin resistance.
引文
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