POTENTIAL ROLE OF PROTEIN-KINASE-B IN INSULIN-INDUCED GLUCOSE-TRANSPORT, GLYCOGEN-SYNTHESIS, AND PROTEIN-SYNTHESIS

Various biological responses stimulated by insulin have been thought t o be regulated by phosphatidylinositol 3-kinase, including glucose tra nsport, glycogen synthesis, and protein synthesis. However, the molecu lar link between phosphatidylinositol 3-kinase and these biological re sponses has been poorly understood. Recently, it has been shown that p rotein kinase B (PKB/c-Akt/Rac) lies immediately downstream from phosp hatidylinositol 3-kinase. Here, we show that expression of a constitut ively active form of PKB induced glucose uptake, glycogen synthesis, a nd protein synthesis in L6 myotubes downstream of phosphatidylinositol 3-kinase and independent of Ras and mitogen-activated protein kinase activation. Introduction of constitutively active PKB induced glucose uptake and protein synthesis but not glycogen synthesis in 3T3L-1 adip ocytes, which lack expression of glycogen synthase kinase 3 different from L6 myotubes. Furthermore, we show that deactivation of glycogen s ynthase kinase 3 and activation of rapamycin-sensitive serine/threonin e kinase by PKB in L6 myotubes might be involved in the enhancement of glycogen synthesis and protein synthesis, respectively. These results suggest that PKB acts as a key enzyme linking phosphatidylinositol 3- kinase activation to multiple biological functions of insulin through regulation of downstream kinases in skeletal muscle, a major target ti ssue of insulin.