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The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression
Jun Nakae, … , David L. Silver, Domenico Accili
Jun Nakae, … , David L. Silver, Domenico Accili
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1359-1367. https://doi.org/10.1172/JCI12876.
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The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression

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Abstract

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.

Authors

Jun Nakae, Tadahiro Kitamura, David L. Silver, Domenico Accili

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Figure 6

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Effects of constitutively active and dominant negative Foxo1 mutants on ...
Effects of constitutively active and dominant negative Foxo1 mutants on G6p and Pepck in LLC cells and in primary hepatocytes. (a) Expression of HA-tagged Δ256- and ADA-Foxo1 mutants in LLC cells was measured as indicated in Methods. Lane 1, untransduced LLC cells; lane 2, LLC cells transduced with the Δ256 mutant; lane 3, LLC cells transduced with the ADA mutant; lane 4, LLC cells cotransduced with both Δ256 and ADA mutants at a 1:10 moi. (b) Insulin inhibits G6p and Pepck in primary cultures of mouse hepatocytes. Hepatocytes were isolated as described in Methods. Cell monolayers were incubated in serum-free medium for 4 hours before the addition of dex/cAMP for 8 hours. Thereafter, cells were incubated in the absence (lanes 1 and 2) or in the presence of insulin (lane 3) for 6 hours. The data are representative of three separate hepatocyte preparations. (c) Effects of Foxo1 mutants on dex/cAMP–induced G6p and Pepck expression in LLC cells. Cells were transduced with the Δ256 mutant at increasing moi, in the absence (lanes 1–3) or presence (lanes 4–6) of a fixed amount of ADA-Foxo1 mutant. After overnight incubation in serum-free medium, cells were incubated in the presence of dex/cAMP for 8 hours. A representative experiment is shown. (d) Effects of Foxo1 mutants on dex/cAMP–induced G6p and Pepck expression in primary cultures of mouse hepatocytes. After transduction with Δ256- and/or ADA-Foxo1 mutant adenoviruses, hepatocyte cultures were incubated in serum-free medium for 4 hours before the addition of dex/cAMP for 8 hours. A representative experiment is shown, and data from three separate experiments for each cell type are summarized in Figure 7.

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