This application is based on new data from the applicant's laboratory indicating that the protein kinase IKKb may act to inhibit the insulin signaling pathway. This function is presumably a result of IKKb-mediated phosphorylation of one or more elements in the pathway whereby insulin receptor tyrosine kinase and its substrates are linked to glucose transport. Data presented in the application show decreased phosphorylation of IRS proteins in response to insulin when cells are transfected with IKKb, and also very significant effects of aspirin to reverse decreased IRS phosphorylation due to TNF and protein serine phosphatase inhibitors. Further, the applicant shows data indicating that poor glucose tolerance in insulin resistant mouse models such as ob/ob mice are ameliorated by aspirin treatment, which blocks IKKb. Based on these findings, the applicant proposes to test the hypothesis that the IKK signaling cascade is activated by conditions associated with insulin resistance and that inhibition of IKKb reverses insulin resistance by sensitizing the IR/IRS/ PI 3-kinase signaling cascade.
Specific aims i nclude attempts to determine upstream and downstream elements in the IKK pathway in respect to various models of insulin resistance. The mode of interaction of IKK with the IR/IRS proteins will also be approached. Other experiments will use animal models of insulin resistance to address the pharmacological profile for IKKb inhibition in vivo using various salicylates, and to directly determine the target of salicylate-mediated insulin sensitization. Finally, clinical studies are proposed to determine whether IKKb inhibition reverses insulin resistance in humans with impaired glucose tolerance.
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