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The Framingham Offspring Study

James B. Meigs, MD, MPH; Murray A. Mittleman, MDCM, DrPH; David M. Nathan, MD; Geoffrey H. Tofler, MD; Daniel E. Singer, MD; Patricia M. Murphy-Sheehy, MPH; Izabela Lipinska, PhD; Ralph B. D'Agostino, PhD; Peter W. F. Wilson, MD

JAMA. 2000;283:221-228.

Context  Increased risk for cardiovascular disease in persons with glucose intolerance (impaired glucose tolerance and type 2 diabetes mellitus) is not fully explained by concomitant elevations in traditional atherosclerosis risk factors. Hyperinsulinemia associated with glucose intolerance may increase risk directly, or its effect could be mediated through impaired hemostatic function.

Objective  To evaluate associations between fasting insulin levels and hemostatic factors in subjects with normal and impaired glucose homeostasis.

Design  Cross-sectional analysis conducted between January 1991 and June 1995.

Setting  The population-based Framingham Offspring Study.

Subjects  A total of 1331 men and 1631 women aged 26 to 82 years, without diagnosed diabetes or cardiovascular disease and classified as having normal glucose tolerance (80.2%) or glucose intolerance (impaired glucose tolerance and impaired fasting glucose combined, 15.2%; previously undiagnosed diabetes, 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 plasminogen activator (tPA) antigen, von Willebrand factor (vWF) antigen, factor VII antigen, fibrinogen, and plasma viscosity. We stratified analyses by sex and glucose tolerance status and adjusted hemostatic factor levels for obesity, 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 glucose tolerance (P<.001 for trend). Levels of PAI-1 and tPA antigens, but not other hemostatic factors, were higher comparing subjects with glucose intolerance 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 significantly across insulin quintiles, but levels of factor VII antigen, fibrinogen, and plasma viscosity did not increase.

Conclusions  Elevated levels of fasting insulin are associated with impaired fibrinolysis and hypercoagulability in subjects with normal glucose tolerance. 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.

Author Affiliations: General Medicine Division and Department of Medicine (Drs Meigs and Singer and Ms Murphy-Sheehy) and the Diabetes Unit and Department of Medicine (Dr Nathan), Massachusetts General Hospital and Harvard Medical School, Institute for Prevention of Cardiovascular Disease, Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School (Drs Mittleman, Tofler, and Lipinska), and the Department of Mathematics, Statistics, and Consulting Unit (Dr D'Agostino) and School of Medicine (Dr Wilson), Boston University, Boston, Mass; and the Framingham Heart Study, Framingham, Mass (Dr Wilson).

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