CC BY
30
Uzbekova Nelli Rafikovna, Doctor of Medicine, Associate Professor Andijan State Medical Institute, Intermediate Level Therapy Usmanova Dilorom Nematzhanovna, Candidate of Medicine, Assistant Andijan State Medical Institute, Intermediate Level Therapy Kodirova Gulchehra Ibrahimovna, Candidate of Medicine, Associate Professor Andijan State Medical Institute, Intermediate Level Therapy Tashtemirova Iroda Mahkambaevna, Candidate of Medicine, Associate Professor Andijan State Medical Institute, Intermediate Level Therapy Yusupova Nodira Abdimuminovna, Assistant, Andijan State Medical Institute, Intermediate Level Therapy E-mail: usmanov.babur@gmail.com
ADIPONECTIN AND ITS SIGNIFICANCE FOR THE DEVELOPMENT OF CLINICAL METABOLIC DISORDERS IN METABOLIC SYNDROME
Abstract. The article defines the role of adiponectin (ADN) in the development of clinical metabolic disorders in metabolic syndrome (MS).
The ADN level was significantly lower in patients with MS. Negative correlations were found between the ADN level and obesity, insulin resistance, free fatty acids, hyperlipidemia, blood pressure; positive correlation was found with the HDL cholesterol. Nevertheless, regardless of sex, age and, and body mass index, only the triglyceride level and diastolic blood pressure are in correlation with ADN.
Keywords: adiponectin, hypertriglyceridemia, insulin resistance, metabolic syndrome.
One of the key epidemiological trends, the significance of which will not lower and may even increase in the near future, is the steady growth of metabolic syndrome in the general population [1; 2; 5].
Metabolic syndrome (MS) is a clustering of pathogeneti-cally interrelated symptoms and metabolic disorders that increase the likelihood of developing atherosclerosis and isch-aemic heart disease (IHD). They often include obesity and/or the abdominal spread of adipose tissue, insulin resistance (IR), atherogenic dyslipidemia, arterial hypertension (AH), hyperuricemia, and a number of other medical conditions [2; 9; 14].
Currently, in the genesis of this clusterind of disorders, more and more attention is paid to the role of adipokines -biologically active proteins, which are expressed and secreted into the blood by adipose tissue [4; 6]. For example, there is evidence of a positive correlation between manifestations ofMS
and expression and plasma levels of such substances as tumor necrosis factor alpha (TNFa), interleukin-6 (IL-6), resistin, leptin and negative with adiponectin [7; 8; 10]. Results of tests on transgenic mice have shown that adinopectin has antiatherogenic and antidiabetogenic effects [16]. The antidiabetogenic effect of adiponectin is associated with an increase in the sensitivity of tissues to insulin under the effect of this protein, while the antiatherogenic effect is explained by a number of effects of adiponectin [13; 16]. These include lowering triglycerides (TG), increasing high-density lipoprotein cholesterol (HDL cholesterol), improving endothelial function, slowing down the transformation of macrophages and smooth myocytes of the vascular wall into foam cells, migration and proliferation of smooth medial myocytes, production of cytokines in the vascular wall, adhesion of monocytes to the vascular endothelium, reduction of free fatty acids (FFA) [12; 13; 15].
Despite the strong interest in the world, which manifested in the study of this adipokine, its role in the development of MC remains unexplained.
The aim of this article was to study the parameters and the role of adiponectin in the development of clinical metabolic disorders in metabolic syndrome.
Materials and methods
40 patients with MS were examined (18 men and 22 women) aged 35-67 years (mean 48.7 ± 5.6 years). The control group (volunteers) had 20 people of the same sex and age.
Metabolic syndrome was diagnosed according to the criteria proposed by the Experts of the US National Cholesterol Education Program (2005). The criteria for MS diagnosis were: waist circumference of more than 94 cm in men and more than 80 cm in women; blood pressure of 130/85 mmHg and above, the fasting plasma glucose of 5.6 mmol/l and more. The body mass index (BMI, Quetelet index) was calculated using the formula BMI = body weight (kg) / height (m2).
