Tissue plasminogen activator, von Willebrand factor, and risk of type 2 diabetes in older men.
OBJECTIVE
The objective of this study was to assess the relationship between putative markers of endothelial dysfunction (tissue plasminogen activator [t-PA] antigen and von Willebrand factor [vWF] antigen) and development of type 2 diabetes, as well as the role of inflammation, adipokines, hepatic function, and insulin resistance in modifying these relationships.


METHODS
This was a prospective study of 3,562 nondiabetic men aged 60-79 years followed up for an average of 7 years during which there were 162 incident cases of type 2 diabetes.


RESULTS
Elevated t-PA (top third) was associated with a near threefold increase in risk of diabetes compared with the risk in 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(trend) < 0.0001); weaker but significant (marginal) associations were seen with vWF (1.24 [0.83-1.85]; P = 0.05 for trend). Both biomarkers of endothelial dysfunction correlated significantly with markers of inflammation (interleukin-6 [IL-6] and 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 (1.06 [0.71-1.60]), but the relationship seen with t-PA remained significant (adjusted RR 2.19 [1.29-3.70]). Subsequent adjustment for insulin attenuated the association further, but t-PA was still associated with a significant increase in risk (1.66 [0.96-2.85]; P(trend) = 0.02).


CONCLUSIONS
t-PA antigen, but not vWF antigen, is independently associated with risk of type 2 diabetes.
Wannamethee
S Goya
SG
Department of Primary Care and Population Sciences, Royal Free and University College Medical School, Rowland Hill St., London NW3 2PF, UK. goya@pcps.ucl.ac.uk
Sattar
Naveed
N
Rumley
Ann
A
Whincup
Peter H
PH
Lennon
Lucy
L
Lowe
Gordon D O
GD
D000328:Adult; D000368:Aged; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology*; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis; D015850:Interleukin-6 / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D011795:Surveys and Questionnaires; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000097:blood*; D005723:gamma-Glutamyltransferase / Q000097:blood; D014841:von Willebrand Factor / Q000378:metabolism*
D015850:Interleukin-6; D008055:Lipids; D014841:von Willebrand Factor; D005723:gamma-Glutamyltransferase; D010959:Tissue Plasminogen Activator