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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL047890-04
Application #
2223975
Study Section
Special Emphasis Panel (SRC (SC))
Project Start
1991-09-30
Project End
1995-09-29
Budget Start
1994-08-01
Budget End
1995-09-29
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Lorenzo, Carlos; Hanley, Anthony J; Rewers, Marian J et al. (2015) Lipoprotein heterogeneity may help to detect individuals with insulin resistance. Diabetologia 58:2765-73
Gao, Chuan; Wang, Nan; Guo, Xiuqing et al. (2015) A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS). PLoS One 10:e0134649
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Wessel, Jennifer; Chu, Audrey Y; Willems, Sara M et al. (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun 6:5897
Palmer, Nicholette D; Goodarzi, Mark O; Langefeld, Carl D et al. (2015) Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium. Diabetes 64:1853-66
Goodarzi, Mark O; Langefeld, Carl D; Xiang, Anny H et al. (2014) Insulin sensitivity and insulin clearance are heritable and have strong genetic correlation in Mexican Americans. Obesity (Silver Spring) 22:1157-64
Lorenzo, Carlos; Hanley, Anthony J; Rewers, Marian J et al. (2014) Disproportionately elevated proinsulinemia is observed at modestly elevated glucose levels within the normoglycemic range. Acta Diabetol 51:617-23
Lorenzo, Carlos; Hanley, Anthony J; Rewers, Marian J et al. (2014) Calcium and phosphate concentrations and future development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetologia 57:1366-74

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