Glucose-insulin homeostasis was determined by the level of fasting blood glucose (FBG), the level of insulin in the blood by the ELISA method in the radioimmune laboratory of the Republican Center for Endocrinology (Tashkent), using "Beckman Coulter" analyzers (Czech Republic). HOMA-IR was calculated (fasting insulin mcIU/ml x fasting blood glucose mmol/l:22.5). The patients with fasting insulin higher than 12.5 mcIU/ml were diagnosed with hyperinsulinemia. The patients with HOMA-IR above 2.27 were considered insulin-resistant.
Parameters of blood lipid composition - total cholesterol (TC), HDL cholesterol, TG was analyzed using Reflotron Plus express analyzer by Roshe (Germany), with Biocon diag-
nostic reagents (Germany). The content of LDL cholesterol, VLDL cholesterol was calculated by the Friedewald formula. The integral indicator - atherogenic index of plasma (AIP) -was calculated using the formula AIP = (TC - HDL cholesterol/HDL cholesterol).
The FFA concentration in the serum was determined using the NEFAFS testing system by Disus (Germany).
The level of adiponectin was determined using a competitive ELISA testing using analyzators by Bio Vender-Laborator-ni medicina E.S. (Czech Republic), in the "Immunogen-Test" laboratory at the Institute of Immunology of the Academy of Sciences of Uzbekistan.
Statistical data processing was carried out by the variation system method using Student's t-test. The results were processed using the Statistica software. To identify the relation of the adiponectin level to different parameters, a Pearson correlation coefficient analysis and regression analysis were performed.
Results
The main clinical metabolic parameters are given in (Table 1). When comparing the content of adiponectin (ADN) in patients with MS and in control group it was discovered that the level of ADN was significantly reduced in patients with MS. In addition, a change in a number of biochemical, anthropomet-ric, hormonal, and hemodynamic parameters was observed in patients with MS. For example, among the biochemical parameters in patients with MS, there was an increase in the levels of insulin, glucose, the NOMA index, TG, FFA, AIP, as well as a decrease in the level of HDL cholesterol. In addition, patients with MS had increase in BMI and WC, as well as a greater increase in DBP and SBP compared to control group.
Table 1.- Adiponectin content and clinical biochemical parameters in patients with metabolic syndrome
Parameters Control (М ± m) MS (М ± m)
Absolute number 20 40
Age, years 47.5 ± 6,6 48.7 ± 5.6
Sex (m/f) 10/10 18/22
BMI, kg/m2 23.5 ± 4.7 31.2 ± 4.6
WC, cm 80.0 ± 5.5 99.1 ± 13.6
SBP, mmHg 122.5 ± 10.2 191.6 ± 16.4
DBP, mmHg 80.3 ± 7.6 103.4 ± 13.2
Glucose, mmol/l 5.0 ± 0.5 6.5 ± 1.9
Инсулин, mcIU/ml 8.5 ± 3.1 16.3 ± 5.2
НОМА-IR 1.81 ± 0.92 3.43 ± 1.05
FFA, mmol/l 0.42 ± 0.15 0.87 ± 0.49
TC, mmol/l 4.2 ± 0.9 6.5 ± 1.7
TG, mmol/l 0.94 ± 0.1 2.76 ± 0.7
HDL Cholesterol, mmol/l 1.12 ± 0.18 0.85 ± 0.11
LDL Cholesterol, mmol/l 2.2 ± 0.8 5.11 ± 1.45
AIP 4.5 ± 0.9 6.1 ± 1.9
Adiponectin, ^g/ml 10.2 ± 4.1 5.79 ± 2.2
In a detailed study of patients with low levels of ADN, men predominated to a greater extent. A direct correlation was found between the ADN level and the age of patients. With an increase in the ADN level, a decrease in the values of BMI and OT is observed. There is an inverse correlation between the ADN level and glucose and insulin levels, HOMA-IR. As the content of ADN increases, FLC and TG levels decrease. The correlation between the ADN level and the concentrations of LDL cholesterol and HDL cholesterol is much less pronounced.
For a more detailed study of the correlations of the ADN level with clinical metabolic parameters, a correlation analysis was performed (Table 2).
