Mechanisms of CVD and Endothelial Dysfunction in Obesity

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DESCRIPTION (provided by applicant): Endothelial cell (EC) dysfunction occurs early in the process of insulin resistance and, indeed, may be an integral component of the dysmetabolic syndrome. We hypothesize that adipokines contribute to both insulin resistance and EC dysfunction, possibly by increasing sensitivity to Angiotensin ll (Angll), in part by altering the balance between the activity of the phosphoinositol-3-kinase (Pt3K) and mitogen activated protein kinase (MAPK) pathways. As a result, the progression of insulin resistance to type 2 diabetes parallels the progression of EC dysfunction to atherosclerosis. Specific Aims will be to determine: 1) The relationship of circulating adipokines to EC function in insulin sensitive (IS) vs. insulin resistant (IR) Mexican Americans (MA). The IR MA will include the spectrum of insulin resistance: early IR, IGT, and type 2 diabetes. EC function will be measured by coronary PET scanning. 2) Whether IR subjects have increased sensitivity to AngII infusion vs. age and gender-matched IS subjects as measured by blood pressure, suppression of plasma renin activity, increasing circulating hsCRP and adipokine levels, and stimulation of plasma aldosterone 3) The effect of AnglI AT1 receptor blocker (ARB) administration on insulin-mediated glucose uptake, EC function, and circulating adipokines and inflammatory markers in IR subjects. 4) The correlations of insulin sensitivity and EC function with measurements of inflammatory gene expression, MAPK and PI3K activity in subcutaneous fat biopsies of IS vs. IR subjects and of (IR) subjects before and after treatment with an ARB. 5) The correlation of EC function with insulin sensitivity, circulating adipokines, and fat adipokine expression in the Zucker lean vs. obese rat models. The results of these investigations will help to 1) identify potential mechanisms by which adipokines alter signaling mechanisms and increase sensitivity to Angll to impair EC function and 2) determine the effect of RAS inhibition on adipokine levels and expression as related to insulin-mediated glucose uptake and EC function. These studies potentially have direct clinical applications as they promise to determine where in the spectrum of insulin resistance and EC dysfunction RAS inhibition is warranted to prevent development of the endpoints of diabetes and atherosclerosis. Early intervention is critical if we are to prevent these two major diseases, which may, indeed, be the same disease.