Abstract
Long-term complications of type 1 diabetes mellitus (T1DM) in children and adolescents are an important problem in modern medicine. Recently, the role of immune mechanisms, in particular, chronic inflammation, in the development of both T1DM and its microvascular complications has been actively discussed. Activation of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) leads to hyperproduction of proinflammatory cytokines, chemokines, adhesion molecules involved in the formation of diabetic microvascular complications. At the same time, TLR2 and TLR4 gene polymorphism alters the immune susceptibility to the endogenous ligands, which may increase the risk of diabetic microangiopathies. The aim of this study is to evaluate the frequency of genotypes and alleles of TLR2 and TLR4 genes distribution and to determine the content of TNFα, IL-1, VCAM-1, fractalkine, endothelin-1 in adolescents with T1DM with microvascular complications. We examined 139 adolescents with T1DM from 14 to 18 years old and 56 healthy teenagers. Patients with T1DM were divided into two groups: Group I – patients with poor glycemic control (HbA1C > 9.0%), (n = 64); Group II – patients with satisfactory glycemic control of T1DM (HbA1C ≤ 9.0%), (n = 75), including adolescents with optimal (HbA1C < 7.5%) and suboptimal glycemic control (7.5% ≤ HbA1C ≤ 9.0%) (ISPAD clinical practice consensus guidelines 2014). According to the presence of microvascular complications, the groups were subdivided into subgroups: Iа (n = 49), IIа (n = 38) – adolescents with verified microvascular disorders: diabetic retinopathy, nephropathy and neuropathy; Ib (n = 15), IIb (n = 37) – without microvascular complications. Allelic variants of TLR genes were determined using test systems GosNII genetics (Moscow). The content of cytokines in blood serum was carried out by the method of enzyme-linked immunosorbent assay “BIOSCIENCE”. Data were analyzed using software packages Statistica version 6.0. The assessment of TLR2 (Arg753Gln) and TLR4 (Thr399Ile) polymorphism distribution did not reveal significant differences between the observed subgroups and the control. In Ia and IIa subgroups (with complications) Asp299Gly variant was noted to be significantly less common when compared to subgroups Ib, IIb and controls. The presence of Gly allele in TLR4 gene was found to disrupt the expression of TNFα and VCAM-1 and can be considered protective for the development of microvascular complications.
Highlights
Long-term microvascular complications affecting both the quality of life and life expectancy of patients with type 1 diabetes mellitus (T1DM) are the primary issues in modern medicine
According to the detected microvascular complications, the groups were subdivided into subgroups: Iа (n = 49), IIа (n = 38) – adolescents with verified microvascular disorders: diabetic retinopathy, nephropathy and neuropathy; Ib (n = 15), IIb (n = 37) – without microvascular complications
While verifying the specific complications of T1DM, it was found that 77.6% of adolescents with poor glycemic control and half patients with satisfactory glycemic control of T1DM had microvascular complications
Summary
Long-term microvascular complications affecting both the quality of life and life expectancy of patients with type 1 diabetes mellitus (T1DM) are the primary issues in modern medicine. It should be noted that the incidence of microvascular complications 2-5 years after the onset of T1DM in adolescents is higher than predicted compared to other age groups [10]. A significant part of adolescents with T1DM, despite having close to the target glycemic profile, show the initial signs of microvascular complications soon after the onset of the underlying disease, which suggests the presence of other concomitant factors, such as environmental, hormonal, immunological, genetic factors, creating the prerequisites for their early formation. Current studies highlight an important role of vascular inflammation in development of diabetic nephro-, neuro-, retinopathy. Identification of the primary links in cascade of proinflammatory reac tions in the vascular wall is of particular interest for developing new diagnosing strategies and early etiopathogenetic treatment, as well as identifying risk groups for microangiopathies. The most promising approach is to examine innate immunity receptors – Toll-like receptors (TLRs) and their genetic poly
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