Skip to main content

Advertisement

Log in

The endothelial dysfunction in patients with type 2 diabetes mellitus is associated with IL-6 gene promoter polymorphism in Chinese population

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

The purpose of this study is to examine the effects of IL-6 gene promoter −174G/C and −572G/C polymorphism on endothelial function of Chinese T2DM and normal glucose regulation (NGR) subjects. 512 newly diagnosed T2DM patients and 483 NGR subjects were recruited and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was performed for the IL-6 gene promoter −174G/C and −572G/C polymorphism. Flow-mediated dilation (FMD) was measured as a non-invasive indicator for endothelial function. The results show that the C allele and CC genotype at −174 of IL-6 gene promoter region was extremely rare in both T2DM and NGR groups; genotypes’ and alleles’ frequency at −572 of IL-6 gene promoter region is of no difference between T2DM and NGR groups; within T2DM group, higher plasma IL-6 concentration and lower FMD was found in patients with −572 GC (2.36 ± 0.69, 4.23 ± 3.82%) or GG (2.32 ± 0.74, 4.24 ± 3.67%) genotype, compared with patients with CC (2.15 ± 0.62, 5.28 ± 3.94%) genotype. The conclusion of the study is that in comparison with patients of CC genotype, the T2DM patients of −572 GC or GG genotype may have more aggravated endothelial dysfunction (ED) and be at higher risk for coronary artery disease (CAD).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

IL-6:

Interleukin-6

T2DM:

Type 2 diabetes mellitus

NGR:

Normal glucose regulation

CAD:

Coronary artery disease

ED:

Endothelial dysfunction

FMD:

Flow-mediated dilation

BMI:

Body mass index

SBP:

Systolic blood pressure

DBP:

Diastolic blood pressure

FPG:

Fasting plasma glucose

2 h PPG:

2 h Postloading plasma glucose

INS:

Insulin

HOMA-IR:

Homeostasis model assay of insulin resistance

TC:

Total cholesterol

TG:

Triglyceride

HDL-c:

High-density lipoprotein–cholesterol

LDL-c:

Low-density lipoproteincholesterol

References

  1. S.M. Haffner, S. Lehto, T. Ronnemaa, K. Pyorala, M. Laakso, Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N. Engl. J. Med. 339(4), 229–234 (1998)

    Article  PubMed  CAS  Google Scholar 

  2. M. Shechter, A. Issachar, I. Marai, N. Koren-Morag, D. Freinark, Y. Shahar, A. Shechter, M.S. Feinberg, Long-term association of brachial artery flow-mediated vasodilation and cardiovascular events in middle-aged subjects with no apparent heart disease. Int. J. Cardiol. 134(1), 52–58 (2009)

    Article  PubMed  Google Scholar 

  3. M.E. Widlansky, N. Gokce, J.F. Keaney Jr, J.A. Vita, The clinical implications of endothelial dysfunction. J. Am. Coll. Cardiol. 42(7), 1149–1160 (2003)

    Article  PubMed  CAS  Google Scholar 

  4. M. Diamant, M.E. Tushuizen, The metabolic syndrome and endothelial dysfunction: common highway to type 2 diabetes and CVD. Curr. Diabetes Rep. 6(4), 279–286 (2006)

    Article  CAS  Google Scholar 

  5. G. Reyes-Soffer, S. Holleran, M.R. Di Tullio, S. Homma, B. Boden-Albala, R. Ramakrishnan, M.S. Elkind, R.L. Sacco, H.N. Ginsberg, Endothelial function in individuals with coronary artery disease with and without type 2 diabetes mellitus. Metabolism 59, 1365–1371 (2010)

    Article  PubMed  CAS  Google Scholar 

  6. X.P. Li, S.P. Zhao, X.Y. Zhang, L. Liu, M. Gao, Q.C. Zhou, Protective effect of high density lipoprotein on endothelium-dependent vasodilatation. Int. J. Cardiol. 73(3), 231–236 (2000)

