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.