Glycogen Synthase Kinase 3α-Specific Regulation of Murine Hepatic Glycogen Metabolism

Katrina MacAulay, Bradley W. Doble, Satish Patel, Tanya Hansotia, Elaine M. Sinclair, Daniel J. Drucker, Andras Nagy, James R. Woodgett

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245 Citations (Scopus)


Glycogen synthase kinase 3 comprises two isoforms (GSK-3α and GSK-3β) that are implicated in type II diabetes, neurodegeneration, and cancer. GSK-3 activity is elevated in human and rodent models of diabetes, and various GSK-3 inhibitors improve glucose tolerance and insulin sensitivity in rodent models of obesity and diabetes. Here, we report the generation of mice lacking GSK-3α. Unlike GSK-3β mutants, which die before birth, GSK-3α knockout (GSK-3α KO) animals are viable but display enhanced glucose and insulin sensitivity accompanied by reduced fat mass. Fasted and glucose-stimulated hepatic glycogen content was enhanced in GSK-3α KO mice, whereas muscle glycogen was unaltered. Insulin-stimulated protein kinase B (PKB/Akt) and GSK-3β phosphorylation was higher in GSK-3α KO livers compared to wild-type littermates, and IRS-1 expression was markedly increased. We conclude that GSK-3 isoforms exhibit tissue-specific physiological functions and that GSK-3α KO mice are insulin sensitive, reinforcing the potential of GSK-3 as a therapeutic target for type II diabetes.

Original languageEnglish
Pages (from-to)329-337
Number of pages9
JournalCell Metabolism
Issue number4
Publication statusPublished - 3 Oct 2007
Externally publishedYes



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