Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells
Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells
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DOI：
10.1007/s001250051238
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发表时间：
1999-07-01
期刊：
影响因子：
8.2
通讯作者：
Prentki, M
中科院分区：
文献类型：
--
作者：
Buteau, J;Roduit, R;Prentki, M
目的/假设。胰高血糖素样肽-1（Glucagon-like peptide-1，GLP-1）是一种有效的葡萄糖肠促胰岛素激素，是治疗II型（非胰岛素依赖型）糖尿病的重要药物。我们已经调查了它是否作为一个生长因子β（INS-1）-细胞，并研究了信号通路和转录因子在这一过程中牵连。通过氚化胸苷掺入测量评估细胞增殖。我们已经研究了胰高血糖素样肽-1对磷脂酰肌醇3-激酶的酶活性的作用。用电泳迁移率变动分析法检测转录因子的DNA结合活性。采用北方技术测定mRNA。胰高血糖素样肽-1引起β（INS-1）-细胞中氚化胸苷掺入和磷脂酰肌醇3-激酶活性以剂量依赖性方式增加，与葡萄糖无相加作用。磷脂酰肌醇3激酶抑制剂wortmannin和LY 294002阻断胰高血糖素样肽-1对DNA合成的影响。胰高血糖素样肽-1在3或11 mmol/l葡萄糖时可增加转录因子胰腺和十二指肠同源盒基因1（PDX-1）DNA结合活性，磷脂酰肌醇3-激酶抑制剂LY 294002可抑制胰高血糖素样肽-1对PDX-1 DNA结合活性的作用。单独的胰高血糖素样肽-i和葡萄糖不改变激活蛋白-1 DNA结合活性。然而，它们协同作用增加了激活蛋白-1的活性。胰高血糖素样肽-i也增加PDX-1的表达。葡萄糖转运蛋白2、葡萄糖激酶和胰岛素mRNA。最后，胰高血糖素样肽-I增加了氚化胸苷在离体大鼠胰岛中的掺入。结果表明，胰高血糖素样肽-1可能作为一个生长因子的β细胞通过磷脂酰肌醇3-激酶介导的事件。胰高血糖素样肽-1还可以通过磷脂酰肌醇3-激酶/PDX-1转导信号通路调节胰岛素基因和编码与葡萄糖转运和代谢有关的酶的基因的表达。
Aims/hypothesis. Glucagon-like peptide-1 is a potent glucoincretin hormone and a potentially important drug in the treatment of Type II (non-insulin-dependent) diabetes mellitus. We have investigated whether it acts as a growth factor in beta (INS-1)-cells and have studied the signalling pathways and transcription factors implicated in this process.Methods. Cell proliferation was assessed by tritiated thymidine incorporation measurements. We have examined the action of glucagon-like peptide-1 on the enzymatic activity of phosphatidylinositol 3-kinase. The DNA binding activity of transcription factors was investigated by electrophoretic mobility shift assay. Measurements of mRNA were done using the northern technique.Results. Glucagon-like peptide-1 caused an increase in tritiated thymidine incorporation in beta (INS-1)-cells and phosphatidylinositol 3-kinase activity in a dose-dependent manner non-additively with glucose. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 blocked the effects of glucagon-like peptide-1 on DNA synthesis. Transcription factor pancreatic and duodenal homebox gene 1 (PDX-1) DNA binding activity was increased by glucagon-like peptide-1 at 3 or 11 mmol/l glucose and the phosphatidylinositol 3-kinase inhibitor LY294002 suppressed the action of glucagon-like peptide-1 on PDX-1 DNA binding activity. Glucagon-like peptide-i and glucose alone did not change activating protein-1 DNA binding activity. They synergised, however, to increase the activity of activating protein-1. Glucagon-like peptide-i also increased the expression of PDX-1. glucose transporter 2, glucokinase and insulin mRNAs. Finally, glucagon-like peptide-i increased the incorporation of tritiated thymidine in isolated rat islets.Conclusion/interpretation. The results suggest that glucagon-like peptide-1 may act as a growth factor for the beta cell by a phosphatidylinositol 3-kinase mediated event. Glucagon-like peptide-1 could also regulate the expression of the insulin gene and genes encoding enzymes implicated in glucose transport and metabolism through the phosphatidylinositol 3-kinase/PDX-1 transduction signalling pathway.