Download PDF
Exp Clin Endocrinol Diabetes 2012; 120(08): 460-465
DOI: 10.1055/s-0032-1306349
Article
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Relations among Glycemic Control, Circulating Endothelial Cells, Nitric Oxide, and Flow Mediated Dilation in Patients with Type 2 Diabetes Mellitus

N. A. Kotb
1   Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
,
R. Gaber
2   Department of Cardiology, Faculty of Medicine, Tanta University, Tanta, Egypt
,
W. Salah
3   Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
,
A. Elhendy
4   Department of Cardiology, Marshfield Clinic, Marshfield WI, USA
› Author Affiliations
Further Information

Publication History

received 15 February 2012
first decision 15 February 2012

accepted 28 February 2012

Publication Date:
25 May 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Objectives:

Circulating endothelial cells (CEC) have been identified as a surrogate marker of endothelial dysfunction. The aim of this study was to determine the association of glycemic control with CEC and endothelial function in patients with type 2 diabetes mellitus (DM).

Methods:

We studied 30 patients with type 2 DM and 20 age and sex matched healthy controls (HC). Number of circulating endothelial cells was measured by flow cytometry. Endothelial function was studied by measuring flow mediated vasodilation (FMD%) in the brachial artery and serum level of nitric oxide (NO).

Results:

CEC count was significantly elevated in patients with DM, than HC (35.3±15.1 vs. 7.3±2.4, p<0.001) and in patients with HbA1c>7 than patients with HbA1c≤7 (47.4±5.5 vs. 19.5±5.7, p<0.001). FMD% and NO were lower in DM patients than HC (3.5±0.85 vs. 9.5±3.1, p<0.001 and 37.8±6.1 vs. 64.1±5.7, p<0.001 respectively). FMD% and NO were lower in patients with HbA1c>7 as compared to patients with HA1c≤7 (2.8±0.4 vs. 4.3±0.4, p<0.001 and 33.1±2.9 vs. 43.9±2.8, respectively, p<0.001). HbA1c correlated negatively with FMD% and NO levels and positively with CEC. CEC count correlated negatively with FMD% and NO. There was a significant positive correlation between CEC count and HBA1c (p<0.001 for all correlations).

Conclusion:

CEC is associated with markers of endothelial dysfunction and disease control in patients with type 2 DM. These findings suggest a potential role of CEC in the pathophysiology of cardiovascular disease in type 2 diabetic and raise the importance of tight glycemic control.

Key words

circulating endothelial cells - nitric oxide - diabetes mellitus - endothelial function
 