    Article  PubMed  CAS  Google Scholar 

  7. F.M. Maggi, S. Raselli, L. Grigore, L. Redaelli, S. Fantappie, A.L. Catapano, Lipoprotein remnants and endothelial dysfunction in the postprandial phase. J. Clin. Endocrinol. Metab. 89(6), 2946–2950 (2004)

    Article  PubMed  CAS  Google Scholar 

  8. S. Nadar, A.D. Blann, G.Y. Lip, Endothelial dysfunction: methods of assessment and application to hypertension. Curr. Pharm. Des. 10(29), 3591–3605 (2004)

    Article  PubMed  CAS  Google Scholar 

  9. S.J. Cleland, N. Sattar, J.R. Petrie, N.G. Forouhi, H.L. Elliott, J.M. Connell, Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease. Clin. Sci. (Lond.) 98(5), 531–535 (2000)

    Article  CAS  Google Scholar 

  10. J. Sinisalo, J. Paronen, K.J. Mattila, M. Syrjala, G. Alfthan, T. Palosuo, M.S. Nieminen, O. Vaarala, Relation of inflammation to vascular function in patients with coronary heart disease. Atherosclerosis 149(2), 403–411 (2000)

    Article  PubMed  CAS  Google Scholar 

  11. J.C. Pickup, M.B. Mattock, G.D. Chusney, D. Burt, NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40(11), 1286–1292 (1997)

    Article  PubMed  CAS  Google Scholar 

  12. H.G. Rus, R. Vlaicu, F. Niculescu, Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 127(2), 263–271 (1996)

    Article  PubMed  CAS  Google Scholar 

  13. A. Waage, G. Slupphaug, R. Shalaby, Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts. Eur. J. Immunol. 20(11), 2439–2443 (1990)

    Article  PubMed  CAS  Google Scholar 

  14. G.J. Blake, P.M. Ridker, Inflammatory bio-markers and cardiovascular risk prediction. J. Intern. Med. 252(4), 283–294 (2002)

    Article  PubMed  CAS  Google Scholar 

  15. B. Schieffer, E. Schieffer, D. Hilfiker-Kleiner, A. Hilfiker, P.T. Kovanen, M. Kaartinen, J. Nussberger, W. Harringer, H. Drexler, Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 101(12), 1372–1378 (2000)

    PubMed  CAS  Google Scholar 

  16. A. Malarstig, L. Wallentin, A. Siegbahn, Genetic variation in the interleukin-6 gene in relation to risk and outcomes in acute coronary syndrome. Thromb. Res. 119(4), 467–473 (2007)

    Article  PubMed  Google Scholar 

  17. M. Bennermo, C. Held, F. Green, L.E. Strandberg, C.G. Ericsson, L.O. Hansson, H. Watkins, A. Hamsten, P. Tornvall, Prognostic value of plasma interleukin-6 concentrations and the −174 G>C and −572 G>C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis. Atherosclerosis 174(1), 157–163 (2004)

    Article  PubMed  CAS  Google Scholar 

  18. W. Lieb, R. Pavlik, J. Erdmann, B. Mayer, S.R. Holmer, M. Fischer, A. Baessler, C. Hengstenberg, H. Loewel, A. Doering, G.A. Riegger, H. Schunkert, No association of interleukin-6 gene polymorphism (−174 G/C) with myocardial infarction or traditional cardiovascular risk factors. Int. J. Cardiol. 97(2), 205–212 (2004)

    Article  PubMed  Google Scholar 

  19. L.T. Kuo, N.I. Yang, W.J. Cherng, S. Verma, M.J. Hung, S.Y. Wang, M.H. Liu, S.Y. Chen, C.H. Wang, Serum interleukin-6 levels, not genotype, correlate with coronary plaque complexity. Int. Heart J. 49(4), 391–402 (2008)

    Article  PubMed  CAS  Google Scholar 

  20. S.L. Ferrari, L. Ahn-Luong, P. Garnero, S.E. Humphries, S.L. Greenspan, Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. J. Clin. Endocrinol. Metab. 88(1), 255–259 (2003)

