Role of translocation of PKCζ in the development of insulin resistance and type 2 diabetes in a rat model using continuous glucose infusion

Abstract

The molecular mechanisms of hyperglycemia‐induced insulin resistance and diabetes were investigated in rats receiving a continuous glucose‐infusion. Rats accommodated systemic glucose oversupply and developed insulin resistance on day five and diabetes on day 15. In the insulin resistant rats, protein and basal activity of phosphatidylinositol (PI) 3‐kinase and protein kinase B (PKB) in skeletal muscle were unchanged, whereas insulin‐induced PI 3‐kinase and PKB/Akt activity were impaired compared with controls. The effect of glucose‐infusion on protein kinase Cζ (PKCζ) activity was independent of changes in PI 3‐kinase activity. Activated PKCζ was mainly located in the cytosol of muscle after five days of glucose‐infusion and contributed to translocation of GLUT4 to plasma membrane (PM), which maintained normoglycemia. After 15 days of glucose‐infusion, PKCζ moved from cytosol to PM. This led to an increase in the association between PKCζ and PKB and a decrease in PDK1‐PKB reactions in the PM, which inhibited PKB activity. The activity of PKCζ per se was also compromised. The reduced activity of PKCζ and PKB resulted in blunted translocation of GLUT4, which eventually led to hyperglycemia and diabetes. Thus, translocation of PKCζ may play a central role in the development of insulin resistance and diabetes.