ANALYSIS OF THERMAL INJURY-INDUCED INSULIN-RESISTANCE IN RODENTS - IMPLICATION OF POSTRECEPTOR MECHANISMS

Burn injury is associated with insulin resistance. The molecular basis of this resistance was investigated by examining insulin receptor sig naling in rats after thermal injury. The impaired insulin-stimulated t ransport of [H-3]2-deoxyglucose into soleus muscle strips confirmed th e insulin resistance following burns. In vivo insulin-stimulated phosp hoinositide 3-kinase activity, pivotal, in translocation of GLUT4, was decreased in burns when assessed by its insulin receptor substrate-1 (IRS-1)-associated activity. Insulin-induced tyrosine kinase activity of insulin receptor (IR) and tyrosine phosphorylation of IRS-I were al so attenuated, Immunoprecipitated IR, however, appeared to have normal insulin-responsive kinase activity. Finally, immunoprecipitated IRS-I was tested for its effect on partially purified recombinant IR and wa s found to inhibit its kinase activity. This inhibitory effect of IRS- 1 was abolished by prior treatment of IRS-1 with alkaline phosphatase, indicating that burn injury-related hyperphosphorylation of IRS-1 is similar to that observed in TNF alpha-induced inhibition of LR signali ng All of these changes were observed in the absence of quantitative c hanges in IR, IRS-1, and phosphoinositide 3-kinase. Alterations in pos treceptor insulin signaling, therefore, may be responsible for the ins ulin resistance after thermal injury.