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The Relationship Between Proinflammatory Cytokine Levels and Fibrinolytic System in Obese Patients

Year 2008, Volume: 2008 Issue: 1, 44 - 51, 01.01.2008

Abstract

Objectives: The aim of this study was to investigate the relationship between proinflammatory cytokines (TNF-α and IL-6), and fibrinolytic system parameters (t-PA, and PAI-1) and insulin resistance in obese individuals. Patients and Methods: The study included 54 obese subjects (BMI ≥30 kg/m2; 41 females, 13 males; mean age 33.5 years) and 30 non-obese healthy individuals (BMI <25 kg/m2; 19 females, 11 males; mean age 22.3 years). Fibrinogen levels were measured by the coagulometric method and the measurements of TNF-α, IL-6, t-PA and PAI-1 were carried out by the ELISA method. Results: Compared with non-obese subjects, obese individuals had significantly higher fibrinogen (p<0.01), PAI-1 (p<0.001), TNF-α (p<0.01), and IL-6 (p<0.001) levels, and significantly lower t-PA level (p<0.001) and t-PA/PAI-1 ratio (p<0.001). We also found an inverse relationship between TNF-α and t-PA levels (p=0.007) and t-PA/PAI-1 ratio (p=0.016) in obese individuals. The presence or absence of insulin resistance did not affect proinflammatory cytokines and fibrinolytic system parameters in obese individuals. Conclusion: Our findings indicate increased inflammatory cytokine levels especially in TNF-α level, and decreased fibrinolysis in obese individuals. These changes may contribute to atherosclerotic process independent from insulin resistance in obesity. Turkish Başlık: Obez Hastalarda Proinflamatuvar Sitokinler ile Fibrinolitik Sistem Arasındaki İlişki Anahtar Kelimeler: Sitokinler; fibrinoliz; insülin direnci; obezite/komplikasyon Amaç: Obez kişilerde proinflamatuar sitokinlerden TNF-α ve IL-6, fibrinolitik sistem parametrelerinden t-PA ve PAI-1 ve insülin direnci arasındaki ilişki araştırıldı. Hastalar ve Yöntemler: Çalışmaya obez (VKİ ≥30 kg/m2) olarak değerlendirilen 54 kişi (41 kadın, 13 erkek; ort. yaş 33.5) ve obezite sorunu olmayan (VKİ <25 kg/m2) 30 kişi (19 kadın, 11 erkek; ort. yaş 22.3) alındı. Fibrinojen düzeyleri koagülometrik olarak ve TNF-α, IL-6, t-PA, PAI-1 düzeyleri ELISA yöntemiyle ölçüldü. Bulgular: Kontrol grubuyla karşılaştırıldığında, obez kişilerde fibrinojen (p<0.01), PAI-1 (p<0.001), TNF-α (p<0.01) ve IL-6 düzeyleri (p<0.001) anlamlı derecede yüksek, t-PA düzeyi (p<0.001) ve t-PA/PAI-1 oranı (p<0.001) anlamlı derecede düşük bulundu. Obezlerde TNF-α ile t-PA (p=0.007) ve t-PA/PAI-1 oranı (p=0.016) arasında ters ilişki saptandı. İnsülin direnci olan ve olmayan obez kişilerde parametreler arasında fark yoktu. Sonuç: Obezitede adipoz dokudan salgılanan özellikle TNF-α gibi inflamatuar sitokinlerin artması fibrinolizde azalmaya yol açar. Obez kişilerde görülen bu değişiklikler, insülin direncinden bağımsız olarak ateroskleroza neden olabilir.

