GSK3 (glycogen synthase kinase-3) regulation is proposed to play a key role in the hormonal control of many cellular processes. Inhibition of GSK3 in animal models of diabetes leads to normalization of blood glucose levels, while high GSK3 activity has been reported in Type II diabetes. Insulin inhibits GSK3 by promoting phosphorylation of a serine residue (Ser-21 in GSK3α, Ser-9 in GSK3β), thereby relieving GSK3 inhibition of glycogen synthesis in muscle. GSK3 inhibition in liver reduces expression of the gluconeogenic genes PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase), as well as IGFBP1 (insulin-like growth factor binding protein-1). Overexpression of GSK3 in cells antagonizes insulin regulation of these genes. In the present study we demonstrate that regulation of these three genes by feeding is normal in mice that express insulin-insensitive GSK3. Therefore inactivation of GSK3 is not a prerequisite for insulin repression of these genes, despite the previous finding that GSK3 activity is absolutely required for maintaining their expression. Interestingly, insulin injection of wild-type mice, which activates PKB (protein kinase B) and inhibits GSK3 to a greater degree than feeding (50% versus 25%), does not repress these genes. We suggest for the first time that although pharmacological inhibition of GSK3 reduces hepatic glucose production even in insulin-resistant states, feeding can repress the gluconeogenic genes without inhibiting GSK3.
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Research Article|
December 06 2005
Analysis of hepatic gene transcription in mice expressing insulin-insensitive GSK3
Christopher Lipina;
Christopher Lipina
1
*Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland, U.K.
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Xu Huang;
Xu Huang
1
†MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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David Finlay;
David Finlay
1
*Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland, U.K.
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Edward J McManus;
Edward J McManus
†MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Dario R. Alessi;
Dario R. Alessi
†MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, U.K.
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Calum Sutherland
Calum Sutherland
2
*Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland, U.K.
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
June 29 2005
Revision Received:
September 08 2005
Accepted:
September 21 2005
Accepted Manuscript online:
September 21 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 392 (3): 633–639.
Article history
Received:
June 29 2005
Revision Received:
September 08 2005
Accepted:
September 21 2005
Accepted Manuscript online:
September 21 2005
Citation
Christopher Lipina, Xu Huang, David Finlay, Edward J McManus, Dario R. Alessi, Calum Sutherland; Analysis of hepatic gene transcription in mice expressing insulin-insensitive GSK3. Biochem J 15 December 2005; 392 (3): 633–639. doi: https://doi.org/10.1042/BJ20051046
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