Circulating levels of endothelial adhesion molecules and risk of diabetes in an ethnically diverse cohort of women

Abstract

Elevated circulating levels of soluble adhesion molecules as markers of endothelial dysfunction have been related to insulin resistance and its associated metabolic abnormalities. However, their associations with type 2 diabetes remain inconclusive. We conducted a prospective nested case-control study to examine the associations between plasma levels of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) and diabetes risk among 82,069 initially healthy women aged 50-79 years from the Women's Health Initiative Observational Study. During a median follow-up of 5.9 years, 1,584 incident diabetes case subjects were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. Baseline median levels of the biomarkers were each significantly higher among case subjects than among control subjects (E-selectin, 49 vs. 37 ng/ml; ICAM-1, 324 vs. 280 ng/ml; and VCAM-1, 765 vs. 696 ng/ml [all P values <0.001]). After adjustment for risk factors, the relative risks of diabetes among women in the highest quartile versus those in the lowest quartile were 3.46 for E-selectin (95% CI 2.56-4.68; P for trend <0.0001), 2.34 for ICAM-1 (1.75-3.13; P for trend <0.0001), and 1.48 for VCAM-1 (1.07-2.04; P for trend = 0.009). E-selectin and ICAM-1 remain significant in each ethnic group. In conclusion, higher levels of E-selectin and ICAM-1 were consistently associated with increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women, implicating an etiological role of endothelial dysfunction in the pathogenesis of type 2 diabetes.

FIG. 1

Joint effect of CRP and plasma levels of endothelial adhesion molecules in predicting diabetes risk. Levels of CRP have been divided into three categories (<1, 1–3, or >3 mg/l); the distribution of biomarkers, including E-selectin (A), ICAM-1 (B), and VCAM-1 (C), was categorized into tertiles. The adjusted RR of diabetes among women in each category is shown relative to women with CRP<1 mg/l and with biomarker levels in the lowest tertile. The model was adjusted for matching factors, BMI, alcohol intake, level of physical activity, cigarette smoking status, the use or nonuse of postmenopausal hormone therapy, and presence or absence of family history of diabetes.