Activation of PKC May Cause Insulin Resistance

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Protein kinase C (PKC) can directly phosphorylate and inactivate the insulin receptor.67 Likewise, overexpression of PKC isoforms in cultured cells causes phosphorylation of the insulin receptor and insulin resistance.14,22 These findings led to the hypothesis that PKC causes insulin resistance in skeletal muscle.23 Several groups have reported that PKC activity and protein were increased in muscle of animals with insulin resis-tance.6,29,45,64,93,94 To determine if one of the PKC isoforms is increased in insulin-resistant muscle and causes serine/threonine phosphorylation of the insulin receptor, we measured the protein content of eight PKC isoforms in the membrane fractions of muscles from lean and obese patients. The only PKC isoform that was increased in the membrane of insulin-resistant muscle (obese) was PKCp. Basal PKCp was higher in the in vitro incubated muscle of obese individuals, and insulin increased PKCp in the membrane fraction in muscle of obese, but not lean, patients.53

To demonstrate a cause-and-effect relationship between PKC activity and insulin action, we incubated human-muscle strips in the presence and absence of PKC activators and inhibitors. In insulin-resistant muscle, the PKC inhibitor GF109203X enhanced insulin stimulation of glucose transport. In insulin-sensitive muscle, incubation with the PKC activator dPPA caused insulin-stimulated glucose transport to be depressed.25 These data suggest that a PKC activator can cause insulin resistance and that a PKC inhibitor can reverse insulin resistance.

Other research groups have made observations that also implicate PKC in the development of lipid-induced insulin resistance. Griffen et al.,41 using a rat model, induced insulin resistance with a 5 h lipid/heparin infusion and observed a 50 percent reduction in insulin-stimulated IRS-1-associated PI-3 kinase activity, blunted IRS-1 tyrosine phosphorylation, and a fourfold increase in PKC activity. In humans, Itani et al.52 also employed a lipid/heparin infusion and reported that insulin-stimulated glucose disposal was reduced by 43 percent, and skeletal-muscle diacylglycerol mass and PKC activity were increased fourfold. These findings not only imply that PKC activation causes skeletal-muscle insulin resistance, but also demonstrate an association between lipid accumulation (diacylglycerols) and PKC activation.

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