PHORBOL ESTERS STIMULATE MUSCLE GLUCOSE-TRANSPORT BY A MECHANISM DISTINCT FROM THE INSULIN AND HYPOXIA PATHWAYS

Glucose transport in skeletal muscle can be stimulated by insulin and also by contractions and hypoxia. Activation of protein kinase C (PKC) stimulates glucose transport in muscle and other insulin-responsive c ells. This study was performed to determine if the diacylglycerol (DAG )/phorbol ester-sensitive PKC isoforms participate in insulin and/or h ypoxia-stimulated glucose transport in skeletal muscle. The phorbol es ter 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA) induced a three - to fourfold increase in glucose transport in rat epitrochlearis musc le. The effects of dPPA on glucose transport and on cell surface GLUT- 4 mere completely additive to the maximal effects of insulin or hypoxi a. Phorbol ester treatment induced 5- to 10-fold increases in phosphor ylation of the myristoylated alanine-rich C kinase substrate protein i n muscle, whereas insulin and hypoxia had negligible effects. Calphost in C, an inhibitor of DAG-sensitive PKC isoforms, decreased glucose tr ansport stimulation by dPPA but not by insulin or hypoxia. These resul ts provide evidence that activation of DAG/phorbol ester-sensitive PKC s is not involved in the pathways by which either insulin or hypoxia s timulates muscle glucose transport. They also show that activation of this group of PKCs increases glucose transport by a mechanism that is independent of and additive to the effects of insulin or hypoxia.