Original Research ArticleClinical usefulness of videocapillaroscopy and selected endothelial cell activation markers in people with Type 1 diabetes mellitus complicated by microangiopathy
Introduction
Diabetes mellitus is known to be associated with a number of complications, among which vascular disease is a prominent clinical problem. Although the pathomechanism of diabetic vasculopathy is not completely understood, the key role of vascular endothelium is established [1]. Endothelial dysfunction or injury predisposes people with diabetes to both micro- and macroangiopathy leading to organ damage [2].
Endothelium plays a key role in the development of vascular disease and represents an early stage in the pathogenesis of microangiopathy in the course of diabetes [1], [3]. Damaged or activated endothelial cells are a target and source of various molecules responsible for the control of vascular tone, coagulation cascade and inflammatory processes [4]. All these phenomena could play an important role in the development of diabetes complications as retinopathy, neuropathy and nephropathy [5]. Disturbances in homeostasis of the endothelium increasing vasoconstricting molecules concentrations and secondary hypertension in microcirculation, play a key role in the pathogenesis of microangiopathy. Hyperglycemia leads to disbalance between vasoconstriction and vasodilatatory factors as well as coagulation and fibrinolysis with predominance of coagulation [6].
Thrombomodulin (TM) is a membrane protein expressed on the surface of endothelial cells. It controls balance between coagulation and fibrinolysis [7]. TM inhibits thrombin dependent conversion of fibrinogen to fibrin. Thrombomodulin, can be released from injured endothelial cells, and its soluble form (soluble thrombomodulin, sTM) has been demonstrated to be a specific biomarker of endothelial cell injury [7].
Vascular endothelial growth factor (VEGF) plays an important role in he development of diabetes complications, and its influence on endothelial cells is essential. VEGF is responsible for a series of events leading to vasculogenesis, the process of de novo formation of vessels (during physiological processes), as well as angiogenesis (during pathological conditions) in the body. In pathology, VEGF correlates with clinical activity of rheumatoid arthritis [8], lupus erythematosus [9], diabetes mellitus [10], especially with microvascular complications in the course of diabetes [11]. Hyperglycemia prevalent during diabetes mellitus causes various conditions which result in overexpression of VEGF. VEGF is responsible for initiating neovascularization, thickening of the basal membrane of endothelium, increase of endothelial cells permeability, regulation of inflammatory response and endothelial cells apoptosis.
Endothelin 1 (ET-1) is a peptide produced and secreted by vascular endothelial cells and its role in maintaining vascular tone, integrity and homeostasis is crucial [12], [13], [14].
ET-1 is a potent mitogen which influences on local cellular growth and survival. Concerning its potent mitogenic and vasoconstrictor functions ET-1 can play a major pathogenic role in the development of complications in diabetes. It has been shown that hyperglycemia increases ET-1 and causes vascular damage by altering blood flow, increasing vascular permeability and extracellular matrix protein production [12], [13], [14]. Moreover, our previous study shows an important role of ET-1 in pathogenesis of the microvascular involvement in SLE patients [15]. In vitro endothelin 1 stimulates revascularization, which plays a key role in the pathogenesis of microvascular complications in diabetes [16], [17].
Nailfold videocapillaroscopy (NVC) has been used as a non-invasive and sensitive technique for evaluating microvascular involvement, mainly in connective tissue diseases, including scleroderma-spectrum disorders [17], systemic lupus erythematosus [16], juvenile idiopathic arthritis [18] and other internal diseases [19].
Morphological and functional changes in capillary microscopy have been reported in diabetic patients, mainly in relation to vascular reactivity after induced ischemia [20]. In our previous study, we evaluated the relationship between microvascular abnormalities in capillaroscopy and diabetic microangiopathy in people with Type 1 diabetes mellitus [10]. There has also been found to be a relationship between the severity of microvasculature changes and metabolic control of diabetes [21]. However little data exists on the relationship between microvascular changes in capillaroscopy, disease feature, and endothelial cell activation markers.
The aim of this study was to compare microvascular changes examined by nailfold videocapillaroscopy with serum concentrations of VEGF, sTM and ET-1 in people with Type 1 diabetes with and without clinical signs of microangiopathy.
Section snippets
Patients and methods
The study included 106 people with Type 1 diabetes treated in Clinical Department of Endocrinology, Diabetology and Internal Diseases, Medical University of Bialystok. The study was approved by the Ethics Committee of the Medical University of Bialystok (resolution No. R-I-002/96/2008), and constant was obtained from each patient.
All people with Type 1 diabetes were treated with insulin. The control group consisted of 40 healthy volunteers comparable in terms of age, sex and body mass index
Results
The NVC patterns of 106 people with Type 1 diabetes mellitus and 40 healthy controls were examined in this study (Table 1). All healthy controls showed normal videocapillaroscopic patterns (hairpin capillaries in a parallel arrangement, score = 0). The videocapillaroscopic feature in people with diabetes showed microvascular changes such as avascular areas, microhaemorrhages or irregular loops with decreased density and dilatation of the venous limb (examples of capillaroscopic score 1 and 3
Discussion
Microvascular abnormalities such as nephropathy, neuropathy and retinopathy are the main clinical complications in diabetes determining life quality and survival of patients [5], [6], [23]. The risk associated with microvascular complications is enormous.
Nailfold capillary microscopy is used as a non-invasive, useful method for investigating microvascular abnormalities observed not only in connective tissue diseases [6], [7], [9], [10], but also in other pathological conditions such as
Conclusions
In conclusion, observed trend for elevated serum levels of VEGF, sTM and ET-1 in people with Type 1 diabetes may reflect the early microcirculation disturbances in the course of diabetes mellitus. Measurements of circulating endothelial cell activation markers can be important for improving diagnosis, monitoring and more effective strategies for the treatment of organ dysfunction in diabetic patients. Abnormalities in nailfold videocapillaroscopy may reflect extent of microvascular involvement
Conflict of interest
The authors declare that they have no conflict of interest.
Financial disclosure
None declared.
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