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FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver
OBJECTIVE: Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on he...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198083/ https://www.ncbi.nlm.nih.gov/pubmed/21940782 http://dx.doi.org/10.2337/db11-0548 |
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author | Kim, Dae Hyun Perdomo, German Zhang, Ting Slusher, Sandra Lee, Sojin Phillips, Brett E. Fan, Yong Giannoukakis, Nick Gramignoli, Roberto Strom, Stephen Ringquist, Steven Dong, H. Henry |
author_facet | Kim, Dae Hyun Perdomo, German Zhang, Ting Slusher, Sandra Lee, Sojin Phillips, Brett E. Fan, Yong Giannoukakis, Nick Gramignoli, Roberto Strom, Stephen Ringquist, Steven Dong, H. Henry |
author_sort | Kim, Dae Hyun |
collection | PubMed |
description | OBJECTIVE: Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism. RESEARCH DESIGN AND METHODS: We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver. RESULTS: FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice. CONCLUSIONS: Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes. |
format | Online Article Text |
id | pubmed-3198083 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-31980832012-11-01 FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver Kim, Dae Hyun Perdomo, German Zhang, Ting Slusher, Sandra Lee, Sojin Phillips, Brett E. Fan, Yong Giannoukakis, Nick Gramignoli, Roberto Strom, Stephen Ringquist, Steven Dong, H. Henry Diabetes Metabolism OBJECTIVE: Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism. RESEARCH DESIGN AND METHODS: We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver. RESULTS: FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice. CONCLUSIONS: Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes. American Diabetes Association 2011-11 2011-10-17 /pmc/articles/PMC3198083/ /pubmed/21940782 http://dx.doi.org/10.2337/db11-0548 Text en © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Metabolism Kim, Dae Hyun Perdomo, German Zhang, Ting Slusher, Sandra Lee, Sojin Phillips, Brett E. Fan, Yong Giannoukakis, Nick Gramignoli, Roberto Strom, Stephen Ringquist, Steven Dong, H. Henry FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver |
title | FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver |
title_full | FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver |
title_fullStr | FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver |
title_full_unstemmed | FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver |
title_short | FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver |
title_sort | foxo6 integrates insulin signaling with gluconeogenesis in the liver |
topic | Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198083/ https://www.ncbi.nlm.nih.gov/pubmed/21940782 http://dx.doi.org/10.2337/db11-0548 |
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