References

  • Caballero Ae. endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obes res 2003;11:1278-89.
  • Festa A, d’Agostino r Jr, Howard G, mykkänen l, Tracy rP, Haffner Sm. Chronic subclinical inflam- mation as part of the insulin resistance syndrome: the Insulin resistance Atherosclerosis Study (IrAS). Circulation 2000;102:42-7.
  • marckmann P, Toubro S, Astrup A. Sustained improvement in blood lipids, coagulation, and fibri- nolysis after major weight loss in obese subjects. eur J Clin nutr 1998;52:329-33.
  • Charles mA, morange P, eschwège e, André P, Vague P, Juhan-Vague I. effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese nondiabetic subjects: the BIGPrO1 Study. Biguanides and the Prevention of the risk of Obesity. diabetes Care 1998;21:1967-72.
  • Scelles V, raccah d, Alessi mC, Vialle Jm, Juhan- Vague I, Vague P. Plasminogen activator inhibitor 1 and insulin levels in various insulin resistance states. diabete metab 1992;18:38-42.
  • mcCarty mF. Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflam- mation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline. med Hypotheses 1999;52:465-77.
  • Hotamisligil GS. mechanisms of TnF-alpha-induced insulin resistance. exp Clin endocrinol diabetes 1999;107:119-25.
  • Yudkin JS, Stehouwer Cd, emeis JJ, Coppack SW. C- reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunc- tion: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999; 19:972-8.
  • World Health Organization. Obesity: Preventing and managing the global epidemic. report of a WHO consultation on obesity. Geneva, World Health Organization. WHO/nuT/nCd/ 98.1. 1997.
  • World Health Organization. definition, diagnosis and classification of diabetes mellitus and its com- plications. report of a WHO Consultation. Geneva; WHO/nCd/nCS/99.2. 1999.
  • matthews dr, Hosker JP, rudenski AS, naylor BA, Treacher dF, Turner rC. Homeostasis model assess- ment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. diabetologia 1985;28:412-9.
  • Gokcel A, Baltali m, Tarim e, Bagis T, Gumurdulu Y, karakose H, et al. detection of insulin resistance in Turkish adults: a hospital-based study. diabetes Obes metab 2003;5:126-30.
  • mertens I, Van Gaal lF. Obesity, haemostasis and the fibrinolytic system. Obes rev 2002;3:85-101.
  • Gillum rF, mussolino me, madans JH. Body fat distribution and hypertension incidence in women and men. The nHAneS I epidemiologic Follow-up Study. Int J Obes relat metab disord 1998;22:127-34.
  • eckel rH, krauss rm. American heart associa- tion call to action: obesity as a major risk factor for coronary heart disease. AHA nutrition Committee. Circulation 1998;97:2099-100.
  • Conlan mG, Folsom Ar, Finch A, davis Ce, Sorlie P, marcucci G, et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk fac- tors for atherosclerosis. The Atherosclerosis risk in Communities (ArIC) Study. Thromb Haemost 1993; 70:380-5.
  • de Pergola G, de mitrio V, Sciaraffia m, Pannacciulli n, minenna A, Giorgino F, et al. lower androgenicity is associated with higher plasma levels of prothrom- botic factors irrespective of age, obesity, body fat dis- tribution, and related metabolic parameters in men. metabolism 1997;46:1287-93.
  • Folsom Ar, Wu kk, rosamond Wd, Sharrett Ar, Chambless le. Prospective study of hemostatic fac- tors and incidence of coronary heart disease: the Atherosclerosis risk in Communities (ArIC) Study. Circulation 1997;96:1102-8.
  • Giltay eJ, elbers Jm, Gooren lJ, emeis JJ, kooistra T, Asscheman H, et al. Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women: modulation by cross-sex hormone administration. Arterioscler Thromb Vasc Biol 1998;18:1716-22.
  • lyon CJ, Hsueh WA. effect of plasminogen activator inhibitor-1 in diabetes mellitus and cardiovascular disease. Am J med 2003;115 Suppl 8A:62S-68S.
  • Vague P, raccah d, Scelles V. Hypofibrinolysis and the insulin resistance syndrome. Int J Obes relat metab disord 1995;19 Suppl 1:S11-5.
  • eliasson mC, Jansson JH, lindahl B, Stegmayr B. High levels of tissue plasminogen activator (tPA) antigen precede the development of type 2 diabetes in a lon- gitudinal population study. The northern Sweden mOnICA study. Cardiovasc diabetol 2003;2:19.
  • kockx m, leenen r, Seidell J, Princen Hm, kooistra T. relationship between visceral fat and PAI-1 in overweight men and women before and after weight loss. Thromb Haemost 1999;82:1490-6.
  • Thögersen Am, Jansson JH, Boman k, nilsson Tk, Weinehall l, Huhtasaari F, et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998;98:2241-7.
  • lowe Gd, Yarnell JW, Sweetnam Pm, rumley A, Thomas HF, elwood PC. Fibrin d-dimer, tissue plas- minogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998;79:129-33.
  • Ziccardi P, nappo F, Giugliano G, esposito k, marfella r, Cioffi m, et al. reduction of inflamma- tory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804-9.
  • Wellen ke, Hotamisligil GS. Obesity-induced inflam- matory changes in adipose tissue. J Clin Invest 2003;112:1785-8.
  • Chan JC, Cheung JC, Stehouwer Cd, emeis JJ, Tong PC, ko GT, et al. The central roles of obesity- associated dyslipidaemia, endothelial activation and cytokines in the metabolic Syndrome-an analysis by structural equation modelling. Int J Obes relat metab disord 2002;26:994-1008.
  • Bastard JP, Jardel C, Bruckert e, Blondy P, Capeau J, laville m, et al. elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin endocrinol metab 2000;85:3338-42.
  • Pradhan Ad, manson Je, rifai n, Buring Je, ridker Pm. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAmA 2001; 286:327-34.
  • ridker Pm, rifai n, Stampfer mJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767-72.
  • Hotamisligil GS. The role of TnFalpha and TnF receptors in obesity and insulin resistance. J Intern med 1999;245:621-5.
  • Yki-Järvinen H. role of insulin resistance in the pathogenesis of nIddm. diabetologia 1995;38:1378- 88.

