The main goal of this project is to characterize insulin's specific actions on the vasculature at physiological conditions, determine how these actions are altered in insulin resistance and diabetic state and how they may relate to the increased development of atherosclerosis. Hypothesis tested is that insulin at physiological conditions is mediating most of its effect through the activation of IRS and PI3- kinase to stimulate glucose metabolism. NO production, vasodilatation, ad inhibit ICAM-1 and PAI- expression induced by other cytokines. These actions of insulin are thought to be antiatherogenic in nature. At higher concentrations of insulin as observed in insulin resistant state, MAP kinase is also activated induce growth and extracellular matrix which can enhance the atherogenic actions of other growth factors. In insulin resistant state, there is a selective resistance to insulin on the vasculature with the IRS-PI 3- kinase pathway but not the MAP kinase pathway. this contrast is due to a differential regulation of IRS protein in mediating insulin's actions. Thus, insulin antiatherogenic actions are diminished due to its resistance of PI 3-kinase and its MAP kinase mediated pathways are enhanced due to the corresponding hyperinsulinemia in insulin resistant state. To test this hypothesis, we will 1) characterize insulin's signal transduction mechanism through the PI 30kinase and the MAP kinase cascade in the vascular cells. Insulin's metabolic and growth promoting activities will be characterized with emphasis on the antiatherogenic actions such as NO production and moderation of vasoactive hormone on ICAM-1 and PAI-1 expression. 2) To determine whether selective insulin resistance is occurring in vivo by using genetic model of insulin resistance. 3) To culture cells from insulin resistant animal and control to determine whether defect in insulin action can be retained in culture. 4) To determine in the vascular stromal tissues from fat of non-insulin resistant, insulin resistant and diabetic patients to determine whether the selective insulin resistance are occurring in clinical settings.
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