THE EFFECTS OF WORTMANNIN, A POTENT INHIBITOR OF PHOSPHATIDYL-INOSITOL 3-KINASE, ON INSULIN-STIMULATED GLUCOSE-TRANSPORT, GLUT4 TRANSLOCATION, ANTILIPOLYSIS, AND DNA-SYNTHESIS

PI 3-kinase, an enzyme that selectively phosphorylates the 3-position of the inositol ring, is acutely activated by insulin and other growth factors. The physiological significance of PI 3-kinase activation and, more specifically, its role in insulin action is an area under intense investigation. In this study, we have examined the role of PI 3-kinase activation in mediating selected metabolic and mitogenic effects of insulin employing the fungal metabolite wortmannin, a potent inhibitor of PI 3-kinase activity. In isolated rat and cultured 3T3-L1 adipocytes, wortmannin inhibited insulin-stimulated glucose transport (IC50 = 9 nM) without a significant effect on basal transport. Insulin-stimulated translocation of GLUT4 in isolated rat adipocytes was markedly inhibited by wortmannin. Wortmannin had no effect on either basal or insulin-stimulated glucose utilization in L6 myocytes, a skeletal muscle cell line in which GLUT1 is the predominant transporter isoform. Wortmannin also partially antagonized the antilipolytic effect of insulin on adenosine deaminase-stimulated lipolysis in isolated rat adipocytes. Furthermore, wortmannin caused a significant reduction in insulin-stimulated DNA synthesis in Fao rat hepatoma cells. We conclude that PI 3-kinase activation is necessary for maximum insulin-stimulated glucose transport, translocation of GLUT4, antilipolysis and DNA synthesis.