Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity

This study was conducted to investigate the possible involvement of protein kinase C (PKC) and serine/threonine phosphorylation of the insulin recepto r in insulin resistance and/or obesity, Insulin receptor tyrosine kinase ac tivity was depressed in muscle from obese insulin-resistant patients compar ed with lean insulin-responsive control subjects. Alkaline phosphatase trea tment resulted in a significant 48% increase in in vitro insulin-stimulated receptor tyrosine kinase activity in obese but not lean muscle. To investi gate the involvement of PKC in skeletal muscle insulin resistance and/or ob esity, membrane-associated PKC activity and the protein content of various PKC isoforms were measured in human skeletal muscle from lean, insulin-resp onsive, and obese insulin-resistant patients. Membrane-associated PKC activ ity was not changed; however, PKC-beta protein content, assayed by Western blot analysis, was significantly higher, whereas PKC-theta, -eta, and -mu w ere significantly lower in muscle from obese patients compared with muscle from lean control subjects. Incubation of muscle strips with insulin signif icantly increased membrane-associated PKC activity in muscle from obese but not lean subjects. PKC-delta, -beta, and -theta were translocated from the cytosol to the membrane fraction in response to insulin treatment, These r esults suggest that in skeletal muscle from insulin-resistant obese patient s, insulin receptor tyrosine kinase activity was reduced because of hyperph osphorylation on serine/threonine residues. Membrane-associated PKC-beta pr otein was elevated under basal conditions, and membrane-associated total PK C activity was increased under insulin-stimulated conditions in muscle from obese insulin-resistant patients. Thus, we postulate that the decreased ty rosine kinase activity of the insulin receptor may be caused by serine/thre onine phosphorylation by PKC.