The role of vascular endothelial growth factor, tumor necrosis factor alpha and interleukin-6 in pathogenesis of diabetic retinopathy
Introduction
Retinopathy is one of the most significant complications of diabetes mellitus type 1, it occurs in 90% of patients after 20–30 years from the disease diagnosis and its advanced form: proliferative retinopathy affects over 60% of diabetic patients [1]. The data of a large prospective clinical trial Diabetes Control and Complications Trial (DCCT) confirms that correct metabolic compliance of diabetes significantly prevents from development of pathologic changes at the eye fundus and from occurrence of signs of retinopathy [2].
The studies carried out in the recent years point towards a relation between advanced glycation end products (AGEs) and the development of angiopathy, diabetic retinopathy included [3], [4], [5]. Yet the detailed mechanism of the damage to eye structures exercised by AGEs in children with diabetes mellitus type 1 remains unclear. Limited number of studies declare putative role of AGEs in the diabetic retinopathy development by means of increase of vascular endothelial growth factor (VEGF) production [6], [7], [8].
It is assumed that VEGF eases the process of the injure to the blood-retina barrier destructing its imperviousness and stimulates the neovascularisation process in the advanced form of retinopathy [9], [10], [11]. Yet, the presently conducted studies concentrate upon the role of VEGF at the early stage of development of changes in the eye apparatus, when the generally accessed markers of the eye function remain still within the normal range. Additionally, the role of pro-inflammatory cytokines in conjunction with VEGF at the early stage of diabetic retinopathy development remains unsolved.
Our previous studies carried out on a group of children with newly diagnosed diabetes mellitus type 1 [12] and children with long-standing diabetes mellitus type 1 signalize the crucial role of TNF-α [13], [14] and IL-6 [15] in the development of diabetic nephropathy and retinopathy. The mechanisms that trigger the activation of TNF-α in type 1 diabetes are not fully understood, but it is likely that local hypoxia, induced by capillary occlusion, and high levels of advanced glycation end-products, which are associated with the development of diabetic complications, may induce TNF-α activation [16], [17].
The recently published studies have shown that IL-6 may be one of the most important mediators of proliferative retinopathy [18], [19]. Interleukin-6 is synthesized by a variety of cells, including fibroblasts, macrophages, epidermal cells, synovial cells, vascular smooth muscle and vascular endothelium [20]. Within the eye, the sources of IL-6 include the retinal pigment epithelial cells, corneal epithelial cells, keratocytes, iris, and ciliary body [21]. In literature IL-6 is assumed to be an indirect inductor of angiogenesis [22], [23].
In the present work we have attempted to elucidate the relation between metabolic compliance of diabetes, VEGF, pro-inflammatory cytokines TNF-α, IL-6 and the development of diabetic retinopathy in children.
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Subjects and methods
Two hundred and two children (106 girls and 96 boys, age 13.2 ± 3.83 years) with type1 diabetes mellitus were recruited from Outpatient Diabetic Clinics at Medical University of Gdańsk. Type 1 DM, was defined in accordance with the criteria of the American Diabetes Association [24].
The analysis of the eye fundus pictures was based on The International Diabetic Retinopathy Division; and thus three stages were identified: (1) non-proliferative retinopathy with or without maculopathy, (2)
Clinical and biochemical characteristics of the children with diabetes mellitus type 1 in relation to the occurrence of diabetic retinopathy
The children with long-standing diabetes mellitus type 1 and diagnosed to have diabetic retinopathy (group 1, n = 39) were older, were characterized by statistically significant longer duration of the disease, significantly lower age at the diagnosis of diabetes, had statistically significant higher HbA1c, CRP, systolic and diastolic blood pressure in relation to the patients who did not develop diabetic retinopathy (group 2, n = 163). On the other hand, no statistically significant differences
Discussion
In the performed studies we have shown a statistically significant higher level of HbA1c in the group of children with diabetes mellitus type 1 showing symptoms of non-proliferative retinopathy in relation to the patients having no signs of damage to the eye apparatus. It is generally acknowledged that the presence of advanced glycation end-products (AGEs) correlates with the development of late complications of diabetes, diabetic retinopathy included, and that their production is induced by
Conflict of interest statement
The authors declare no conflict of interest.
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