The role of glycogen synthase kinase 3 beta in insulin-stimulated glucose metabolism

To characterize the contribution of glycogen synthase kinase 3 beta (GSK3 b eta) inactivation to insulin-stimulated glucose metabolism, wild-type (WT-G SK), catalytically inactive (KM-GSK), and uninhibitable (SSA-GSK) forms of GSK3 beta were expressed in insulin-responsive 3T3-L1 adipocytes using aden ovirus technology, WT-GSK but not KM-GSK, reduced basal and insulin-stimula ted glycogen synthase activity without affecting the -fold stimulation of t he enzyme by insulin. S9A-GSK similarly decreased cellular glycogen synthas e activity, but also partially blocked insulin stimulation of the enzyme. S SA-GSK expression also markedly inhibited insulin stimulation of IRS-1-asso ciated phosphatidylinositol 3-kinase activity, but only weakly inhibited in sulin-stimulated Akt/PKB phosphorylation and glucose uptake, with no effect on GLUT4 translocation, To further evaluate the role of GSK3 beta in insul in signaling, the GSK3 beta inhibitor lithium was used to mimic the consequ ences of insulin-stimulated GSK3 beta inactivation. Although lithium stimul ated the incorporation of glucose into glycogen and glycogen synthase enzym e activity, the inhibitor was without effect on GLUT4 translocation and pp7 0 S6 kinase, Lithium stimulation of glycogen synthesis was insensitive to w ortmannin, which is consistent with its acting directly on GSK3 beta downst ream of phosphatidylinositol 3-kinase. These data support the hypothesis th at GSK3 beta contributes to insulin regulation of glycogen synthesis, but i s not responsible for the increase in glucose transport.