title: Signs of dysregulated fibrinolysis precede the development of type 2 diabetes mellitus in a population-based study.
abstract: BACKGROUND
  Diabetic patients experience stimulated coagulation and dysfibrinolysis, which is associated with an increased risk of cardiovascular events. This imbalance may precede the manifest diagnosis. We investigated whether elevated antigen levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), the tPA/PAI-1 complex, or von Willebrand Factor (VWF) precede type 2 diabetes mellitus (T2DM) diagnosis, and whether this elevation occurs before increased fasting plasma glucose (FPG) or 2-hour plasma glucose (2hPG) in individuals who later develop T2DM.
  
  
  METHODS
  We conducted a prospective incident case-referent study within the Västerbotten Intervention Programme. Cardiovascular risk factor data as well as FPG and 2hPG and blood samples for future research were collected at a baseline health examination between 1989 and 2000, (n= 28 736). During follow-up in January 2001, 157 cases had developed T2DM. Referents without T2DM were matched for sex, age, and year of participation (n=277). Subgroup analysis was performed for cases with normal baseline glucose levels (FPG <6.1 mmol/L and 2hPG < 8.9 mmol/L) and cases with elevated levels (FPG 6.1-6.9 mmol/L and/or 2hPG 8.9-12.1 mmol/L).
  
  
  RESULTS
  After adjusting for BMI, family history of diabetes, physical activity, smoking, systolic blood pressure and levels of C-reactive protein and triglycerides, independent associations were found between incident T2DM and elevated levels of tPA (OR=1.54, 95% CI 1.06-2.23), PAI-1 (OR=1.61, 95% CI 1.14-2.28), and tPA/PAI-1 complex (OR=2.45, 95% CI 1.56-3.84). In participants with normal glucose levels, PAI-1 (OR=2.06, 95% CI 1.10 - 3.86) exhibited an independent relationship with incident T2DM after the adjustments.
  
  
  CONCLUSIONS
  Elevated levels of fibrinolytic variables precede the manifestation of T2DM after adjusting for metabolic and cardiovascular risk factors and can be detected several years before changes in glucose tolerance.
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden. jenny.hernestal-boman@medicin.umu.se
authors.forename: Jenny
authors.initials: J
authors.lastname: Hernestål-Boman
authors.forename: Margareta
authors.initials: M
authors.lastname: Norberg
authors.forename: Jan-Hakan
authors.initials: JH
authors.lastname: Jansson
authors.forename: Mats
authors.initials: M
authors.lastname: Eliasson
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
authors.forename: Bernt
authors.initials: B
authors.lastname: Lindahl
authors.forename: Lars
authors.initials: L
authors.lastname: Johansson
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D018450:Disease Progression; D042241:Early Diagnosis; D005215:Fasting / Q000097:blood; D005260:Female; D005342:Fibrinolysis; D006801:Humans; D015994:Incidence; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000097:blood; D015854:Up-Regulation; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D014841:von Willebrand Factor; D010959:Tissue Plasminogen Activator