    Article  PubMed  CAS  Google Scholar 

  21. J.M. Fernandez-Real, J. Vendrell, C. Richart, C. Gutierrez, W. Ricart, Platelet count and interleukin 6 gene polymorphism in healthy subjects. BMC Med. Genet. 2, 6 (2001)

    Article  PubMed  CAS  Google Scholar 

  22. Y. Tong, Z. Wang, Y. Geng, J. Liu, R. Zhang, Q. Lin, X. Li, D. Huang, S. Gao, D. Hu, Y. Li, J. Cheng, Z. Lu, The association of functional polymorphisms of IL-6 gene promoter with ischemic stroke: analysis in two Chinese populations. Biochem. Biophys. Res. Commun. 391(1), 481–485 (2010)

    Article  PubMed  CAS  Google Scholar 

  23. Y.H. Hamid, C.S. Rose, S.A. Urhammer, C. Glumer, R. Nolsoe, O.P. Kristiansen, T. Mandrup-Poulsen, K. Borch-Johnsen, T. Jorgensen, T. Hansen, O. Pedersen, Variations of the interleukin-6 promoter are associated with features of the metabolic syndrome in Caucasian Danes. Diabetologia 48(2), 251–260 (2005)

    Article  PubMed  CAS  Google Scholar 

  24. A.D. Pradhan, J.E. Manson, N. Rifai, J.E. Buring, P.M. Ridker, C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286(3), 327–334 (2001)

    Article  PubMed  CAS  Google Scholar 

  25. C. de Luca, J.M. Olefsky, Inflammation and insulin resistance. FEBS Lett. 582(1), 97–105 (2008)

    Article  PubMed  Google Scholar 

  26. Y.H. Lee, R.E. Pratley, The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diabetes Rep 5(1), 70–75 (2005)

    Article  CAS  Google Scholar 

  27. A. Kitamura, G. Hasegawa, H. Obayashi, K. Kamiuchi, M. Ishii, M. Yano, T. Tanaka, M. Yamaguchi, H. Shigeta, M. Ogata, N. Nakamura, T. Yoshikawa, Interleukin-6 polymorphism (−634C/G) in the promotor region and the progression of diabetic nephropathy in type 2 diabetes. Diabet. Med. 19(12), 1000–1005 (2002)

    Article  PubMed  CAS  Google Scholar 

  28. C.F. Terry, V. Loukaci, F.R. Green, Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 275(24), 18138–18144 (2000)

    Article  PubMed  CAS  Google Scholar 

  29. R.B. Goldberg, Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J. Clin. Endocrinol. Metab. 94(9), 3171–3182 (2009)

    Article  PubMed  CAS  Google Scholar 

  30. R. Ross, Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340(2), 115–126 (1999)

    Article  PubMed  CAS  Google Scholar 

  31. D.S. Celermajer, K.E. Sorensen, V.M. Gooch, D.J. Spiegelhalter, O.I. Miller, I.D. Sullivan, J.K. Lloyd, J.E. Deanfield, Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340(8828), 1111–1115 (1992)

    Article  PubMed  CAS  Google Scholar 

  32. H. Daxecker, M. Raab, S. Markovic, A. Karimi, A. Griesmacher, M.M. Mueller, Endothelial adhesion molecule expression in an in vitro model of inflammation. Clin. Chim. Acta 325(1–2), 171–175 (2002)

    Article  PubMed  CAS  Google Scholar 

  33. S. Cardaropoli, F. Silvagno, E. Morra, G.P. Pescarmona, T. Todros, Infectious and inflammatory stimuli decrease endothelial nitric oxide synthase activity in vitro. J. Hypertens. 21(11), 2103–2110 (2003)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by grant from Hangzhou Committee of Science and Technology (2005B012), we also thank all participants in the study.

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chu Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, X., Ma, L., Peng, F. et al. The endothelial dysfunction in patients with type 2 diabetes mellitus is associated with IL-6 gene promoter polymorphism in Chinese population. Endocrine 40, 124–129 (2011). https://doi.org/10.1007/s12020-011-9442-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-011-9442-9

Keywords

Navigation