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PP2A inhibition results in hepatic insulin resistance despite Akt2 activation
In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecula...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838779/ https://www.ncbi.nlm.nih.gov/pubmed/24150286 |
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author | Galbo, Thomas Perry, Rachel J. Nishimura, Erica Samuel, Varman T. Quistorff, Bjørn Shulman, Gerald I. |
author_facet | Galbo, Thomas Perry, Rachel J. Nishimura, Erica Samuel, Varman T. Quistorff, Bjørn Shulman, Gerald I. |
author_sort | Galbo, Thomas |
collection | PubMed |
description | In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecular defect underlying insulin resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated Akt activity and decrease glucose production. PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1 in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes. Paradoxically, PP2A inhibition exacerbated insulin resistance in vivo. This was explained by phosphorylation of both hepatic glycogen synthase (GS) (inactivation) and phosphorylase (activation) resulting in impairment of glycogen storage. Our findings underline the significance of GS and Phosphorylase as hepatic PP2A substrates and importance of glycogen metabolism in acute plasma glucose regulation. |
format | Online Article Text |
id | pubmed-3838779 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-38387792013-12-04 PP2A inhibition results in hepatic insulin resistance despite Akt2 activation Galbo, Thomas Perry, Rachel J. Nishimura, Erica Samuel, Varman T. Quistorff, Bjørn Shulman, Gerald I. Aging (Albany NY) Research Paper In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecular defect underlying insulin resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated Akt activity and decrease glucose production. PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1 in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes. Paradoxically, PP2A inhibition exacerbated insulin resistance in vivo. This was explained by phosphorylation of both hepatic glycogen synthase (GS) (inactivation) and phosphorylase (activation) resulting in impairment of glycogen storage. Our findings underline the significance of GS and Phosphorylase as hepatic PP2A substrates and importance of glycogen metabolism in acute plasma glucose regulation. Impact Journals LLC 2013-10-21 /pmc/articles/PMC3838779/ /pubmed/24150286 Text en Copyright: © 2013 Galbo et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
spellingShingle | Research Paper Galbo, Thomas Perry, Rachel J. Nishimura, Erica Samuel, Varman T. Quistorff, Bjørn Shulman, Gerald I. PP2A inhibition results in hepatic insulin resistance despite Akt2 activation |
title | PP2A inhibition results in hepatic insulin resistance despite Akt2 activation |
title_full | PP2A inhibition results in hepatic insulin resistance despite Akt2 activation |
title_fullStr | PP2A inhibition results in hepatic insulin resistance despite Akt2 activation |
title_full_unstemmed | PP2A inhibition results in hepatic insulin resistance despite Akt2 activation |
title_short | PP2A inhibition results in hepatic insulin resistance despite Akt2 activation |
title_sort | pp2a inhibition results in hepatic insulin resistance despite akt2 activation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838779/ https://www.ncbi.nlm.nih.gov/pubmed/24150286 |
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