Endothelial dysfunction occurs in diagnosed type 2 diabetes mellitus
but may also precede development of diabetes.
To determine whether elevated plasma levels of biomarkers reflecting
endothelial dysfunction (E-selectin; intercellular adhesion molecule 1 [ICAM-1];
and vascular cell adhesion molecule 1 [VCAM-1]) predict development of type
2 diabetes in initially nondiabetic women.
Design and Setting
Prospective, nested case-control study within the Nurses' Health Study,
an ongoing US study initiated in 1976.
Of 121 700 women initially enrolled, 32 826 provided blood
samples in 1989-1990; of those free of diabetes, cardiovascular disease, or
cancer at baseline, 737 developed incident diabetes by 2000. Controls (n =
785) were selected according to matched age, fasting status, and race.
Main Outcome Measure
Risk of confirmed clinically diagnosed type 2 diabetes by baseline levels
of E-selectin, ICAM-1, and VCAM-1.
Baseline median levels of the biomarkers were significantly higher among
cases than among controls (E-selectin, 61.2 vs 45.4 ng/mL; ICAM-1, 264.9 vs
247.0 ng/mL; VCAM-1, 545.4 vs 526.0 ng/mL [all P values
≤.004]). Elevated E-selectin and ICAM-1 levels predicted incident diabetes
in logistic regression models conditioned on matching criteria and adjusted
for body mass index (BMI), family history of diabetes, smoking, diet score,
alcohol intake, activity index, and postmenopausal hormone use. The adjusted
relative risks for incident diabetes in the top quintile vs the bottom quintiles
were 5.43 for E-selectin (95% confidence interval [CI], 3.47-8.50), 3.56 for
ICAM-1 (95% CI, 2.28-5.58), and 1.12 for VCAM-1 (95% CI, 0.76-1.66). Adjustment
for waist circumference instead of BMI or further adjustment for baseline
levels of C-reactive protein, fasting insulin, and hemoglobin A1c or
exclusion of cases diagnosed during the first 4 years of follow-up did not
alter these associations.
Endothelial dysfunction predicts type 2 diabetes in women independent
of other known risk factors, including obesity and subclinical inflammation.