Endocrine

, Volume 38, Issue 2, pp 266–275 | Cite as

Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients

  • Lu-lu Chen
  • Yun-fei Liao
  • Tian-shu Zeng
  • Fan Yu
  • Hui-qing Li
  • Yong Feng
Original Article

Abstract

Circulating endothelial progenitor cells (EPCs) play an important role in the development and progression of diabetic vascular complications. The aim of this study was to investigate the effects of gliclazide plus metformin (GLIMET) compared with metformin alone (MET) on number and function of circulating EPCs in T2DM patients. Patients with newly diagnosed T2DM were randomly divided into two groups, receiving the following treatments for 16 weeks: MET group (assuming metformin 500–2500 mg/day, n = 24) and GLIMET group [assuming gliclazide (modified release, 30–60 mg/day) + metformin (250–1000 mg/day), n = 23]. Circulating EPCs were quantified by flow cytometry, and the ability to uptake LDL and stain for lectin were used as another method of characterizing EPCs ex vivo. The functions of circulating EPCs were evaluated by colony-forming units (CFU) and migration. The status of oxidative stress was analyzed by serum-free malonaldehyde (MDA) and superoxide dismutase (SOD). There were no significant differences in clinical characteristics and number and function of circulating EPCs between two groups at baseline. Glycemic responses were similar after treatments. Compared with MET group, GLIMET group was associated with an increase in circulating EPCs number, DiLDL–lectin-positive EPCs, and migration. The mean improvements in MDA and SOD of GLIMET group were more strongly upregulated than those of MET group. This study demonstrated that both metformin mono-treatment and metformin plus gliclazide combination treatment provided with improvements in number and function of circulating EPCs. Compared with metformin mono-treatment, early use of combination therapy with gliclazide plus metformin made more effective improvements in circulating EPCs.

Keywords

Endothelial progenitor cell Type 2 diabetes Metformin Gliclazide Oxidative stress 

Notes

Acknowledgments

This study was supported by grants from scientific and technological project of Hubei province (No. 2007AA302B04) and the scientific research foundation from health department of Hubei province (No. JX3A04).

Disclosure

The authors declare that there is no conflict of interest that would prejudice its impartiality.

