Tissue - specific role of glycogen synthase kinase - 3 β in glucose homeostasis and insulin 1 action 2

23 Dysregulation of the protein kinase, glycogen synthase kinase–3 (GSK-3), has been 24 implicated in the development of Type 2 Diabetes Mellitus. GSK-3 protein expression 25 and kinase activity are elevated in diabetes, while selective GSK-3 inhibitors have shown 26 promise as modulators of glucose metabolism and insulin sensitivity. There are two 27 GSK-3 isoforms in mammals, GSK-3α and GSK-3β. Mice engineered to lack GSK-3β 28 die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3α 29 are viable and exhibit improved insulin-sensitivity and hepatic glucose homeostasis. 30 To assess the potential role of GSK-3β in insulin function, a conditional gene targeting 31 approach was undertaken whereby mice were generated in which expression of GSK-3β 32 was specifically ablated within insulin-sensitive tissues. Liver-specific GSK-3β KO mice 33 are viable, glucose and insulin tolerant and display 'normal' metabolic characteristics and 34 insulin signaling. Mice lacking expression of GSK-3β in skeletal muscle are also viable 35 but in contrast to the liver-deleted animals, display improved glucose tolerance that is 36 coupled to enhanced insulin-stimulated glycogen synthase regulation and glycogen 37 deposition. These data indicate that not only are there distinct roles for GSK-3α and 38 GSK-3β within the adult, but also tissue-specific phenotypes associated with each of 39 these isoforms. 40