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Signs of dysregulated fibrinolysis precede the development of type 2 diabetes mellitus in a population-based study
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. (Arcum)ORCID iD: 0000-0003-2475-7131
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Medicine, Sunderby Hospital, Luleå, Sweden. (Arcum)
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2012 (English)In: Cardiovascular Diabetology, ISSN 1475-2840, E-ISSN 1475-2840, Vol. 11, 152- p.Article in journal (Refereed) Published
Abstract [en]

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 Vasterbotten 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.

Place, publisher, year, edition, pages
BioMed Central, 2012. Vol. 11, 152- p.
Keyword [en]
Diabetes mellitus type 2, Tissue plasminogen activator, Plasminogen activator inhibitor-1, Von Willebrand factor, Fibrinolysis, Population study, Vasterbotten Intervention Programme
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-64956DOI: 10.1186/1475-2840-11-152ISI: 000313126800001OAI: oai:DiVA.org:umu-64956DiVA: diva2:609762
Available from: 2013-03-07 Created: 2013-02-04 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Fibrinolytic factors in relation to anthropometry and incident type 2 diabetes.
Open this publication in new window or tab >>Fibrinolytic factors in relation to anthropometry and incident type 2 diabetes.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Fibrinolysfaktorer i relation till antropometri och incident typ 2 diabetes.
Abstract [en]

Fibrinolytic imbalance is associated with cardiovascular disease and its risk factors. The longitudinal changes in the fibrinolytic factors tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and tPA/PAI-1 complex have been inadequately studied in the general population and in relation to incident type 2 diabetes mellitus (T2DM). The measurements, questionnaires and blood samples prospectively collected in the World Health Organisation-project MONItoring trends and determinants in CArdiovascular disease (MONICA) and in the Västerbotten Intervention Programme (VIP) enable such studies. The samples have been stored since 1985, at the Northern Sweden Medical Research Biobank. However, it is unknown how these factors are affected by long-term storage.

The aims of this thesis were to evaluate the effects of long-term storage on fibrinolytic factors, and to determine how these factors are related to incident T2DM, how these factors change over time and how these factors are related to changes in anthropometric measurements.

Storage time was shown to have a negligible impact on plasma antigen levels of fibrinolytic factors. After adjustments for traditional diabetic and cardiovascular risk markers the fibrinolytic factors tPA, PAI-1 and tPA/PAI-1 complex were associated with incident T2DM. PAI-1 was associated with incident T2DM in subjects with normal fasting and 2-hour plasma glucose levels. In MONICA-Västerbotten, tPA, PAI-1 and tPA/PAI-1 complex increased over 9 years in both men and women. PAI-1 appears to interact in a complex manner with anthropometric, inflammatory, glycaemic and lipidemic measurements, but the pattern of components correlating with the changes in PAI-1 differed markedly between the sexes.

In conclusion, PAI-1 is a potential risk marker of incident T2DM. PAI-1 increased markedly over nine years, but the pathophysiological background to these findings needs to be further investigated, separately for each sex.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. 81 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1626
National Category
Endocrinology and Diabetes Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Public health; Medicine, cardiovascular disease
Identifiers
urn:nbn:se:umu:diva-86360 (URN)978-91-7459-796-7 (ISBN)
Public defence
2014-03-21, Forumsalen, Campus, Skellefteå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2014-02-28 Created: 2014-02-24 Last updated: 2014-03-17Bibliographically approved

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Hernestål-Boman, JennyNorberg, MargaretaJansson, Jan-HåkanEliasson, MatsLindahl, BerntJohansson, Lars

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