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Protein Kinase C Mediates Insulin-Induced Glucose Transport in Primary Cultures of Rat Skeletal Muscle

Faculty of Life Sciences (L.B., A.A., A.B., T.T., S.R.S.) Gonda-Goldschmied Center Bar-Ilan University Ramat-Gan 52900, Israel
Institute of Molecular Oncology (T.K.) and Department of Microbiology (M.O.) Showa University Tokyo 142-8555, Japan

Insulin activates certain protein kinase C (PKC) isoforms that are involved in insulin-induced glucose transport. In this study, we investigated the possibility that activation of PKC by insulin participates in the mediation of insulin effects on glucose transport in skeletal muscle. Studies were performed on primary cultures of rat skeletal myotubes. The role of PKC in insulin-induced glucose uptake was evaluated both by selective pharmacological blockade and by overexpression of wild-type and point-mutated inactive PKC isoforms in skeletal myotubes. We found that insulin induces tyrosine phosphorylation and translocation of PKC to the plasma membrane and increases the activity of this isoform. Insulin-induced effects on translocation and phosphorylation of PKC were blocked by a low concentration of rottlerin, whereas the effects of insulin on other PKC isoforms were not. This selective blockade of PKC by rottlerin also inhibited insulin-induced translocation of glucose transporter 4 (GLUT4), but not glucose transporter 3 (GLUT3), and significantly reduced the stimulation of glucose uptake by insulin. When overexpressed in skeletal muscle, PKC and PKC were both active. Overexpression of PKC induced the translocation of GLUT4 to the plasma membrane and increased basal glucose uptake to levels attained by insulin. Moreover, insulin did not increase glucose uptake further in cells overexpressing PKC. Overexpression of PKC did not affect basal glucose uptake or GLUT4 location. Stimulation of glucose uptake by insulin in cells overexpressing PKC was similar to that in untransfected cells. Transfection of skeletal myotubes with dominant negative mutant PKC did not alter basal glucose uptake but blocked insulin-induced GLUT4 translocation and glucose transport. These results demonstrate that insulin activates PKC and that activated PKC is a major signaling molecule in insulin-induced glucose transport.

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