Obez Hastalarda Proinflamatuvar Sitokinler ile Fibrinolitik Sistem Arasındaki İlişki

Year 2008, Volume: 2008 Issue: 1, 44 - 51, 01.01.2008

Abstract

Amaç: Obez kişilerde proinflamatuar sitokinlerden
TNF-a ve IL-6, fibrinolitik sistem parametrelerinden
t-PA ve PAI-1 ve insülin direnci arasındaki ilişki araştırıldı.
Hastalar ve Yöntemler: Çalışmaya obez (VKİ ≥30
kg/m2) olarak değerlendirilen 54 kişi (41 kadın, 13
erkek; ort. yaş 33.5) ve obezite sorunu olmayan (VKİ
< 25 kg/m2) 30 kişi (19 kadın, 11 erkek; ort. yaş 22.3)
alındı. Fibrinojen düzeyleri koagülometrik olarak ve
TNF-a, IL-6, t-PA, PAI-1 düzeyleri ELISA yöntemiyle
ölçüldü.
Bulgular: Kontrol grubuyla karşılaştırıldığında, obez
kişilerde fibrinojen (p < 0.01), PAI-1 (p < 0.001), TNF-a
(p < 0.01) ve IL-6 düzeyleri (p < 0.001) anlamlı derecede
yüksek, t-PA düzeyi (p < 0.001) ve t-PA/PAI-1 oranı
(p < 0.001) anlamlı derecede düşük bulundu. Obezlerde
TNF-a ile t-PA (p=0.007) ve t-PA/PAI-1 oranı (p=0.016)
arasında ters ilişki saptandı. İnsülin direnci olan ve
olmayan obez kişilerde parametreler arasında fark
yoktu.
Sonuç: Obezitede adipoz dokudan salgılanan özellikle
TNF-a gibi inflamatuar sitokinlerin artması fibrinolizde
azalmaya yol açar. Obez kişilerde görülen bu değişiklikler,
insülin direncinden bağımsız olarak ateroskleroza
neden olabilir.