References

  1. 1.
    G.P. Fadini, C. Agostini, A. Avogaro, Endothelial progenitor cells and vascular biology in diabetes mellitus: current knowledge and future perspectives. Curr. Diabetes Rev. 1, 41–58 (2005)CrossRefPubMedGoogle Scholar
  2. 2.
    G.P. Fadini, S. Sartore, C. Agostini, A. Avogaro, Significance of endothelial progenitor cells in subjects with diabetes. Diabetes Care 30, 1305–1313 (2007)CrossRefPubMedGoogle Scholar
  3. 3.
    G.P. Fadini, M. Miorin, M. Facco, S. Bonamico, I. Baesso, F. Grego, M. Menegolo, S.V. de Kreutzenberg, A. Tiengo, C. Agostini, A. Avogaro, Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J. Am. Coll. Cardiol. 45, 1449–1457 (2005)CrossRefPubMedGoogle Scholar
  4. 4.
    O.M. Tepper, R.D. Galiano, J.M. Capla, C. Kalka, P.J. Gagne, G.R. Jacobowitz, J.P. Levine, G.C. Gurtner, Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106, 2781–2786 (2002)CrossRefPubMedGoogle Scholar
  5. 5.
    G.P. Fadini, S. Sartore, M. Albiero, I. Baesso, E. Murphy, M. Menegolo, F. Grego, S. Vigili de Kreutzenberg, A. Tiengo, C. Agostini, A. Avogaro, Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler. Thromb. Vasc. Biol. 26, 2140–2146 (2006)CrossRefPubMedGoogle Scholar
  6. 6.
    D.P. Macfarlane, K.R. Paterson, M. Fisher, Oral antidiabetic agents as cardiovascular drugs. Diabetes Obes. Metab. 9, 23–30 (2007)CrossRefPubMedGoogle Scholar
  7. 7.
    Y. Sahin, K. Unluhizarci, A. Yilmazsoy, A. Yikilmaz, E. Aygen, F. Kelestimur, The effects of metformin on metabolic and cardiovascular risk factors in nonobese women with polycystic ovary syndrome. Clin. Endocrinol. (Oxf) 67, 904–908 (2007)CrossRefGoogle Scholar
  8. 8.
    UK Prospective Diabetes Study UKPDS Group, Effect of intensive blood glucose control with metformin on complications in overnight patients with type 2 diabetes (UKPDS 34). Lancet 352, 854–865 (1998)CrossRefGoogle Scholar
  9. 9.
    ADVANCE Collaborative Group, A. Patel, S. MacMahon, J. Chalmers, B. Neal, L. Billot, M. Woodward, M. Marre, M. Cooper, P. Glasziou, D. Grobbee, P. Hamet, S. Harrap, S. Heller, L. Liu, G. Mancia, C.E. Mogensen, C. Pan, N. Poulter, A. Rodgers, B. Williams, S. Bompoint, B.E. de Galan, R. Joshi, F. Travert, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008)CrossRefPubMedGoogle Scholar
  10. 10.
    American Diabetes Association, Standards of Medical Care in Diabetes-2008. Diabetes Care 31, S12–54S (2008)CrossRefGoogle Scholar
  11. 11.
    M. Brownlee, The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 (2005)CrossRefPubMedGoogle Scholar
  12. 12.
    J. Haendeler, S. Dimmeler, Inseparably tied: functional and antioxidative capacity of endothelial progenitor cells. Circ. Res. 98, 157–158 (2006)CrossRefPubMedGoogle Scholar
  13. 13.
    G. Formoso, E.A. De Filippis, N. Michetti, P. Di Fulvio, A. Pandolfi, T. Bucciarelli, G. Ciabattoni, A. Nicolucci, G. Davì, A. Consoli, Decreased in vivo oxidative stress and decreased platelet activation following metformin treatment in newly diagnosed type 2 diabetic subjects. Diabetes Metab. Res. Rev. 24, 231–237 (2008)CrossRefPubMedGoogle Scholar
  14. 14.
    C.M. Sena, T. Louro, P. Matafome, E. Nunes, P. Monteiro, R. Seiça, Antioxidant and vascular effects of gliclazide in type 2 diabetic rats fed high fat diet. Physiol. Res. 58, 203–209 (2009)PubMedGoogle Scholar
  15. 15.
    The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20, 1183–1197 (1997)Google Scholar
  16. 16.
    J.M. Hill, G. Zalos, J.P. Halcox, W.H. Schenke, M.A. Waclawiw, A.A. Quyyumi, T. Finkel, Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N. Engl. J. Med. 348, 593–600 (2003)CrossRefPubMedGoogle Scholar
  17. 17.
    W. Kim, M.H. Jeong, S.H. Cho, J.H. Yun, H.J. Chae, Y.K. Ahn, M.C. Lee, X. Cheng, T. Kondo, T. Murohara, J.C. Kang, Effect of green tea consumption on endothelial function and circulating endothelial progenitor cells in chronic smokers. Circ. J 70, 1052–1057 (2006)CrossRefPubMedGoogle Scholar
  18. 18.
    Y. Numaguchi, T. Sone, K. Okumura, M. Ishii, Y. Morita, R. Kubota, K. Yokouchi, H. Imai, M. Harada, H. Osanai, T. Kondo, T. Murohara, The impact of the capability of circulating progenitor cell to differentiate on myocardial salvage in patients with primary acute myocardial infarction. Circulation 114, I114–I119 (2006)CrossRefPubMedGoogle Scholar
  19. 19.
    C. Murphy, G.S. Kanaganayagam, B. Jiang, P.J. Chowienczyk, R. Zbinden, M. Saha, S. Rahman, A.M. Shah, M.S. Marber, M.T. Kearney, Vascular dysfunction and reduced circulating endothelial progenitor cells in young healthy UK south Asian men. Arterioscler. Thromb. Vasc. Biol. 27, 936–942 (2007)CrossRefPubMedGoogle Scholar
  20. 20.
    N. Werner, S. Kosiol, T. Schiegl, P. Ahlers, K. Walenta, A. Link, M. Böhm, G. Nickenig, Circulating endothelial progenitor cells and cardiovascular outcomes. N. Engl. J. Med. 353, 999–1007 (2005)CrossRefPubMedGoogle Scholar
  21. 21.
    S. Rafii, D. Lyden, Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat. Med. 9, 702–712 (2003)CrossRefPubMedGoogle Scholar
  22. 22.
    J. Kao, J. Tobis, R.L. McClelland, M.R. Heaton, B.R. Davis, D.R. Holmes, J.W. Currier, Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am. J. Cardiol. 93, 1347–1350 (2004)CrossRefPubMedGoogle Scholar
  23. 23.
    J.A. Johnson, S.R. Majumdar, S.H. Simpson, E.L. Toth, Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 25, 2244–2248 (2002)CrossRefPubMedGoogle Scholar
  24. 24.
    M. Gulliford, R. Latinovic, Mortality in type 2 diabetic subjects prescribed metformin and sulphonylurea drugs in combination: cohort study. Diabetes Metab. Res. Rev. 20, 239–245 (2004)CrossRefPubMedGoogle Scholar
  25. 25.
    K.H. Kahler, M. Rajan, G.G. Rhoads, M.M. Safford, K. Demissie, S.E. Lu, Impact of oral antihyperglycemic therapy on all-cause mortality among patients with diabetes in the veterans health administration. Diabetes Care 30, 1689–1693 (2007)CrossRefPubMedGoogle Scholar
  26. 26.
    J.M. Evans, S.A. Ogston, A. Emslie-Smith, A.D. Morris, Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 49, 930–936 (2006)CrossRefPubMedGoogle Scholar
  27. 27.
    C. