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The roleof adipokines, triglycerides and freefatty acids in the development of insulin resistance in the presence of metabolicsyndrome
7. Park J. H., Park Y. S., Lee J. B., Park K. H. et al., Meloxicam inhibits fipronil-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells.//J Appl Toxicol. - 2015. Mar 13. - doi: 10.1002/jat.3136.
8. Tukhtaev K. R., Tulemetov S. K., Zokirova N. B., Tukhtaev N. K. Effect oflong term exposure low doses of lambda-cyhalothrin on the level of lipid peroxidation and antioxidant enzymes of the pregnant rats and their offspring.//Medical and Health Science Journal -2012. - Vol. 13. - P. 93-98. URL: http: www.pradec.en
9. Tukhtaev K. R., Tulemetov S. K., Zokirova N. B., Tukhtaev N. K. et al. Prolonged exposure of low doses of Fipronil causes oxidative stress in pregnant rats and their offspring.//The Internet Journal of Toxicology. - 2013. - Vol. 10. - No. 1. URL: http: www.ispub. com/IJT0/10/1/14550.
10. Tukhtaev K. R., Zokirova N. B., Tulemetov S. K., Tukhtaev N. K. Effect of prolonged exposure of low doses of lamda-cyhalothrin on the thyroid function of the pregnant rats and their offspring//Medical and Health Science Journal - 2012. - Vol. 13. - P. 86-92. URL: http: www.pradec.en
11. Tukhtaev K. R., Zokirova N. B., Tulemetov S. K., Tukhtaev N. K. et al. Effect of Prolonged exposure low doses of Fipronil on thyroid function of pregnant rats and their offspring.//The Internet Journal of Toxicology. - 2013. - Vol. 10. - No. 1. URL: http: www.ispub. com/IJT0/10/1/14550.
12. Vidau C., González-Polo R. A., Niso-Santano M., Gómez-Sánchez R. et al. Fipronil is a powerful uncoupler of oxidative phosphorylation that triggers apoptosis in human neuronal cell line SHSY5Y.//Neurotoxicology. -2011. - Vol. 32 (6). - P. 935-943.
13. Zhang B., Xu Z., Zhang Y., Shao X. et al. Fipronil induces apoptosis through caspase-dependent mitochondrial pathways in Drosophila S2 cells.//Pestic Biochem Physiol. - 2015. - Vol. 119. - P. 81-89.
DOI: http://dx.doi.org/10.20534/ESR-17-3.4-59-62
Uzbekova Nelly Rafikovna, Candidate of medical sciences, Associate Professor of the Department of Intermediate Level Therapy of Andijan State Medical Institute Vakhobov Bakhrom Mumindzhanovich, Candidate of medical sciences, Associate Professor of the Department of Intermediate Level Therapy of Andijan State Medical Institute Khuzhamberdiyev Mamazair Akhmedovich, Doctor of medical sciences, Professor, Head of the Department of Intermediate Level Therapy of Andijan State Medical Institute E-mail: [email protected]
The role of adipokines, triglycerides and free fatty acids in the development of insulin resistance in the presence of metabolic syndrome
Abstract: The objective of the study was to investigate the possible role of adipokines (leptin, adiponectin), triglycerides (TG) and free fatty acids (FFA) in the development of insulin resistance (IR) in patients with metabolic syndrome (MS).
The study included 170 patients with MS (67 men and 103 women) at the age of 51,5±3,93 years. It was determined that the increase of TG, FFA, leptin and the decrease of adiponectin were observed in the patients with MS with high HOMA index. However, the analysis of data in the groups of patients with different body mass demonstrated that the development of IR in patients with obesity may be influenced by the increase of TG, FFA and leptin concentrations, while in patients without significant obesity — by the increase of TG, FFA levels and the decrease of adiponectin.
Thus, it is possible to assume that leptin, adiponectin, TG and FFA may influence the development of IR, however, their role depends on the severity of obesity.
Keywords: adipokines, leptin, adiponectin, triglycerides, free fatty acids, insulin resistance, metabolic syndrome.
Insulin resistance is an important pathogenic factor in the number of diseases and disorders such as diabetes mellitus of the 2nd type, atherosclerosis, arterial hypertension (AH), atherogenic dislipoproteinemia [1; 2; 3; 14]. Insulin resistance (IR) means the reduction in the response of insulin-sensitive tissues to insulin in the case of its sufficient concentration [3; 12; 13; 17]. In this case, these disorders are combined into a single complex called "metabolic syndrome".
In the pathogenesis of metabolic syndrome (MS) the special role is assigned to obesity or abdominal fat distribution, which con-
tribute to the development of IR [1; 2; 8; 9; 13]. Therefore, with regard to the mechanisms of development of IR with MS a special attention is paid to the change of adipokine levels in the blood -biologically active proteins that are produced by fatty tissue (leptin, adiponectin, visfatin, resistin, interleukin-6, tumor necrosis factor alpha) [5; 7; 8; 15]. Moreover, an important role in the development of IR can be assigned to triglycerides (TG) and free fatty acids (FFA) that are produced in the course of lipolysis by fatty tissue and in the blood stream by lipoproteins, which contain a great amount of
Section 5. Medical science
TG [9, 18]. However, the role of each of these substances in the development of IR is still not clarified; and also it is not clear how the change in their concentrations is connected with the presence of obesity and pathogenesis of IR in the case ofMS [4; 12; 20].
The objective of the study was to investigate the role of fatty tissue hormones - adipokines (leptin, adiponectin), triglycerides and free fatty acids - in the development of insulin resistance in patients with metabolic syndrome.
Material and methods
170 patients with MS (67 men and 103 women) at the age of 35-70 years (on average - 51,5±3,93 years) were examined. The control group (volunteers) included 58 people of similar sex and age.
Metabolic syndrome was diagnosed according to the criteria, which were proposed by the Expert Panel of the National Cholesterol Education Program of USA (2005). The criteria ofMS were as follows: waist circumference - over 94 cm in men and over 80 cm in women; blood pressure - 130/85 mm Hg and higher, the glucose level in blood plasma on an empty stomach - 5,6 mmol/l and higher. The body mass index (BMI, Quetelet index) was calculated using BMI formula = body mass (kg)/height (m 2).
Glucose-insulin homeostasis was determined according to the fasting blood glucose level, the insulin level in blood by immunoenzyme method in radio-immune laboratory ofthe Republican Endocrinology Center (Tashkent city), using the kits of the firm "Beckman Coulter" (Czech Republic). HOMA index was calculated (insulin on an empty stomach microunits/ml x fasting blood glucose mmol/l:22,5). Hyper-insulinemia was diagnosed, if the insulin level on an empty stomach was higher than 12,5 microunits/ml. The patients were considered to be insulin-resistant, if HOMA index was above 2,77.
The values of lipid blood composition (total cholesterol (TC), HDL cholesterol and TG) were determined using the express-analyzer "Reflotron plus" of the firm "Roshe" (Germany), with the help of reagents kits "Biocon" (Germany). The levels of LDL cholesterol, VLDL cholesterol were calculated using W. Friedwald formula. Integral index - atherogenic coefficient (AC) - was calculated using the following formula: AC= (TC - HDL cholesterol/HDL cholesterol).
The concentration of FFA in the blood serum was determined with the help of NEFAFS test-system of the firm "Disus" (Germany) in the laboratory of the Department of Biochemistry of Tashkent Medical Academy.
The levels of leptin and adiponectin were estimated through a competitive immune-enzyme analysis, using the kits of the firm "Bio Vender-Laboratorni medicina E. S." (Czech Republic), in the laboratory "Immunogen-test" at the Institute of Immunology of the Uzbekistan Academy of Sciences.
Statistical data processing was performed by the variational method with the use of Student's t-tests. The results were processed with the help of the program package "Statistica-6". Correlation and regression analyses were performed in order to identify the connections between HOMA index and different parameters. The level of significance was considered to be reliable at p < 0.05.
Results and their discussion
The results of the study have shown that patients with MS with reduced insulin sensitivity (the 2nd and 3rd groups according to HOMA index) have a higher body mass index and a more pronounced abdominal fat distribution. In addition, the increase of TG, FFA, TC levels and the decrease of HDL cholesterol were observed in these patients (Table 1).
Correlation analysis confirms these relationships and denotes the connection of HOMA index with abdominal obesity and atherogenic changes of lipid spectrum, which does not depend from BMI. These changes are consistent with the well-known notions about the close relationship between abdominal obesity and IR, as well as about the important role of IR in the development of atherogenic dislipoproteinemia in the case of obesity with MS [4; 6; 16]. However, the mechanisms of the development of IR with MS are still insufficiently studied. One of the approaches in the study of this issue is to research the role of substances, which are produced by fatty tissue, such as adipokines, TG and FFA. The results have shown that the decrease of insulin sensitivity of the tissue was accompanied by the increase of TG, FFA, leptin levels in the blood and the decrease of adiponectin concentration.
Table 1. - Clinical and metabolic parameters in the patients with MS with different values of HOMA index
Values of НОМА index
Parameters 1 group (n=37) 2 group (n=65) 3 group (n=68)
HOMA index 1,22±0,28 2,32±0,54 б,85±2,13
(0,81-1,54) (1,55-2,99) (3,00-12,88)
Men/women 15/22 25/40 27/41
Age/years 54,7±10,42 50,8±8,02 52,3±9,18
Body mass index kg/m 2 2б,2±3,93 33,б±4,71*** 38,б±б,04***
Waist circumference, cm 94,0±10,21 9S,1±11,0* 104,2±12,б**
Leptin, ng/ml 18,б±3,б8 23,5±4,1б** 30,9±б,42***
Adiponectin, ^g/ml 7,б±3,52 б,15±3,11* 5,75±2,77**
Glucose on an empty stomach, mmol/l 5,9±1,13 б,б±1,32* 8,7±2,78***
Insulin, microunits/ml 7,1±2,0б 11,3±4,41** 18,13±9,41***
Total cholesterol, mmol/l б,21±1,б4 б,90±1,93* 7,51±2,5б**
TG, mmol/l 1,94±1,03 2,18±1,97* 2,43±1,34**
HDL cholesterol, mmol/l 1,02±0,1б 0,94±0,13* 0,84±0,10**
LDL cholesterol, mmol/l 4,32±1,85 4,85±2,03* 5,33±2,71**
Atherogenic index 4,91±1,78 5,41±2,21* б,8±2,9б**
FFA, mmol/l 0,б0±0,35 0,75±0,42* 0,8б±0,б9**
Note: * - The values of significance of differences between the groups: the differences are reliable in comparison with the 1st group at: * - p < 0,05; ** -p < 0,01; *** -p < 0,001.
The role of adipokines, triglycerides and free fatty acids in the development of insulin resistance in the presence.
According to correlation analysis, each of these factors has connections with IR, which do not depend from BMI (Table 2).
The literature also provides information on the connection of IR with FFA, leptin and adiponectin concentrations, which does not depend from BMI [4; 10; 12]. In other words, we can say that the change in the levels of TG, FFA and adipokines reflects not only obesity, but also IR, and therefore, we can assume that these substances may be involved in the development of IR [12]. However, it is still insufficiently studied, whether these substances may be involved in the pathogenesis of IR in individuals with normal and excessive body mass, or the change of their concentration has a greater importance for the development of IR in the case of obesity with MS [15; 17; 20].
Table 2. - The connection of HOMA index with clinical and metabolic parameters in patients with MS
Parameter Correlation
Age, years -0,22*
Body mass index, kg/m 2 0,45*
Waist circumference, cm 0,43*
Leptin, ng/ml 0,33*
Adiponectin, ng/ml -0,37*
TG, mmol/l 0,39*
FFA, mmol/l 0,44*
Total cholesterol, mmol/l 0,23*
HDL cholesterol, mmol/l -0,36*
Atherogenic index 0,30*
Note: *- the significance of correlation at p < 0,05
Table 3. - The blood levels of TG, FFA, leptin and adiponectin in patients with MS with different values of BMI and HOMA index
Parameters Patients with MS with normal and excessive body mass (BMI < 28kg/m 2) Patients with obesity (BMI > 28kg/m 2)
HOMA < 1,5 HOMA > 2,77 HOMA < 1,5 HOMA > 2,77
Number of patients 20 17 12 40
Men/women 8/12 7/10 5/7 17/23
Age, years 53,7±9,2 51,9±8,51* 50,7±8,04 52,9±9,36
Body mass index, kg/m 2 24,4±2,67 26,9±3,96* 33,1±4,80### 37,7±5,73*###
HOMA index 1,14±0,31 4,85±1,49*** 1,31±0,49 5,76±2,08***#
TG, mmol/l 1,93±1,03 2,11±1,83** 2,04±1,62 2,42±1,61#
FFA, mmol/l 0,60±0,35 0,72±0,39** 0,71±0,43 0,85±0,17*#
Leptin, ng/ml 12,6±3,09 16,7±5,03** 21,5±4,04### 28,5±5,87**###
Adiponectin, |xg/ml 7,5±3,58 6,11±3,42** 6,03±3,41 5,75±2,93*#
Note: 1. The differences are reliable in comparison with individuals without obesity in HOMA category at: * - p < 0,05; ** - p < 0,01; *** - p < 0,001. 2. The differences are reliable in comparison with the insulin sensitive individuals in BMI category at: # -p < 0,05; ## -p < 0,01; ### -p < 0,001.
