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Molecular and Cellular Biology, October 2008, p. 6314-6328, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00763-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Tissue-Specific Role of Glycogen Synthase Kinase 3β in Glucose Homeostasis and Insulin Action ^,

Satish Patel,¹ Bradley W. Doble,^1,2 Katrina MacAulay,¹ Elaine M. Sinclair,¹ Daniel J. Drucker,¹ and James R. Woodgett^1*

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada,¹ McMaster Stem Cell and Cancer Research Institute, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada²

Received 12 May 2008/ Returned for modification 7 July 2008/ Accepted 31 July 2008

Dysregulation of the protein kinase glycogen synthase kinase 3 (GSK-3) has been implicated in the development of type 2 diabetes mellitus. GSK-3 protein expression and kinase activity are elevated in diabetes, while selective GSK-3 inhibitors have shown promise as modulators of glucose metabolism and insulin sensitivity. There are two GSK-3 isoforms in mammals, GSK-3 and GSK-3β. Mice engineered to lack GSK-3β die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3 are viable and exhibit improved insulin sensitivity and hepatic glucose homeostasis. To assess the potential role of GSK-3β in insulin function, a conditional gene-targeting approach whereby mice in which expression of GSK-3β was specifically ablated within insulin-sensitive tissues were generated was undertaken. Liver-specific GSK-3β knockout mice are viable and glucose and insulin tolerant and display "normal" metabolic characteristics and insulin signaling. Mice lacking expression of GSK-3β in skeletal muscle are also viable but, in contrast to the liver-deleted animals, display improved glucose tolerance that is coupled with enhanced insulin-stimulated glycogen synthase regulation and glycogen deposition. These data indicate that there are not only distinct roles for GSK-3 and GSK-3β within the adult but also tissue-specific phenotypes associated with each of these isoforms.

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* Corresponding author. Mailing address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Phone: (416) 586-8811. Fax: (416) 586-8839. E-mail: woodgett{at}mshri.on.ca

Published ahead of print on 11 August 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, October 2008, p. 6314-6328, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00763-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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