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Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice

Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice a...

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Autores principales: Berglund, Eric D., Li, Candice Y., Ayala, Julio E., McGuinness, Owen P., Wasserman, David H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524103/
https://www.ncbi.nlm.nih.gov/pubmed/23285006
http://dx.doi.org/10.1371/journal.pone.0052355
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author Berglund, Eric D.
Li, Candice Y.
Ayala, Julio E.
McGuinness, Owen P.
Wasserman, David H.
author_facet Berglund, Eric D.
Li, Candice Y.
Ayala, Julio E.
McGuinness, Owen P.
Wasserman, David H.
author_sort Berglund, Eric D.
collection PubMed
description Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also exhibit improved insulin-stimulated suppression of endogenous glucose production even though Glut4 is not present in the liver. It is unclear, however, if hepatic gluco-regulation is altered in G4Tg mice in the basal, non-insulin-stimulated state. The current studies were performed to examine fasting hepatic glucose metabolism in G4Tg mice and to determine whether gluco-regulatory adaptations exist in the non-insulin-stimulated condition. To test this question, phloridzin-glucose clamps were used to match blood glucose and pancreatic hormone levels while tracer dilution techniques were used to measure glucose flux. These techniques were performed in chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and wild-type (WT) littermates. Results show reduced blood glucose, hepatic glycogen content, and hepatic glucokinase (GK) activity/expression as well as higher endogenous glucose production, glucose disposal, arterial glucagon, and hepatic glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT controls. Clamping blood glucose for 90 min at ∼115 mg/dLin G4Tg and WT mice normalized nearly all variables. Notably, however, net hepatic glycogen synthetic rates were disproportionately elevated compared to changes in blood glucose. In conclusion, these studies demonstrate that basal improvements in glucose tolerance due to increased uptake in extra-hepatic sites provoke important gluco-regulatory adaptations in the liver. Although changes in blood glucose underlie the majority of these adaptations, net hepatic glycogen synthesis is sensitized. These data emphasize that anti-diabetic therapies that target skeletal muscle, heart, and/or adipose tissue likely positively impact the liver.
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spelling pubmed-35241032013-01-02 Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice Berglund, Eric D. Li, Candice Y. Ayala, Julio E. McGuinness, Owen P. Wasserman, David H. PLoS One Research Article Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also exhibit improved insulin-stimulated suppression of endogenous glucose production even though Glut4 is not present in the liver. It is unclear, however, if hepatic gluco-regulation is altered in G4Tg mice in the basal, non-insulin-stimulated state. The current studies were performed to examine fasting hepatic glucose metabolism in G4Tg mice and to determine whether gluco-regulatory adaptations exist in the non-insulin-stimulated condition. To test this question, phloridzin-glucose clamps were used to match blood glucose and pancreatic hormone levels while tracer dilution techniques were used to measure glucose flux. These techniques were performed in chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and wild-type (WT) littermates. Results show reduced blood glucose, hepatic glycogen content, and hepatic glucokinase (GK) activity/expression as well as higher endogenous glucose production, glucose disposal, arterial glucagon, and hepatic glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT controls. Clamping blood glucose for 90 min at ∼115 mg/dLin G4Tg and WT mice normalized nearly all variables. Notably, however, net hepatic glycogen synthetic rates were disproportionately elevated compared to changes in blood glucose. In conclusion, these studies demonstrate that basal improvements in glucose tolerance due to increased uptake in extra-hepatic sites provoke important gluco-regulatory adaptations in the liver. Although changes in blood glucose underlie the majority of these adaptations, net hepatic glycogen synthesis is sensitized. These data emphasize that anti-diabetic therapies that target skeletal muscle, heart, and/or adipose tissue likely positively impact the liver. Public Library of Science 2012-12-17 /pmc/articles/PMC3524103/ /pubmed/23285006 http://dx.doi.org/10.1371/journal.pone.0052355 Text en © 2012 Berglund et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Berglund, Eric D.
Li, Candice Y.
Ayala, Julio E.
McGuinness, Owen P.
Wasserman, David H.
Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice
title Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice
title_full Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice
title_fullStr Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice
title_full_unstemmed Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice
title_short Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice
title_sort regulation of endogenous glucose production in glucose transporter 4 over-expressing mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524103/
https://www.ncbi.nlm.nih.gov/pubmed/23285006
http://dx.doi.org/10.1371/journal.pone.0052355
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