References

  • Caballero Ae. endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obes res 2003;11:1278-89.
  • Festa A, d’Agostino r Jr, Howard G, mykkänen l, Tracy rP, Haffner Sm. Chronic subclinical inflam- mation as part of the insulin resistance syndrome: the Insulin resistance Atherosclerosis Study (IrAS). Circulation 2000;102:42-7.
  • marckmann P, Toubro S, Astrup A. Sustained improvement in blood lipids, coagulation, and fibri- nolysis after major weight loss in obese subjects. eur J Clin nutr 1998;52:329-33.
  • Charles mA, morange P, eschwège e, André P, Vague P, Juhan-Vague I. effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese nondiabetic subjects: the BIGPrO1 Study. Biguanides and the Prevention of the risk of Obesity. diabetes Care 1998;21:1967-72.
  • Scelles V, raccah d, Alessi mC, Vialle Jm, Juhan- Vague I, Vague P. Plasminogen activator inhibitor 1 and insulin levels in various insulin resistance states. diabete metab 1992;18:38-42.
  • mcCarty mF. Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflam- mation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline. med Hypotheses 1999;52:465-77.
  • Hotamisligil GS. mechanisms of TnF-alpha-induced insulin resistance. exp Clin endocrinol diabetes 1999;107:119-25.
  • Yudkin JS, Stehouwer Cd, emeis JJ, Coppack SW. C- reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunc- tion: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999; 19:972-8.
  • World Health Organization. Obesity: Preventing and managing the global epidemic. report of a WHO consultation on obesity. Geneva, World Health Organization. WHO/nuT/nCd/ 98.1. 1997.
  • World Health Organization. definition, diagnosis and classification of diabetes mellitus and its com- plications. report of a WHO Consultation. Geneva; WHO/nCd/nCS/99.2. 1999.
  • matthews dr, Hosker JP, rudenski AS, naylor BA, Treacher dF, Turner rC. Homeostasis model assess- ment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. diabetologia 1985;28:412-9.
  • Gokcel A, Baltali m, Tarim e, Bagis T, Gumurdulu Y, karakose H, et al. detection of insulin resistance in Turkish adults: a hospital-based study. diabetes Obes metab 2003;5:126-30.
  • mertens I, Van Gaal lF. Obesity, haemostasis and the fibrinolytic system. Obes rev 2002;3:85-101.
  • Gillum rF, mussolino me, madans JH. Body fat distribution and hypertension incidence in women and men. The nHAneS I epidemiologic Follow-up Study. Int J Obes relat metab disord 1998;22:127-34.
  • eckel rH, krauss rm. American heart associa- tion call to action: obesity as a major risk factor for coronary heart disease. AHA nutrition Committee. Circulation 1998;97:2099-100.
  • Conlan mG, Folsom Ar, Finch A, davis Ce, Sorlie P, marcucci G, et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk fac- tors for atherosclerosis. The Atherosclerosis risk in Communities (ArIC) Study. Thromb Haemost 1993; 70:380-5.
  • de Pergola G, de mitrio V, Sciaraffia m, Pannacciulli n, minenna A, Giorgino F, et al. lower androgenicity is associated with higher plasma levels of prothrom- botic factors irrespective of age, obesity, body fat dis- tribution, and related metabolic parameters in men. metabolism 1997;46:1287-93.
  • Folsom Ar, Wu kk, rosamond Wd, Sharrett Ar, Chambless le. Prospective study of hemostatic fac- tors and incidence of coronary heart disease: the Atherosclerosis risk in Communities (ArIC) Study. Circulation 1997;96:1102-8.
  • Giltay eJ, elbers Jm, Gooren lJ, emeis JJ, kooistra T, Asscheman H, et al. Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women: modulation by cross-sex hormone administration. Arterioscler Thromb Vasc Biol 1998;18:1716-22.
  • lyon CJ, Hsueh WA. effect of plasminogen activator inhibitor-1 in diabetes mellitus and cardiovascular disease. Am J med 2003;115 Suppl 8A:62S-68S.
  • Vague P, raccah d, Scelles V. Hypofibrinolysis and the insulin resistance syndrome. Int J Obes relat metab disord 1995;19 Suppl 1:S11-5.
  • eliasson mC, Jansson JH, lindahl B, Stegmayr B. High levels of tissue plasminogen activator (tPA) antigen precede the development of type 2 diabetes in a lon- gitudinal population study. The northern Sweden mOnICA study. Cardiovasc diabetol 2003;2:19.
  • kockx m, leenen r, Seidell J, Princen Hm, kooistra T. relationship between visceral fat and PAI-1 in overweight men and women before and after weight loss. Thromb Haemost 1999;82:1490-6.
  • Thögersen Am, Jansson JH, Boman k, nilsson Tk, Weinehall l, Huhtasaari F, et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998;98:2241-7.
  • lowe Gd, Yarnell JW, Sweetnam Pm, rumley A, Thomas HF, elwood PC. Fibrin d-dimer, tissue plas- minogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998;79:129-33.
  • Ziccardi P, nappo F, Giugliano G, esposito k, marfella r, Cioffi m, et al. reduction of inflamma- tory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804-9.
  • Wellen ke, Hotamisligil GS. Obesity-induced inflam- matory changes in adipose tissue. J Clin Invest 2003;112:1785-8.
  • Chan JC, Cheung JC, Stehouwer Cd, emeis JJ, Tong PC, ko GT, et al. The central roles of obesity- associated dyslipidaemia, endothelial activation and cytokines in the metabolic Syndrome-an analysis by structural equation modelling. Int J Obes relat metab disord 2002;26:994-1008.
  • Bastard JP, Jardel C, Bruckert e, Blondy P, Capeau J, laville m, et al. elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin endocrinol metab 2000;85:3338-42.
  • Pradhan Ad, manson Je, rifai n, Buring Je, ridker Pm. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAmA 2001; 286:327-34.
  • ridker Pm, rifai n, Stampfer mJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767-72.
  • Hotamisligil GS. The role of TnFalpha and TnF receptors in obesity and insulin resistance. J Intern med 1999;245:621-5.
  • Yki-Järvinen H. role of insulin resistance in the pathogenesis of nIddm. diabetologia 1995;38:1378- 88.
There are 33 citations in total.

