Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: the EURODIAB Prospective Complications Study

Stijn A Peeters,Casper G Schalkwijk,Coen D Stehouwer,Jacqueline Buijs,John H Fuller,Lian Engelen,Nish Chaturvedi

doi:10.1186/s12933-015-0195-2

Abstract

BackgroundImpaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, −2, −3, −9, −10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED).Methods493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, −2, −3, −9, −10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED.ResultsPatients with CVD (n = 118) showed significantly higher levels of TIMP-1 [β = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED.ConclusionsThese data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0195-2) contains supplementary material, which is available to authorized users.

Highlights

Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes
In type 1 diabetes, hyperglycaemia, low-grade inflammation (LGI) and endothelial dysfunction (ED) have been found to be associated with higher plasma and tissue levels of MMPs and TIMP [5,9,12], and LGI and ED are consistently associated with macro- and microvascular complications [13,14,15]. In view of these considerations, we hypothesized that high plasma levels of MMPs and TIMP are related to macro- and microvascular complications in individuals with type 1 diabetes, possibly through associations with LGI and ED. We investigated these hypotheses in a cross-sectional study of patients with type 1 diabetes, in whom we assessed macro- and microvascular disease and measured plasma levels of MMP-1, −2, −3, −9, −10 and TIMP-1, as well as biomarkers of LGI and ED
Levels of HbA1c, LDL, triglycerides, MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, TIMP-1 and markers of LGI and ED were significantly higher in individuals with vascular complications compared to those without

Summary

Introduction

Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. The exact mechanisms leading to vascular damage in type 1 diabetes have not been fully established [3], but impaired regulation of extracellular matrix (ECM) remodeling by matrix metalloproteinases (MMPs) may contribute to the development of vascular complications [4,5]. More than 20 different MMPs have been identified, which, according to their various functions, can be divided into collagenases (e.g. MMP-1), gelatinases (MMP-2 and MMP-9), stromelysines (e.g. MMP-3 and MMP-10), matrilysines, and others These enzymes can be excreted by various cells (e.g. fibroblasts, endothelial cells, monocytes and macrophages) or can be incorporated in the cellular membrane. Tissue inhibitors of metalloproteinases (TIMP-1-4) and α2-macroglobulin inhibit the action of MMPs [6]

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