Abstract

Objective To assess the relationship between putative markers of endothelial dysfunction (tissue plasminogen activator antigen, t-PA; and von Willebrand factor antigen, vWF) and development of type 2 diabetes; and the role of inflammation, adipokines, hepatic function and insulin resistance in modifying these relationships.

Research Design and Methods Prospective study of 3562 non-diabetic men aged 60–79 followed up for an average 7 years during which there were 162 incident type 2 diabetes.

Results Elevated t-PA (top third) was associated with a near three-fold increase in risk of diabetes compared to those in the bottom third after adjustment for lifestyle factors and waist circumference (relative risk, RR 2.98; 95%CI, 1.79–5.00; p<0.0001 for trend); weaker but significant (marginal) associations were seen with vWF (RR 1.24; 95%CI, 0.83-1.85; p=0.05 for trend). Both biomarkers of endothelial dysfunction correlated significantly with markers of inflammation (interleukin-6 (IL-6), C-reactive protein (CRP)), hepatic function (gamma-glutamyl transferase (GGT)), and insulin resistance; with t-PA showing stronger associations with adiposity, hepatic function and insulin resistance than vWF. T-PA was also significantly and inversely associated with adiponectin. Adjustment for IL-6, adiponectin and GGT attenuated the association of incident diabetes with vWF (RR 1.06; 95%CI, 0.71–1.60) but the relationship seen with t-PA remained significant [adjusted RR 2.19; 95%CI, 1.29–3.70). Subsequent adjustment for insulin attenuated the association further but t-PA was still associated with a significant increase in risk (adjusted RR 1.66; 95% CI 0.96–2.85); p=0.02 for trend).

Conclusion T-PA antigen, but not vWF antigen, is independently associated with risk of type 2 diabetes.