Details

Primary Language Turkish
Journal Section Articles
Authors

Murat Gerenli This is me

Murat Gerenli This is me

ARMAĞAN Tuğrul This is me

Muzaffer Demir This is me

Ender Arıkan This is me

Ender Arıkan This is me

Sibel Güldiken This is me

Şennur Azcan This is me

Publication Date January 1, 2008
Published in Issue Year 2008 Volume: 2008 Issue: 1

Cite

APA Gerenli, M., Gerenli, M., Tuğrul, A., Demir, M., et al. (2008). Obez Hastalarda Proinflamatuvar Sitokinler ile Fibrinolitik Sistem Arasındaki İlişki. Balkan Medical Journal, 2008(1), 44-51.
AMA Gerenli M, Gerenli M, Tuğrul A, Demir M, Arıkan E, Arıkan E, Güldiken S, Azcan Ş. Obez Hastalarda Proinflamatuvar Sitokinler ile Fibrinolitik Sistem Arasındaki İlişki. Balkan Medical Journal. January 2008;2008(1):44-51.
Chicago Gerenli, Murat, Murat Gerenli, ARMAĞAN Tuğrul, Muzaffer Demir, Ender Arıkan, Ender Arıkan, Sibel Güldiken, and Şennur Azcan. “Obez Hastalarda Proinflamatuvar Sitokinler Ile Fibrinolitik Sistem Arasındaki İlişki”. Balkan Medical Journal 2008, no. 1 (January 2008): 44-51.
EndNote Gerenli M, Gerenli M, Tuğrul A, Demir M, Arıkan E, Arıkan E, Güldiken S, Azcan Ş (January 1, 2008) Obez Hastalarda Proinflamatuvar Sitokinler ile Fibrinolitik Sistem Arasındaki İlişki. Balkan Medical Journal 2008 1 44–51.
IEEE M. Gerenli, M. Gerenli, A. Tuğrul, M. Demir, E. Arıkan, E. Arıkan, S. Güldiken, and Ş. Azcan, “Obez Hastalarda Proinflamatuvar Sitokinler ile Fibrinolitik Sistem Arasındaki İlişki”, Balkan Medical Journal, vol. 2008, no. 1, pp. 44–51, 2008.
ISNAD Gerenli, Murat et al. “Obez Hastalarda Proinflamatuvar Sitokinler Ile Fibrinolitik Sistem Arasındaki İlişki”. Balkan Medical Journal 2008/1 (January 2008), 44-51.
JAMA Gerenli M, Gerenli M, Tuğrul A, Demir M, Arıkan E, Arıkan E, Güldiken S, Azcan Ş. Obez Hastalarda Proinflamatuvar Sitokinler ile Fibrinolitik Sistem Arasındaki İlişki. Balkan Medical Journal. 2008;2008:44–51.
MLA Gerenli, Murat et al. “Obez Hastalarda Proinflamatuvar Sitokinler Ile Fibrinolitik Sistem Arasındaki İlişki”. Balkan Medical Journal, vol. 2008, no. 1, 2008, pp. 44-51.
Vancouver Gerenli M, Gerenli M, Tuğrul A, Demir M, Arıkan E, Arıkan E, Güldiken S, Azcan Ş. Obez Hastalarda Proinflamatuvar Sitokinler ile Fibrinolitik Sistem Arasındaki İlişki. Balkan Medical Journal. 2008;2008(1):44-51.