The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression
The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression
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DOI：
10.1172/jci12876
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发表时间：
2001-11-01
影响因子：
15.9
通讯作者：
Accili, D
中科院分区：
文献类型：
--
作者：
Nakae, J;Kitamura, T;Accili, D
2型糖尿病的特点是胰岛素无法抑制肝脏和肾脏的葡萄糖生成。胰岛素通过间接和直接机制抑制葡萄糖的产生。后者导致关键的糖异生和糖原分解酶，磷酸烯醇丙酮酸羧激酶（Pepck）和葡萄糖-6-磷酸酶（G6p）的转录抑制。这种作用所需的转录因子尚未完全确定。在糖源性肾上皮细胞中，地塞米松（dex）和cAMP可诱导Pepck和G6p表达，但胰岛素无法抑制其表达。对胰岛素无反应与叉头转录因子Foxo1的表达减少有关，叉头转录因子Foxo1是Akt激酶的底物，通过磷酸化被胰岛素抑制。用编码Foxo1的重组腺病毒转导肾细胞导致胰岛素抑制dex/ camp诱导的G6p表达。此外，Foxo1显性阴性突变体的表达导致dex/ camp诱导的小鼠肝细胞和肾LLC-PK1-FBPase（+）细胞的G6p和Pepck表达部分抑制。这些发现与Foxo1通过介导胰岛素降低G6p糖皮质激素/cAMP反应的能力参与胰岛素对葡萄糖产生的调节的可能性一致。
Type 2 diabetes is characterized by the inability of insulin to suppress glucose production in the liver and kidney. Insulin inhibits glucose production by indirect and direct mechanisms. The latter result in transcriptional suppression of key gluconeogenetic and glycogenolytic enzymes, phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6p). The transcription factors required for this effect are incompletely characterized. We report that in glucogenetic kidney epithelial cells, Pepck and G6p expression are induced by dexamethasone (dex) and cAMP, but fail to be inhibited by insulin. The inability to respond to insulin is associated with reduced expression of the forkhead transcription factor Foxo1, a substrate of the Akt kinase that is inhibited by insulin through phosphorylation. Transduction of kidney cells with recombinant adenovirus encoding Foxo1 results in insulin inhibition of dex/cAMP-induced G6p expression. Moreover, expression of dominant negative Foxo1 mutant results in partial inhibition of dex/cAMP-induced G6p and Pepck expression in primary cultures of mouse hepatocyes and kidney LLC-PK1-FBPase(+) cells. These findings are consistent with the possibility that Foxo1 is involved in insulin regulation of glucose production by mediating the ability of insulin to decrease the glucocorticoid/cAMP response of G6p.