Tissue-specific role of glycogen synthase kinase 3β in glucose homeostasis and insulin action

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 alpha and GSK-3 beta. Mice engineered to lack GSK-3 beta die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3 alpha are viable and exhibit improved insulin sensitivity and hepatic glucose homeostasis. To assess the potential role of GSK-3 beta in insulin function, a conditional gene-targeting approach whereby mice in which expression of GSK-3 beta was specifically ablated within insulin-sensitive tissues were generated was undertaken. Liver-specific GSK-3 beta knockout mice are viable and glucose and insulin tolerant and display normal metabolic characteristics and insulin signaling. Mice lacking expression of GSK-3 beta 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 alpha and GSK-3 beta within the adult but also tissue-specific phenotypes associated with each of these isoforms.