Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus.
BACKGROUND
Endothelial dysfunction occurs in diagnosed type 2 diabetes mellitus but may also precede development of diabetes.


OBJECTIVE
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.


METHODS
Prospective, nested case-control study within the Nurses' Health Study, an ongoing US study initiated in 1976.


METHODS
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.


METHODS
Risk of confirmed clinically diagnosed type 2 diabetes by baseline levels of E-selectin, ICAM-1, and VCAM-1.


RESULTS
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 < or =.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 A(1c) or exclusion of cases diagnosed during the first 4 years of follow-up did not alter these associations.


CONCLUSIONS
Endothelial dysfunction predicts type 2 diabetes in women independent of other known risk factors, including obesity and subclinical inflammation.
Meigs
James B
JB
General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Mass 02114, USA. jmeigs@partners.org
Hu
Frank B
FB
Rifai
Nader
N
Manson
JoAnn E
JE
D000328:Adult; D015415:Biomarkers / Q000097:blood*; D015992:Body Mass Index; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology; D019040:E-Selectin / Q000097:blood; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006306:Health Surveys; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D015415:Biomarkers; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1