Pancreatic glucokinase is activated by insulin-like growth factor-I.
Pancreatic glucokinase is activated by insulin-like growth factor-I.
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DOI：
10.1210/en.2006-1149
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发表时间：
2007-06
期刊：
影响因子：
4.8
通讯作者：
Kazuya Yoshida;K. Murao;H. Imachi;W. Cao;Xiao Yu;Junhua Li;R. A. Ahmed;Noriko Kitanaka;N. Wong;T. Unterman;M. Magnuson;T. Ishida
中科院分区：
文献类型：
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作者：
Kazuya Yoshida;K. Murao;H. Imachi;W. Cao;Xiao Yu;Junhua Li;R. A. Ahmed;Noriko Kitanaka;N. Wong;T. Unterman;M. Magnuson;T. Ishida
葡萄糖激酶（GK）在调节胰岛细胞的葡萄糖使用和葡萄糖刺激的胰岛素分泌中起关键作用。igf - 1受体的基因靶向下调胰岛GK活性。这一发现促使我们研究利用一种已知表达igf -1受体的胰岛细胞系INS-1来控制GK基因活性的潜在机制。这些细胞暴露于IGF-I诱导GK蛋白的表达和酶的活性以剂量依赖的方式。此外，IGF-I诱导含有GK启动子的报告结构的活性，同时影响内源性GK mRNA水平。IGF-I对GK启动子活性的刺激作用被磷脂酰肌醇3-激酶特异性抑制剂wortmannin和LY294002所抵消。细胞暴露于igf - 1会引起Akt和fox01的快速磷酸化，fox01是Akt信号传导的已知靶点。组成型活性Akt刺激GK启动子的活性，而Akt的显性负突变或GK启动子中fox01应答元件的突变会破坏IGF-I刺激启动子活性的能力。此外，用小干扰RNA敲低fox01细胞破坏了IGF-I对GK表达的影响。这些结果表明，磷脂酰肌醇3-激酶/Akt/FoxO1通路参与IGF-I刺激下GK基因表达的调控。
Glucokinase (GK) plays a key role in the regulation of glucose use and glucose-stimulated insulin secretion in pancreatic islet cells. Gene targeting of the IGF-I receptor down-regulated pancreatic islet GK activity. That finding prompted us to examine the potential mechanism that may control GK gene activity using an islet cell line, INS-1, known to express IGF-I receptor. Exposure of these cells to IGF-I induced GK protein expression and activity of the enzyme in a dose-dependent manner. In addition, IGF-I induced activity of a reporter construct containing the GK promoter in parallel with the effect on endogenous GK mRNA levels. The stimulatory effect of IGF-I on GK promoter activity was abrogated by wortmannin and LY294002, specific inhibitors of phosphatidylinositol 3-kinase. Exposure of cells to IGF-I elicited a rapid phosphorylation of Akt and FoxO1, a known target of Akt signaling. Constitutively active Akt stimulates the activity of the GK promoter, and a dominant-negative mutant of Akt or mutagenesis of a FoxO1 response element in the GK promoter abolished the ability of IGF-I to stimulate the promoter activity. Furthermore, cell knockdown of FoxO1 with small interfering RNA disrupted the effect of IGF-I on GK expression. These results demonstrate that the phosphatidylinositol 3-kinase/Akt/FoxO1 pathway contributes to the regulation of GK gene expression in response to IGF-I stimulation.