Table 3 provides information on TG, FFA, leptin and adiponectin levels in patients with different values of body mass and HOMA index. As shown, TG, FFA and leptin levels in the presence of IR change only in patients with obesity (BMI > 28kg/m 2), while the adiponectin concentrations change in the examined individuals without pronounced obesity (BMI < 28kg/m 2).
According to the correlation analysis, the TG and FFA levels are still connected with IR in patients with BMI<28kg/m 2,
although this correlation is less pronounced in comparison with the group of patients, who suffer from MS with obesity (Table 4). Therefore, we can assume that TG, FFA and adiponectin may be involved in the development of IR in patients with MS without pronounced obesity; however adiponectin, in contrast to FFA and leptin, is not connected with the development of IR in patients with obesity.
Table 4. - The connection of HOMA index with TG, FFA, leptin and adiponectin levels in patients with MS with different BMI
Parameter Patients with excessive body mass (BMI <28 kg/m 2) Patients with obesity (BMI > 28 kg/m 2)
TG, mmol/l 0,30* 0,41*
FFA, mmol/l 0,29* 0,40*
Leptin, ng/ml 0,27 0,33*
Adiponectin, |xg/ml -0,29* -0,16*
Note: *- correlation is reliable atp < 0,05
The reasons of the detected differences in the connection between TG, FFA, adipokines levels and IR under different degrees of body mass excess remain unknown. However, it is possible to assume that these differences may be caused by the differences in the production of other substances by fatty tissue (for example, other adipokines, which, influencing the insulin sensitivity, may decrease the impacts of leptin and adiponectin on IR) [6; 10; 11]. However, another study shows that adiponectin levels decrease in the presence of IR in persons with normal and excessive body mass, as well as in patients with obesity [5; 16; 19]. Apparently, this was due to the fact that the adiponectin concentration in patients with obesity and without IR was as high as in patients with normal and excessive
body mass without IR [4; 9; 20]. Adiponectin level with normal insulin sensitivity and obesity reduced considerably. Thus, apparently, an important reason for the lack of impact of adiponectin on IR in patients with MS and obesity is a low dispersion of its concentrations in this group and respectively a low degree of its impact.
Regression analysis revealed that HOMA index was influenced by the levels of adiponectin (| = - 0,30, p < 0,01), leptin (| = 0,22, p < 0,01), TG (| = 0,25, p < 0,01), FFA (| = 0,24, p < 0,01).
In the course of analysis of the literature review we did not reveal any studies that simultaneously investigate the impact of TG, FFA and different adipokines on the development of IR in the case of MS. However, there are works, which also show that adiponectin
Section Б. Medical science
and leptin are independent predictors of IR [5; 6; 14]. However, there are still many ambiguities with regard to the influence of adiponectin and TG on insulin sensitivity. It is assumed that adiponectin exerts this impact through stimulating influence on TG and FFA oxidation through the decrease of the glucose production by hepa-tocytes [18; 20]. These effects are not connected with the impact of adipokine on the insulin signal transduction [4; 20]. Signal pathways of influence of adiponectin remain unknown [4; 20]. However, the connection between adiponectin and IR in patients with MS, which we detected in our study, makes us suggest that the decrease of adiponectin level plays an important role in the development of IR in patients with MS.
Conclusions
1. The levels of leptin, adiponectin, TG, FFA in patients with MS change not only in the case of obesity, but also in the case of insulin resistance.
2. The independent role of leptin, adiponectin, TG and FFA in the development of insulin resistance in patients with MS was identified.
