Protein kinase C modulates insulin action in human skeletal muscle

There is good evidence from cell lines and rodents that elevated protein ki nase C (PKC) overexpression/activity causes insulin resistance. Therefore, the present study determined the effects of PKC activation/inhibition on in sulin-mediated glucose transport in incubated human skeletal muscle and pri mary adipocytes to discern a potential role for PKC in insulin action. Rect us abdominus muscle strips or adipocytes from obese, insulin-resistant, and insulin-sensitive patients were incubated in vitro under basal and insulin (100 nM)-stimulated conditions in the presence of GF 109203X (GF), a PKC i nhibitor, or 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA), a PKC acti vator. PKC inhibition had no effect on basal glucose transport. GF increase d (P < 0.05) insulin-stimulated 2-deoxyglucose (2-DOG) transport approximat ely twofold above basal. GF plus insulin also increased (P < 0.05) insulin receptor tyrosine phosphorylation 48% and phosphatidylinositol 3-kinase (PI 3-kinase) activity similar to 50% (P < 0.05) vs. insulin treatment alone. Similar results for GF on glucose uptake were observed in human primary adi pocytes. Further support for the hypothesis that elevated PKC activity is r elated to insulin resistance comes from the finding that PKC activation by dPPA was associated with a 40% decrease (P < 0.05) in insulin-stimulated 2- DOG transport, incubation of insulin-sensitive muscles with GF also resulte d in enhanced insulin action (similar to 3-fold above basal). These data de monstrate that certain PKC inhibitors augment insulin-mediated glucose upta ke and suggest that PKC may modulate insulin action in human skeletal muscl e.