Its results confirm the data on the positive correlation of the
insulin, HOMA-IR, FFA and TG concentrations. The strongest correlation was found between TG level and ADN (r = -0.46). In addition, significant correlations of the ADN level with concentrations of HDL cholesterol and SBP were found.
Comparison of MS patients by sex and age led to a slight decrease in the correlation of ADN content with BMI, OT, FFA levels, TG, and correlations of ADN concentration with glucose - insulin homeostasis and HDL cholesterol levels were not detected (Table 2). Comparison by sex and age did not affect the correlation between the ADN level in blood plasma with DBP, while the correlation with the SBP was slightly higher, and acquired a reliable character.
ADN level with age and negative with BMI, OT, glucose levels,
Table 2.- Correlation of adiponectin levels with clinical metabolic parameters in patients with metabolic syndrome
Parameter Adiponectin (without matching) Adiponectin (after matching by sex and age)
AGE 0.28* -
BMI -0.37* -0.28*
WC -0.33* -0.25*
Type 2 diabetes -0.03 -
Glucose -0.26* -0.18
Insulin -0.27* -0.17
HOMA-IR -0.34* -0.23*
FFA -0.27* -0.24*
TC -0.00 -0.12
TG -0.46* -0.4*
HDL Cholesterol 0.27* 0.21
LDL Cholesterol 0.19 0.13
AIP -0.12 -0.25*
SBP -0.23 -0.26*
DBP -0.33* -0.35*
Note: * - correlation is accurate (p < 0.05);
Regression analysis has shown that only the TG content (r = -0.33, p = 0.04) and sex (r = -0.28, p = 0.04) are independent factors associated with the ADN level (r = 0.36, p = 0.04). ADN level (r = -0.31, p = 0.02), FFA (r = 0.44, p = 0.04) and HDL cholesterol (r = 0.26, p = 0.04) of all above parameters were independent factors associated with the concentration of TG in the blood. An independent link was established on sex, age and BMI, as well as a link between ADN levels and TG.
Discussion
In recent years, the role of ADN in the genesis of many disorders in MS [4; 8; 13; 14] has been often discussed in the literature. Identified by various authors of the connection of reduced levels of ADN with abdominal fat distribution and
IR, hypertriglyceridemia, hypocholesterolemia, hypertension, prove the increasing role of this protein in the genesis of MS [3; 10; 11; 15].
Our analysis allowed us to identify a number of the ADN level correlations with some sex, age, clinical and biochemical parameters in patients with MS.
We were able to show that the ADN level is lower in men than in women, as well as its increase with age of patients. These data are consistent with the results of studies conducted by foreign authors [12; 13; 14]. Reduced levels of ADN in men can be one of the factors that predispose them to an increased incidence of MS [3; 7]. Moreover, once again data on the negative correlation ofADN levels with obesity, OT, glucose, basal insu-
lin, HOMA-IR, TG levels, FFA, BP and a positive correlation with HDL cholesterol was confirmed [11; 12].
The mechanisms responsible for reducing the level of ADN in patients with MS are still little studied. It is assumed that the main role may be played by TNFa and IL-6, the expression and secretion of which in adipose tissue increases with obesity [12; 14]. It is known that these cytokines reduce the expression of ADN [12; 13]. Moreover, a decrease in the ADN level may be mediated by hyperinsulinemia, since insulin also reduces the production ofADN [3; 8]. In addition to the effect of insulin on the ADN level, the reverse effect is also described in the literature - a decrease in the level of insulin under the effect of ADN. So in mice transgenic for ADN, as well as in mice that were injected with ADN, a decrease in insulin levels was observed, and this effect is related to an increase in tissue sensitivity to insulin [16]. However, despite the relation of the ADN level with the insulin content and HOMA-IR that we found, it decreased and became unsubstantiated after comparing patients by sex and age.
