Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study.
Endothelial dysfunction may precede development of type 2 diabetes. We tested the hypothesis that elevated levels of hemostatic markers of endothelial dysfunction, plasminogen activator inhibitor-1 (PAI-1) antigen, and von Willebrand factor (vWF) antigen predicted incident diabetes independent of other diabetes risk factors. We followed 2,924 Framingham Offspring subjects (54% women, mean age 54 years) without diabetes at baseline (defined by treatment, fasting plasma glucose > or =7 or 2-h postchallenge glucose > or =11.1 mmol/l) over 7 years for new cases of diabetes (treatment or fasting plasma glucose > or =7.0 mmol/l). We used a series of regression models to estimate relative risks for diabetes per interquartile range (IQR) increase in PAI-1 (IQR 16.8 ng/ml) and vWF (IQR 66.8% of control) conditioned on baseline characteristics. Over follow-up, there were 153 new cases of diabetes. Age- and sex-adjusted relative risks of diabetes were 1.55 per IQR for PAI-1 (95% CI 1.41-1.70) and 1.49 for vWF (1.21-1.85). These effects remained after further adjustment for diabetes risk factors (including physical activity; HDL cholesterol, triglyceride, and blood pressure levels; smoking; parental history of diabetes; use of alcohol, nonsteroidal anti-inflammatory drugs, exogenous estrogen, or hypertension therapy; and impaired glucose tolerance), waist circumference, homeostasis model assessment of insulin resistance, and inflammation (assessed by levels of C-reactive protein): the adjusted relative risks were 1.18 per IQR for PAI-1 (1.01-1.37) and 1.39 for vWF (1.09-1.77). We conclude that in this community-based sample, plasma markers of endothelial dysfunction increased risk of incident diabetes independent of other diabetes risk factors including obesity, insulin resistance, and inflammation.
Meigs
James B
JB
General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, USA. jmeigs@partners.org
O'donnell
Christopher J
CJ
Tofler
Geoffrey H
GH
Benjamin
Emelia J
EJ
Fox
Caroline S
CS
Lipinska
Izabela
I
Nathan
David M
DM
Sullivan
Lisa M
LM
D'Agostino
Ralph B
RB
Wilson
Peter W F
PW
D000328:Adult; D015415:Biomarkers / Q000032:analysis; D002097:C-Reactive Protein / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006487:Hemostasis; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance; D008297:Male; D008404:Massachusetts; D008875:Middle Aged; D009765:Obesity; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012307:Risk Factors; D014841:von Willebrand Factor / Q000378:metabolism
D015415:Biomarkers; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D014841:von Willebrand Factor; D002097:C-Reactive Protein