The dissertation is devoted to the study of the role of genetic polymorphism (rs1799983 gene NOS3, rs1800629 gene TNFα, rs6842241 gene EDNRA and rs5351 gene EDNRB) in the development of endothelial dysfunction in type 2 diabetes mellitus (T2DM). Supplemented and specified data on flow and presence of complications in patients with diabetes mellitus with different severity: with an average degree of diabetes occurred hyperinsulinemia and insulin resistance, at a severe degree - hypoinsulinemia and decreased function of beta cells. Excessive body weight or obesity have been associated with hypertriglyceridemia, leptinoresistance and hyperleptinemia. Among diabetic complications, the most frequent was sensory polyneuropathy (88.1%), nephropathy (84.2%), retinopathy (78.3%) and arterial hypertension (46.7%). The original index of severity of the disease (IDS) was proposed, the magnitude of which directly depended on the number and severity of complications, and vice versa – from the age of the patient. According to IDS was developed prediction model of diabetes mellitus, which included meaningful combinations of genotypes and markers of endothelial disfunction, which were distributed in this way according to the specific contribution: endothelin 1>NOx>rs5351>rs6842241>rs1799983>TNFα. The progression of diabetes was seen as slow at IDS level less than 2.7 units, moderate – 2.7-7.0, and fast – 7.1-11.3. The role of endothelin-1 in increasing glycemia, albuminuria, increasing the degree of decompensation of diabetes and nephropathy is shown; the effect of NOx on reducing the glomerular filtration rate and the deterioration of the function of the kidneys; the influence of TNFα and diene conjugates on all key parameters of T2DM.
In the cohort of Ukrainian patients, the distribution of alleles rs1799983 of the NOS3 gene was associated with the development of the disease (χ2=5.82; р=0.016). The presence of the minor allele T in the genotype increased chances of development of T2DM by 1.6 times (OR=1.59; 95% CI 1.09-2.32), contributed decompensation diabetes by HbA1c levels and worsening renal function (by blood levels of creatinine, albuminuria and glomerular filtration rate) and was associated with lower blood levels of NOx and eNOS. The distribution of alleles rs1800629 of the TNFα gene was associated with the development of the disease (χ2=5.91; р=0.015). Minor allele A increased the chances of T2DM in 1.7 times (OR=1.71, 95% CI 1.11-2.65) and contributed to the development of nephropathy (χ2=6.38; p=0.041). Endothelin receptor gene polymorphisms were associated with the development of the disease: for rs6842241 of the EDNRA gene, the increased risk was associated with the minor allele A (p=0.005); for rs5351 of the EDNRB gene with an ancestral C allele (p=0.026). The presence of these alleles contributed to a significantly higher level in endothelin-1 in blood (p <0.001). Polymorphisms of genes of endothelin receptors had significance (p <0.001) for development: rs6842241– arterial hypertension, rs5351 – sensory polyneuropathy and nephropathy. The estimated probability of boundary value and a positive outlook for all diabetic complications: retinopathy was defined by genotype rs1800629 and rs5351, polyneuropathy – rs1799983 and rs5351, diabetic nephropathy by glomerular filtration rate – rs1799983, rs1800629 and rs5351, diabetic nephropathy by albuminuria levels and hypertension – rs1799983, rs6842241 and rs5351, lower rates of macroangiopathy of lower extremities – rs1799983 and rs1800629.
