Rosiglitazone, insulin treatment, and fasting correct defective activationof protein kinase C-zeta/lambda by insulin in vastus lateralis muscles andadipocytes of diabetic rats

Atypical protein kinases C (PKCs), sigma and lambda, and protein kinase B(P KB) are thought to function downstream of phosphatidylinositol 8-kinase (PI 3-kinase) and regulate glucose transport during insulin action in skeletal muscle and adipocytes. Insulin-stimulated glucose transport is defective i n type II diabetes mellitus, and this defect is ameliorated by thiazolidine diones and lowering of blood glucose by chronic insulin therapy or short-te rm fasting. Presently, we evaluated the effects of these insulin-sensitizin g modalities on the activation of insulin receptor substrate-1 (IRS-1)-depe ndent PI 3-kinase, PKC-sigma/lambda, and PKB in vastus lateralis skeletal m uscles and adipocytes of nondiabetic and Goto-Kakizaki (GK) diabetic rats. Insulin provoked rapid increases in the activity of PI 3-kinase, PKC-sigma/ lambda, and PKB in muscles and adipocytes of nondiabetic rats, but increase s in IRS-l-dependent PI 3-kinase and PKC-sigma/lambda, but not PKB, activit y were substantially diminished in GK muscles and adipocytes. Rosiglitazone treatment for 10-14 days, 10-day insulin treatment, and 60-h fasting rever sed defects in PKC-Uh activation in GK muscles and adipocytes and increased glucose transport in GK adipocytes, without necessarily increasing IRS-1-d ependent PI 8-kinase or PKB activation. Our findings suggest that insulin-s ensitizing modalities, viz. thiazolidinediones, chronic insulin treatment, and short-term fasting, similarly improve defects in insulin-stimulated glu cose transport at least partly by correcting defects in insulin-induced act ivation of PKC-sigma/lambda.