The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivityonto glucose-6-phosphatase expression

Citation
J. Nakae et al., The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivityonto glucose-6-phosphatase expression, J CLIN INV, 108(9), 2001, pp. 1359-1367
Citations number
79
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF CLINICAL INVESTIGATION
ISSN journal
0021-9738 → ACNP
Volume
108
Issue
9
Year of publication
2001
Pages
1359 - 1367
Database
ISI
SICI code
0021-9738(200111)108:9<1359:TFTFF(>2.0.ZU;2-B
Abstract
Type 2 diabetes is characterized by the inability of insulin to suppress gl ucose production in the liver and kidney. Insulin inhibits glucose producti on by indirect and direct mechanisms. The latter result in transcriptional suppression of key gluconeogenetic and glycogenolytic enzymes, phosphoenolp yruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6p). The transcri ption factors required for this effect are incompletely characterized. We r eport that in glucogenetic kidney epithelial cells, Pepck and G6p expressio n are induced by dexamethasone (dex) and cAMP, but fail to be inhibited by insulin. The inability to respond to insulin is associated with reduced exp ression of the forkhead transcription factor Foxo1, a substrate of the Akt kinase that is inhibited by insulin through phosphorylation. Transduction o f kidney cells with recombinant adenovirus encoding Foxo1 results in insuli n inhibition of dex/cAMP-induced G6p expression. Moreover, expression of do minant negative Foxo1 mutant results in partial inhibition of dex/cAMP-indu ced G6p and Pepck expression in primary cultures of mouse hepatocyes and ki dney LLC-PK1-FBPase(+) cells. These findings are consistent with the possib ility that Foxo1 is involved in insulin regulation of glucose production by mediating the ability of insulin to decrease the glucocorticoid/cAMP respo nse of G6p.