3. The development of insulin resistance in persons with MS and obesity is influenced by the increase of leptin, TG and FFA concentrations, while in persons with MS without pronounced obesity - by the decrease of adiponectin and the increase of TG, FFA levels.
References:
1. Веселовская Н. Г., Чумакова Г. А., Козаренко А. А. Адипокины как корригируемые факторы риска сердечно-сосудистых заболеваний // Рос. кардиол. журнал. - Москва, - 2010. - № 6. - C. 88-93.
2. Гопций Е. В. Уровень адипоцитокинов и показателей углеводного обмена у больных артериальной гипертензией с ожирением в зависимости от уровня лептина//Тер. вестник Узбекистана. - Ташкент, - 2012. - № 1. - C. 23-27.
3. Дзидзария М. И. Роль инсулинорезистентности в формировании метаболического синдрома и пути ее коррекции//Рус. мед. журнал. - Москва, - 2007. - № 11 (28). - С. 948-951.
4. Танянский Д. А., Фирова Э. М., Шатилина Л. В., Денисенко А. Д. Роль адипокинов и неэстерифицированных жирных кислот в развитии инсулинорезистентности // Пробл. эндокринологии. - Москва, - 2009. - Т. 55, - № 3. - С. 13-17.
5. Шамсиева З. И., Нишанова Ф. П., Исмаилова К. А. Лептин и его роль в регуляции жировой массы//Новости дерматовенерологии и репродуктивного здоровья. - Ташкент, - 2012. - № 4. - C. 66-68.
6. Abbasi F., Chu J., Lamendola C. Discrimination between obesity and insulin resistance in the relationship with adiponektin//Diabe-tes. - 2004. - No. 53. - P. 585-590.
7. Almanza-Perez J. C., Blancas-Flores G., Garcia-Macedo R. Leptin and its association with obesity and type 2 diabetes//Gac. Med. Mex. - 2008. - No. 144 (6). - P. 535-542.
8. Antuna-Puente B., Feve B., Fellahi S. Adipocines: the missing link between insulin resistance and obesity // Diabet. Metab. - 2008. -No. 34 (1). - P. 2-11.
9. Boden G. Obesity, free fatty acids, and insulin resistance // Curr. Opin. Endocrinol. Diab. - 2007. - No. 8. - P. 235-239.
10. Chubenko E. A., Beliaeva O. D., Berkovich O. A. Leptin and metabolic syndrome // Diabet. Med. - 2009. - No. 26. - P. 177-181.
11. Conde J., Scotece M., Gómez R. At the crossroad between immunity and metabolism: focus on leptin//Expert. Rev. Clin. Immunol. -2010. - No. 6 (5). - P. 801-808.
12. Hotamisligil G. S. Molecular mechanisms of insulin resistance and the role of the adipocyte//J. Obes. Relat. Metab. Disord. - 2008. -No. 24 suppl. 4. - P. 23-27.
13. Luis D. A., Perez Castrillón J. L., Duenas A. Leptin and obesity // Minerva Med. - 2009. - No. 100 (3). - P. 229-236.
14. Mattu H. S., Randeva H. S. Role of adipokines in cardiovascular disease // J. Endocrinol. - 2013. - No. 216 (1). - P. 17-36.
15. Maury E., Brichard S. M. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome//Mol. Cell Endocrinol. -2010. - No. 314 (1). - P. 1-16.
16. Ricci R., Bevilacqua F. The potential role ofleptin and adiponectin in obesity: a comparative review//Vet J. -2012. - No. 191 (3). - P. 292-298.
17. Sesti G. Pathophysiology of insulin resistance. Best Pract. Res // Clin. Endocrinol. Metab. -2006. - No. 20 (4). - P. 665-679.
18. Sumarac-Dumanovk M., Jeremk D. Adipokines and lipids // J. Med. Pregl. - 2009. - No. 62, suppl 3. - P. 47-53.
19. Xita N., Tsatsoulis A. Adiponectin in diabetes mellitus // Curr. Med. Chem. - 2012. - No. 19 (32). -P. 5451-5458.
20. Ziemke F., Mantzoros C. S. Adiponectin in insulin resistance: lessons from translational research // Am. J. Clin. Nutr. - 2010. - No. 91 (1). - P. 258-261.
