INSULIN INSULIN RESISTANCE HYPERGLYCEMIA AND CARDIOVASCU

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Noninsulin dependent diabetes mellitus is associated with increased risk for coronary artery peripheral vascular and cerebrovascular disease (CVD). This could be attributed to metabolic derangements typical of diabetes, disorders of platelet function and coagulation mechanisms, and hypertension. However, the major part of excess risk of CVD in NIDDM cannot be attributed to diabetes per se, because the risk precedes NIDDM, and is uncorrelated with the degree of hyperglycemia. Because insulin resistance is a major cause of NIDDM and appears to precede overt diabetes, it is hypothesized that insulin resistance, per se, and/or the hyperinsulinemia which characterizes resistance without full blown diabetes may be the factor(s) which are responsible for CVD in individuals at risk for NIDDM. This application is for a Central Laboratory Facility, and is responsive to an NIH Request for Cooperative Agreement (RFA NIH-91-HL-03-P). It is submitted in cooperation with a Field Center Application also submitted from the University of Southern California (M. Saad, P.I.). In this application, we propose to make a series of measurements which will establish the degree of insulin resistance as well as cardiovascular risk factors in a group of 1600 subjects to be tested in specific field centers. In this application we propose the formation of two cores: an Assay Core, to carry out a series of biochemical measurements, and a Kinetic Analysis Core, to calculate insulin sensitivity (SI) and glucose effectiveness (SG) from the assay results. This laboratory conceived, validated and developed the minimal model approach which is proposed to be used to assess insulin sensitivity (i.e., resistance). Assays will be performed in 4 laboratories at USC: Bergman (insulin, glucose, C-peptide), Meiselman (blood and plasma viscosity, red blood cell aggregation, zeta sedimentation ratio, and hematological indices), Francis (Fibrinogen, factor VIIc, plasminogen activator inhibitor a, prothrombin factor F1.2, and fibrin D-dimer fragment). In addition, lipoprotein risk factors for CVD will be measured off-site by Dr. Barbara Howard and Dr. Linda Curtiss. Additionally, we propose a Kinetic Analysis Core, which will calculate SI and SG from our assay results. Minimal model calculations will additionally be compared to the same parameters calculated by different software. Results of these determinations will be transferred electronically to a Coordinating Center for analysis. It is believed that this combined Assay/Kinetic Analysis facility will provide an efficient, accurate and precise assessment of insulin resistance in different subject groups, and as such will yield an accurate assessment of the importance of insulin resistance and hyperinsulinemia in the development of cardiovascular disease.