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

To characterize the contribution of glycogen synthase kinase 3 beta (GSK3 beta) inactivation to insulin-stimulated glucose metabolism, wild-type (WT-GSK), catalytically inactive (KM-GSK), and uninhibitable (SSA-GSK) forms of GSK3 beta were expressed in insulin-responsive 3T3-L1 adipocytes using adenovirus technology, WT-GSK but not KM-GSK, reduced basal and insulin-stimulated glycogen synthase activity without affecting the -fold stimulation of the enzyme by insulin. S9A-GSK similarly decreased cellular glycogen synthase activity, but also partially blocked insulin stimulation of the enzyme. SSA-GSK expression also markedly inhibited insulin stimulation of IRS-1-associated phosphatidylinositol 3-kinase activity, but only weakly inhibited insulin-stimulated Akt/PKB phosphorylation and glucose uptake, with no effect on GLUT4 translocation, To further evaluate the role of GSK3 beta in insulin signaling, the GSK3 beta inhibitor lithium was used to mimic the consequences of insulin-stimulated GSK3 beta inactivation. Although lithium stimulated the incorporation of glucose into glycogen and glycogen synthase enzyme activity, the inhibitor was without effect on GLUT4 translocation and pp70 S6 kinase, Lithium stimulation of glycogen synthesis was insensitive to wortmannin, which is consistent with its acting directly on GSK3 beta downstream of phosphatidylinositol 3-kinase. These data support the hypothesis that GSK3 beta contributes to insulin regulation of glycogen synthesis, but is not responsible for the increase in glucose transport.