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Submitted on January 5, 2005
Revised on January 24, 2006
Accepted on January 27, 2006

Progression of Plasminogen Activator Inhibitor-1 and Fibrinogen Levels in Relation to Incident Type 2 Diabetes

Andreas Festa MD, Ken Williams MS, Russell P. Tracy PhD, Lynne E. Wagenknecht DRPH, and Steven M. Haffner MD^*

From the Department of Medicine, University of Texas Health Science Center, San Antonio, Tex (A.F., K.W., S.M.H.); the Laboratory for Clinical Biochemistry Research, Department of Pathology, University of Vermont College of Medicine, Burlington, Vt (R.P.T.); the Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (L.E.W.); and Eli Lilly & Company, Area Medical Center, Vienna, Austria (A.F.).

^* To whom correspondence should be addressed. E-mail: haffner{at}uthscsa.edu.

Background--Several studies have shown that fibrinolytic and coagulation abnormalities as well as low-grade inflammation predict cardiovascular disease and type 2 diabetes. We studied in the Insulin Resistance Atherosclerosis Study the relation of incident diabetes to dynamic changes of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen.

Methods and Results--After a follow-up of 5.2 years, diabetes developed in 140 (16.6%) of 843 individuals (57% women; mean age [range], 54.7 [40, 69] years) (converters versus nonconverters). Baseline and follow-up levels of PAI-1 and fibrinogen (demographically and smoking adjusted) were higher in converters versus nonconverters (mean [SE]): at baseline, 23.7 ng/mL (1.5) versus 14.5 (0.4) and 286.2 mg/dL (4.8) versus 273.6 (2.1); at follow-up, 45.3 ng/mL (3.2) versus 25.9 (0.8) and 292.0 mg/dL (5.6) versus 275.2 (2.5); all P<0.05. In a demographically and smoking-adjusted logistic regression model, the change in PAI-1 was related to incident diabetes (OR for a 1-SD change [CI], 1.75 [1.37, 2.22]; P<0.001) after adjusting for baseline PAI-1 levels. After further adjusting for insulin sensitivity (S_I) or waist, change in PAI-1 remained significantly related to incident diabetes (OR, 1.66 [1.28, 2.15], and 1.64 [1.28, 2.10]; P<0.001). In contrast, change in fibrinogen was not significantly related to incident diabetes.

Conclusions--Progression of PAI-1 levels over time, in addition to high baseline PAI-1 levels, is associated with incident diabetes. PAI-1 levels (but not fibrinogen) further increase with the rising glucose levels and the development of diabetes. These findings extend the current knowledge on the relation of fibrinolysis and coagulation abnormalities to the development of type 2 diabetes.

Key words: diabetes mellitus • epidemiology • fibrinogen • inflammation • plasminogen activator inhibitor-1

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