ADAMTS13 activity as a novel risk factor for incident type 2 diabetes mellitus: a population-based cohort study

Paul S De Vries,Eric J G Sijbrands,Oscar H Franco,Thijs T W Van Herpt,M Arfan Ikram,Symen Ligthart,Abbas Dehghan,Frank W G Leebeek,Moniek P M De Maat,Mandy Van Hoek,Albert Hofman

doi:10.1007/s00125-016-4139-5

Abstract

Aims/hypothesisADAMTS13 is a protease that breaks down von Willebrand factor (VWF) multimers into smaller, less active particles. VWF has been associated with an increased risk of incident type 2 diabetes mellitus. Here, we determine whether ADAMTS13 activity and VWF antigen are associated with incident diabetes.MethodsThis study included 5176 participants from the Rotterdam Study, a prospective population-based cohort study. Participants were free of diabetes at baseline and followed up for more than 20 years. Cox proportional hazards models were used to examine the association of ADAMTS13 activity and VWF antigen with incident diabetes.ResultsADAMTS13 activity was associated with an increased risk of incident diabetes (HR 1.17 [95% CI 1.08, 1.27]) after adjustment for known risk factors and VWF antigen levels. Although ADAMTS13 activity was positively associated with fasting glucose and insulin, the association with incident diabetes did not change when we adjusted for these covariates. ADAMTS13 activity was also associated with incident prediabetes (defined on the basis of both fasting and non-fasting blood glucose) after adjustment for known risk factors (HR 1.11 [95% CI 1.03, 1.19]), while the VWF antigen level was not. VWF antigen was associated with incident diabetes, but this association was attenuated after adjustment for known risk factors.Conclusions/interpretationADAMTS13 activity appears to be an independent risk factor for incident prediabetes and type 2 diabetes. As the association between ADAMTS13 and diabetes did not appear to be explained by its cleavage of VWF, ADAMTS13 may have an independent role in the development of diabetes.

Highlights

A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) reduces the activity of von Willebrand factor (VWF) in platelet adhesion and aggregation by cleaving prothrombotic VWF multimers [1, 2]
ADAMTS13 activity was associated with an increased risk of incident diabetes (HR 1.17 [95% CI 1.08, 1.27]) after adjustment for known risk factors and VWF antigen levels
VWF antigen was associated with incident diabetes, but this association was attenuated after adjustment for known risk factors

Summary

Introduction

A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) reduces the activity of von Willebrand factor (VWF) in platelet adhesion and aggregation by cleaving prothrombotic VWF multimers [1, 2]. Elevated levels of VWF have been associated with an increased risk of type 2 diabetes [13,14,15,16,17] which has been attributed primarily to the role of VWF as a marker of endothelial dysfunction rather than to its role in thrombosis [18]. VWF may be associated with diabetes through its prothrombotic effect This would be in line with emerging evidence that vascular disease may contribute to the development of diabetes [19]. Low ADAMTS13 activity and high VWF levels may exacerbate small vessel disease, which in turn may contribute to the development of diabetes [20,21,22]. We previously showed that type 2 diabetes patients have higher ADAMTS13 activity compared with controls [8, 23], which is inconsistent with a mechanism involving VWF’s prothrombotic function

Methods

Results

Conclusion