Defective insulin-induced GLUT4 translocation in skeletal muscle of high fat-fed rats is associated with alterations in both Akt/protein kinase B andatypical protein kinase C (zeta/lambda) activities

The cellular mechanism by which high-fat feeding induces skeletal muscle in sulin resistance was investigated in the present study. Insulin-stimulated glucose transport was impaired (similar to 40-60%) in muscles of high fat-f ed rats. Muscle GLUT4 expression was significantly lower in these animals ( similar to 40%, P < 0.05) but only mi type IIa-enriched muscle. Insulin sti mulated the translocation of GLUT4 to both the plasma membrane and the tran sverse (T)-tubules in chow-fed rats. In marked contrast, GLUT4 translocatio n was completely abrogated in the muscle of insulin-stimulated high fat-fed rats. High-fat feeding markedly decreased insulin receptor substrate (IRS) -1-associated phosphatidylinositol (PI) 3-kinase activity but not insulin-i nduced tyrosine phosphorylation of the insulin receptor and IRS proteins in muscle. Impairment of PI 3-kinase function was associated with defective A kt/protein kinase B kinase activity (similar to 40%, P < 0.01) in insulin-s timulated muscle of high fat-fed rats, despite unaltered phosphorylation (S er473/Thr308) of the enzyme. Interestingly, basal activity of atypical prot ein kinase C (aPKC) was elevated in muscle of high fat-fed rats compared wi th chow-fed controls. Whereas insulin induced a twofold increase in aPKC ki nase activity in the muscle of chow-fed rats, the hormone failed to further increase the kinase activity in high fat-fed rat muscle. In conclusion, it was found that GLUT4 translocation to both the plasma membrane and the T-t ubules is impaired in the muscle of high fat-fed rats. We identified PI 3-k inase as the first step of the insulin signaling pathway to be impaired by high-fat feeding, and this was associated with alterations in both Akt and aPKC kinase activities.