Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study.
BACKGROUND
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.


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


METHODS
The population-based Framingham Offspring Study.


METHODS
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.


METHODS
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.
Meigs
J B
JB
General Medicine Division and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Institute for Prevention of Cardiovascular Disease, Boston 02114, USA. jmeigs@partners.org
Mittleman
M A
MA
Nathan
D M
DM
Tofler
G H
GH
Singer
D E
DE
Murphy-Sheehy
P M
PM
Lipinska
I
I
D'Agostino
R B
RB
Wilson
P W
PW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001779:Blood Coagulation Factors / Q000378:metabolism*; D001786:Blood Glucose; D001809:Blood Viscosity; D002318:Cardiovascular Diseases / Q000097:blood; D003430:Cross-Sectional Studies; D005215:Fasting; D005260:Female; D005342:Fibrinolysis; D018149:Glucose Intolerance / Q000503:physiopathology; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D006946:Hyperinsulinism / Q000503:physiopathology*; D007333:Insulin Resistance; D016014:Linear Models; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity; D012307:Risk Factors
D001779:Blood Coagulation Factors; D001786:Blood Glucose; D008074:Lipoproteins