Tissue-Specific Role of Glycogen Synthase Kinase 3β in Glucose Homeostasis and Insulin Action Academic Article uri icon

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  • ABSTRACT 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-3α and GSK-3β. Mice engineered to lack GSK-3β die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3α 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-3α and GSK-3β within the adult but also tissue-specific phenotypes associated with each of these isoforms.


  • Patel, Satish
  • Doble, Bradley
  • MacAulay, Katrina
  • Sinclair, Elaine M
  • Drucker, Daniel J
  • Woodgett, James R

publication date

  • October 15, 2008

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