Hyperinsulinemia, hyperglucemia, and impaired hemostasis - The Framingham offspring study

Context Increased risk for cardiovascular disease in persons with glucose i ntolerance (impaired glucose tolerance and type 2 diabetes mellitus) is not fully explained by concomitant elevations in traditional atherosclerosis r isk factors. Hyperinsulinemia associated with glucose intolerance may incre ase risk directly, or its effect could be mediated through impaired hemosta tic function. Objective To evaluate associations between fasting insulin levels and hemos tatic factors in subjects with normal and impaired glucose homeostasis. Design Cross-sectional analysis conducted between January 1991 and June 199 5. Setting The population-based Framingham Offspring Study. Subjects A total of 1331 men and 1631 women aged 26 to 82 years, without di agnosed diabetes or cardiovascular disease and classified as having normal glucose tolerance (80.2%) or glucose intolerance (impaired glucose toleranc e and impaired fasting glucose combined, 15.2%; previously undiagnosed diab etes, 4.7%) using an oral glucose tolerance test. Main Outcome Measures Trends across quintiles of fasting insulin in levels of plasminogen activator inhibitor 1 (PAI-1) antigen, tissue-type plasminog en activator (tPA) antigen, von Willebrand factor (VWF) antigen, factor VII antigen, fibrinogen, and plasma viscosity. We stratified analyses by sex a nd glucose tolerance status and adjusted hemostatic factor levels for obesi ty, lipid levels, and traditional cardiovascular disease risk factors. Results Mean levels of all hemostatic factors (except for fibrinogen in men ) increased across fasting insulin quintiles among subjects with normal glu cose tolerance (P<.001 for trend). Levels of PAI-1 and tPA antigens, but no t other hemostatic factors, were higher comparing subjects with glucose int olerance with those with normal glucose tolerance (P<.001). Among subjects with glucose intolerance, levels of PAI-1 and tPA antigen in men and women (P<.01 for trend) and VWF antigen in men (P<.05 for trend) increased signif icantly across insulin quintiles, but levels of factor VII antigen, fibrino gen, and plasma viscosity did not increase. Conclusions Elevated levels of fasting insulin are associated with impaired fibrinolysis and hypercoagulability in subjects with normal glucose tolera nce. Hyperinsulinemia is associated primarily with impaired fibrinolysis in subjects with glucose intolerance. Excess risk for cardiovascular disease associated with hyperinsulinemia and glucose intolerance may be mediated in part by enhanced potential for acute thrombosis.