In general, our data do not confirm the findings of foreign researchers on the direct effect of ADN on the indices of glucose-insulin homeostasis in animals [6; 16]. Of all the parameters, the ADN level was correlated with the TG level. According to the results of regression analysis, this correlation did not depend on sex and age, parameters of lipid and car-
bohydrate metabolism. At the same time, the ADN level was an independent determinant only for TG. The mechanisms and their consequences which are realized independent of the listed factors, the correaltion between ADN and TG, remain unknown so far. However, the literature data suggest that this correlation can be realized through a direct effect of ADN on the formation of TG in hepatocytes, as a result of which VLNP production by the liver is reduced [16]. For example, trans-genosis of leptyndefective mice (ob/ob) with ADN resulted in a decrease in TG accumulation in the hepatocytes of these animals [6; 16].
This effect is the product of the intracellular target of ADN-AMP-sensitive protein kinase, an enzyme that reduces the formation of intracellular TG in hepatocytes. These data are also confirmed by foreign researchers [8; 16].
Conclusion
In summary, data on the ADN level correlation with a number of clinical metabolic manifestations of MS were confirmed. Negative correlation was found between the ADN level and abdominal obesity, insulin resistance, FFA level, hyperlipidemia, ABP, and a positive correlation with HDL cholesterol. Nevertheless, regardless of sex, age and BMI, only the TG and DBP levels are in correlation with ADN. Once again it is confirmed that ADN, in turn, is an independent determinant only for TG.
References:
1.
Порядин Г. В., Осколок Л. Н. Патофизиологические аспекты метаболического синдрома // Леч. дело.- М., 2011.-№ 4.- С. 4-10.
Рекомендации ВНОК по ведению больных с метаболическим синдромом / - М.: Медицина, 2013.- 62 с. Танянский Д. А., Фирова Э. М., Шатилина Л. В., Денисенко А. Д. Роль адипокинов и неэстерифицированных жирных кислот в развитии инсулинорезистентности // Пробл. эндокринологии.- М., 2009.- Т. 55.- № 3.- С. 13-17. Титов В. Н. Лептин и адипонектин в патогенезе метаболического синдрома // Клин. медицина.- М., 2014.- Т. 92.-№ 4.- С. 20-30.
Чазова И. Е., Мычка В. Б. Метаболический синдром / - М.: Медиа Медика, 2008.- 349 с. Abe A. Adipocytokines and assay method in metabolic syndrome // Rinsho Byori.2010.- Vol. 58(8).- P. 823-829. Chiarugi P., Fiaschi T. Adiponectin in health and diseases: from metabolic syndrome to tissue // Expert Opin. Ther. Targets. 2010.- Vol. 14(2).- P. 193-206.
Gelsinger C., Tschoner A., Kaser S. Adipokine update - new molecules, new functions // Wien Med. Wochenschr.2010.-Vol. 160(15-16).- P. 377-390.
Grundy S. M., Brewer H. B., Cleeman J. I., Smith S. C., Lenfant D. Definition of metabolic syndrome: report of the National Heart, Lung and Blood Institute / American Heart Association conference on scientific issues related to definition // Circulation. 2009.- Vol. 109.- Р. 433-438.
10. Kershaw E. E., Flier J. S. Adipose tissue as an endocrine organ // J. Clin. Endocrinol. Metab. 2004.- Vol. 89 (6).- P. 25482556.
11. Lago F., Gomez R., Gomez-Reino J.J. Adipokines as novel modulators of lipid metabolism // Trends Biochem Sci. 2009.-Vol. 34(10).- P. 500-510.
12. Mangge H., Almer G., Truschnig-Wilders M. Inflammation, adiponectin, obesity and cardiovascular risk // Curr. Med. Chem. 2010.- Vol. 17(36).- P. 4511-4520.
9.
13. Maury E., Brichard S. M. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome // Mol. Cell Endocrinol. 2010.- Vol. 314(1).- P. 1-16.
14. Oda E. The metabolic syndrome as a concept of adipose tissue disease // Hypertens.Res. 2008.- Vol. 31.- P. 1283-1292.
15. Phillips S. A., Kung J. T. Mechanisms of adiponectin regulation and use as a pharmacological target // Curr. Opin. Pharmacol. 2010.- Vol. 10(6).- P. 676-683.
16. Yamauchi T., Kamon J., Waki H. Globular adiponectin protected ob/ob mice from diabetis and apoE-deficint mice from atherosclerosis // J. Biol. Chem. 2003.- Vol. 278(6).- P. 2461-2468.
