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Open Access Highly Accessed Original investigation

Signs of dysregulated fibrinolysis precede the development of type 2 diabetes mellitus in a population-based study

Jenny Hernestål-Boman1*, Margareta Norberg1, Jan-Hakan Jansson1, Mats Eliasson12, Jan W Eriksson3, Bernt Lindahl1 and Lars Johansson1

Author Affiliations

1 Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

2 Department of Medicine, Sunderby Hospital, Luleå, Sweden

3 Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg and AstraZeneca R&D, Mölndal, Sweden

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Cardiovascular Diabetology 2012, 11:152  doi:10.1186/1475-2840-11-152

Published: 18 December 2012

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.

Keywords:
Diabetes mellitus type 2; Tissue plasminogen activator; Plasminogen activator inhibitor-1; Von Willebrand factor; Fibrinolysis; Population study; Västerbotten Intervention Programme