  • References

  • 1 Celermajer DS. Endothelial dysfunction: does it matter? Is it reversible?. J Am Coll Cardiol 1997; 30: 325-333
    CrossrefPubMedGoogle Scholar
  • 2 Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813-820
    CrossrefPubMedGoogle Scholar
  • 3 Swerdlow AJ, Jones ME. Mortality during 25 years of follow-up of a cohort with diabetes. Int J Epidemiol 1996; 25: 1250-1261
    CrossrefPubMedGoogle Scholar
  • 4 Jarvisalo MJ, Raitakari M, Toikka JO et al. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 2004; 109: 1750-1755
    CrossrefPubMedGoogle Scholar
  • 5 Dogra G, Rich L, Stanton K et al. Endothelium-dependent and independent vasodilation studies at normoglycaemia in type I diabetes mellitus with and without microalbuminuria. Diabetologia 2001; 44: 593-601
    CrossrefPubMedGoogle Scholar
  • 6 Henry RM, Ferreira I, Kostense PJ et al. Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilation, but impaired glucose metabolism is not: the Hoorn Study. Atherosclerosis 2004; 174: 49-56
    CrossrefPubMedGoogle Scholar
  • 7 James PE, Lang DT, Tufnell-Barret T et al. Vasorelaxation by red cells and impairment in diabetes. Cir Res 2004; 94: 976-983
    CrossrefPubMedGoogle Scholar
  • 8 Sydo K, Mondon CE, Cooke JP. Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA. Vasc Med 2005; 10: S35-S43
    CrossrefPubMedGoogle Scholar
  • 9 Corretti MC, Anderson TJ, Benjamin EJ et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilatation of the brachial artery: a report of the International Brachial artery Reactivity Task Force. J Am Coll Cardiol 2002; 16: 257-265
    PubMedGoogle Scholar
  • 10 Mabley JG, Soriano FG. Role of nitrosative stress and poly (ADPribose) polymerase activation in diabetic vascular dysfunction. Current Vascular Pharmacol 2005; 3: 247-252
    PubMedGoogle Scholar
  • 11 King GL, Loeken MR. Hyperglycemia-induced oxidative stress in diabetic complications. Histochemistry and Cell Biology 2004; 122: 333-338
    CrossrefPubMedGoogle Scholar
  • 12 Zou MH, Shi C, Cohen RA. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H (2) receptor mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes 2002; 51: 198-203
    PubMedGoogle Scholar
  • 13 Rajagopalan S, Brook R, Mehta RH et al. Effect of Losartan in aging-related endothelial impairment. Am J Cardiol 2002; 89: 562-566
    CrossrefPubMedGoogle Scholar
  • 14 Zhang X, Zhao SP, Li XP et al. Endothelium-dependent and independent functions are impaired in patients with coronary heart disease. Atherosclerosis 2000; 149: 19-24
    CrossrefPubMedGoogle Scholar
  • 15 Macey M, McCarthy D, Azam U et al. Ethylene diamine tetraacetic acid plus citrate-theophylline-adenosine-dipyridamole (EDTA-CTAD): a novel anticoagulant for the flow cytometric assessment of platelet and neutrophil activation ex vivo in whole blood. Cytometry B Clin Cytom 2003; 51: 30-40
    PubMedGoogle Scholar
  • 16 Goon P, Boos C, Stonelake S et al. Detection and quantification of mature circulating endothelial cells using flow cytometry and immunomagnetic beads: A methodological comparison. Thromb Haemost 2006; 96: 45-52
    PubMedGoogle Scholar
  • 17 Woywodt A, Blann AD, Kirsch T et al. Isolation and enumeration of circulating endothelial cells by immunomagnetic isolation: proposal of a definition and a consensus protocol. J Thromb Haemost 2006; 4: 671-677
    CrossrefPubMedGoogle Scholar
  • 18 Granger DL, Taintor RR, Boockvar KS et al. Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. Methods Enzymol 1996; 268: 142-151
    PubMedGoogle Scholar
  • 19 Grisham MB, Johnson GG, Lancaster Jr JR. Quantitation of nitrate and nitrite in extracellular fluids. Methods Enzymol 1996; 268: 237-246
    PubMedGoogle Scholar
  • 20 Felmeden DC, Blann AD, Spencer CG et al. A comparison of flow-mediated dilatation and von Willebrand factor as markers of endothelial cell function in health and in hypertension: relationship to cardiovascular risk and effects of treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. Blood Coagul Fibrinolysis 2003; 14: 425-431
    CrossrefPubMedGoogle Scholar
  • 21 Hashimoto M, Kozaki K, Eto M et al. Association of coronary risk factors and endothelium-dependent flow-mediated dilatation of the brachial artery. Hypertens Res 2000; 23: 233-238
    CrossrefPubMedGoogle Scholar
  • 22 Makin AJ, Chung NAY, Silverman SH et al. Assessment of endothelial damage in atherosclerotic vascular disease by quantification of circulating endothelial cells. Eur Heart J 2004; 25: 371-376
    CrossrefPubMedGoogle Scholar
  • 23 Khan SS, Solomon MA, McCoy Jr JP. Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry. Cytometry. Part B. Clinical Cytometry 2005; 64: 1-8
    PubMedGoogle Scholar
  • 24 Nakatani K, Takeshita S, Tsujimoto H et al. Circulating endothelial cells in Kawasaki disease. Clinical and Experimental Immunology 2003; 131: 536-540
    CrossrefPubMedGoogle Scholar
  • 25 Woywodt A, Streiber F, de Groot K et al. Circulating endothelial cells as markers for ANCA associated small-vessel vasculitis. Lancet 2003; 361: 206-210
    CrossrefPubMedGoogle Scholar
  • 26 McClung JA, Naseer N, Saleem M et al. Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA (1)c. Diabetologia 2005; 48: 345-350
    CrossrefPubMedGoogle Scholar
  • 27 Mutin M, Canavy I, Blann A et al. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood 1999; 93: 2951-2958
    PubMedGoogle Scholar
  • 28 Zou NH, Shi, Cohen RA. High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H (2) receptor mediated apoptosos and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes 2002; 51: 198-203
    PubMedGoogle Scholar
  • 29 Du X, Stocklauser-Farber K, Rosen P. Generation of reactive oxygen intermediates, activation of NF-Kappa B and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase?. Free Radical Biology & Medicine 1999; 27: 752-763
    CrossrefPubMedGoogle Scholar
  • 30 Nakao-Hayashi J, Ito H, Kawashima S. An oxidative mechanism is involved in high glucose-induced serum protein modification causing inhibition of endothelial cell proliferation. Atherosclerosis 1992; 97: 89-95
    CrossrefPubMedGoogle Scholar
  • 31 Curcio F, Ceriello A. Decreased cultured endothelial cell proliferation in high glucose medium is reversed by antioxidant: new insights on the pathphysiological mechanisms of diabetic vascular complications. In Vitro Cellular& Developmental Biology 1992; 28: 787-790
    PubMedGoogle Scholar
  • 32 Lorenzi M, Nordebrg JA, Toledo S. High glucose prolongs cell cycle traversal of cultured human endothelial cells. Diabetes 1987; 36: 1261-1267
    CrossrefPubMedGoogle Scholar
  • 33 McClung JA, Saleem M, Rossi GP et al. Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA (1)c. Diabetologia 2005; 48: 345-350
    CrossrefPubMedGoogle Scholar
  • 34 Tank C, Chow WS, Ai VH et al. Advanced end glycation products and endothelial dysfunction in type 2 diabetes. Diabetes care 2002; 25: 1055-1059
    CrossrefPubMedGoogle Scholar
  • 35 Henry RM, Ferreira, Kostensa PJ. et al. Type 2 diabetes is associated with impaired endothelial dependent flow mediated dilatation but impaired glucose metabolism is not. The Hoom study. Atherosclerosis 2004; 174: 49-56
    CrossrefPubMedGoogle Scholar
  • 36 Windeban KA, Feldman E. diabetes and the nervous system. In: Neurology and General Medicine. Aminoff M. (ed.). Philadelphia, PA: Churchill Livingstone; 2001: 341-346
    Google Scholar
  • 37 Singh R, Barden A Motit et al. Advanced glycation end-product; a review. Diabetologia 2001; 44: 129-146
    CrossrefPubMedGoogle Scholar
  • 38 Shahid SM, Mahboob T. Correlation between glycosylated hemoglobin (HbA1c) and serum Nitric oxide (NO). Aust J Basic Appl Sci 2009; 3: 1323-1327
    PubMedGoogle Scholar
  • 39 Holmen C, Elsheikh E, Stenvinkel P. Circulating inflammatory endothelial cells contribute to endothelial progenitor cell dysfunction in patients with vasculitis and kidney involvement. J Am Soc Nephrol 2005; 16: 3110-3120
    CrossrefPubMedGoogle Scholar