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The factors promoting development of non-alcoholic fatty liver disease in patients with obesity and different state of carbohydrate metabolism have been studied. 43 patients were examined; these included 26 patients with abdominal obesity (BMI=52.9±7.9 kg/m2). The control group consisted of 17 conditionally healthy donors without obesity (BMI=18.9-24.9 kg/m2), seven of them formed a comparison group that was included to compare the results of study on the levels of tissue-specific expression of HSP70 mRNA. The study of mRNA expression was performed by real-time PCR. The concentration of IL-6 and TNF-a was measured in blood serum by the ELISA method. In patients with obesity with diabetes mellitus type 2 (DM2), a significant increase in the serum level of proinflammatory cytokines was found in comparison with the group of patients without DM2 and control. The results of histological examination of liver biopsy specimens in obese patients revealed the most pronounced changes in the group of DM2 patients. Regardless of the stage of nonalcoholic fatty liver disease in obese DM2 patients, an increase in the area of fatty inclusions (relative to the group without type 2 diabetes) was recorded. The study of the HSP70 gene expression in peripheral blood mononuclear cells allowed its significant increase relative to the comparison group. The relationship between the level of expression of the HSP70 gene in metabolically active tissues (visceral, subcutaneous adipose tissue and liver) established in all obese patients with the serum content of proinflammatory cytokines (IL-6 and TNF-a) may indicate suppression of HSP70 expression in these tissues, background of systemic and local inflammation in obesity.

The relationship between the rs2302382, rs8111428 and Glu354Gln (rs1800437) polymorphisms in GIPR (glucosedependent insulinotropic polypeptide receptor) gene and plasma levels of mediators involved in the regulation of carbohydrate metabolism in obese patients with type 2 diabetes (before and after a test breakfast) was investigated. The contribution of polymorphic variants of rs2302382, rs8111428 in GIPR gene in the predisposition to type 2 diabetes in individuals belonging to the Slavic population of Russia was found. Polymorphisms rs2302382 and rs8111428 in the GIPR gene were characterized by the nonequilibrium cohesion. The decrease in the level of expression of the GIPR gene in adipose tissue of the small intestine mesentery in the carriers of the CC genotype rs2302382 and AA rs8111428 was associated with the increase in the plasma leptin level, whereas during normal expression, the plasma content of insulin, and GIP (in persons with the genotype of the polymorphism rs2302382 and AG polymorphism rs8111428), resistin and ghrelin (in individuals with the genotype of the polymorphism rs2302382) increased. We propose the stimulating effect of GIP on the secretion of resistin, leptin and ghrelin, with an increase in insulin production in obese patients with type 2 diabetes.

Chemerin is a mediator of adipose tissue involved in the regulation of many processes, including lipogenesis, and inflammatory response. The role of chemerin in the development of insulin resistance has been insufficiently studied and needs detailed understanding. The aim of the study was to investigate chemerin production in obese patients with different states of carbohydrate metabolism. The study included 155 patients with a diagnosis of obesity; 34 patients with overweight. The control group 1 consisted of 43 conditionally healthy donors who did not have obesity. For comparison of the results of a study to determine the levels of tissue-specific mRNA expression of the genes IL-6, TNF-a, RARRES2, (encoding IL-6, TNF-a and chemerin) in adipose tissue introduced a control group 2 - 30 patients without obesity. Study on the relative level of mRNA expression of the genes IL-6, TNF-a and RARRES2 (encoding IL-6, TNF-a and chemerin) was carried out using real time PCR. Concentrations of IL-6, TNF-a, and chemerin were measured in serum/plasma using an enzyme-linked immunosorbent assay (ELISA). We found significant differences in the plasma level of chemerin and tissue-specific features of RARRES2 gene expression in obese patients, depending on the degree of obesity and the state of carbohydrate metabolism. Multidirectional associations of RARRES2 gene expression with TNF-a and IL-6 genes in adipose tissues of different localization are shown: in obese patients (BMI £40 kg/m2) without type 2 diabetes - negative, and type 2 diabetes - positive. Identified relationship chemerin plasma content and the expression level of its gene in biopsies with various parameters of carbohydrate and lipid metabolism, proinflammatory molecules indicate chemerin involved in metabolic and immune processes in obesity.

We investigated the tissue-specific features of the production of adipokines (leptin and adipsin) by adipose tissue in obese patients depending on the degree of obesity and the state of carbohydrate metabolism. An increase in the content of adipsin and leptin in the blood plasma was found. In patients with varying degrees of obesity with and without type 2 diabetes mellitus (DM 2), we determined the level of tissue-specific expression of LEP and CFD genes encoding leptin and adipsin, respectively. The contribution of different adipose tissue depots to the blood plasma level of adipsin and leptin in obese patients with and without DM 2 was established. The disturbance of reciprocal relationships between adipsin and leptin in obesity is associated with the development of insulin resistance.

We studied association of single nucleotide polymorphism Glu298Asp (rs1799983) of the NOS3 gene with the risk of metabolic syndrome in the Slavic population. Blood samples were obtained from 128 patients with metabolic syndrome and 100 healthy individuals. Polymorphism Glu298Asp of the NOS3 gene was genotyped by allele-specific PCR. Allele Asp (OR=1.95, 95%CI 1.29-2.95, p=0.007) and genotype Asp/Asp (OR=2.56, 95%CI 0.98-6.72, p=0.04) were associated with the risk of metabolic syndrome in Slavic population. Patients with metabolic syndrome carrying genotype Asp/Asp had higher serum endothelin-1 level in comparison with Glu/Asp and Glu/Glu carriers.

The relationship between nitric oxide production and metabolic disorders and the role of endothelial nitric oxide synthase (eNOS or NOS3) in metabolic syndrome (MS) remain poorly understood and need deeper investigation. In this context the role of the NOS3 gene in pathogenesis of MS is of special interest. The aim of the study was to investigate association of NOS3 single nucleotide polymorphism C774T with risk of MS in the Slavic population of the Kaliningrad region and the relationship of this polymorphic variant with some parameters of endothelial dysfunction. The study included 128 patients (48 men and 80 women aged from 36 to 52 years) with MS. The control group consisted of 126 healthy volunteers (60 men and 66 women aged from 30 to 40 years). Genotyping was performed by real-time PCR. Serum nitrite levels were determined spectrophotometrically by the Griess method. Serum levels of endothelin-1 and eNOS were evaluated by ELISA. The study has shown association of T allele (OR=2.06; p=0.0004; CI: 1.38-3.08) and CT genotype (OR=1.97; p=0.014; CI: 1.14-3.40 ) C774T polymorphism of the NOS3 gene with risk of MS in the Slavic population of the Kaliningrad region. Allele C (OR=0.48; p=0.0004; CI: 0.32-0.72) and homozygous CC genotype (OR=0.41; p=0.001; CI: 0.24-0,69) C774T polymorphism of the NOS3 gene were associated with reduced risk of the development of MS. Significant differences in serum levels of eNOS and endothelin-1 depended on the CT and TT genotypes of C774T polymorphism of the NOS3 gene in MS.

In this review we discuss the molecular mechanisms of insulin resistance concomitant with metabolic inflammation. We also analyze the world results of experimental and clinical studies which aimed at identifying the molecular targets for the development of new prevention and treatment of insulin resistance.