MOLECULAR PHARMACOLOGY OF INSULIN RESISTANCE IN BURNS

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Burn injury is associated with uncontrolled catabolism of proteins, fats, and carbohydrates affecting morbidity and mortality. Under physiological conditions, insulin enhances glucose uptake and retards protein catabolism. This pivotal action of insulin is desensitized following burns. This proposal aims to (1) investigate the molecular mechanism of burn-induced insulin resistance and (2) define the therapeutic role of a closely-related peptide, insulin-like growth factor-1 (IGF-1). (1) Beta-adrenoceptor (betaAR) signaling system is desensitized in myocardial and adipose tissues after burns. Recently, a definitive link between defective betaAR signaling and insulin resistance has been established by genetic analyses. Furthermore, TNF, whose release and function are controlled by betaAR, induces insulin resistance. The hypothesis being tested is, that insulin resistance of burns is related to desensitization of betaAR signaling and to enhanced expression and effects of TNF. Lipolysis in vitro and 2-Deoxy -glucose uptake in vivo combined with biochemical assays of betaAR/G-protein/adenylate cyclase/protein kinase A systems and of insulin receptor/insulin receptor substrate- 1/phosphatidylinositol 3-kinase systems will investigate the betaAR and insulin signaling in adipocytes and muscles of burned rats. TNF expression will also be analyzed in those tissues. The link between betaAR and insulin function will be tested by administration of specific beta2AR agonist, clenbuterol, and examining in vivo glucose uptake in muscle (and adipocyte). The association between TNF and insulin function will be tested in vivo, by glucose uptake in the presence and absence of anti-TNF antibodies. (2) IGF-1 has been shown to facilitate intracellular signaling of insulin and improve insulin resistance in many pathological states. IGF-1, administered to burned patients, results in enhanced wound healing and shorter hospital stay. The molecular mechanisms of these actions in burns are unclear. The hypothesis that beneficial effects of IGF-1 are mediated through IGF-1R which enhances signaling via post insulin receptor transducing molecules will be tested in adipocytes and muscle, using the same techniques and assays described above for assessment of insulin actions. These studies will contribute to the fundamental knowledge of the molecular pharmacological bases of burn-induced insulin resistance and provide insights and rationale for therapeutic manipulation of insulin resistance.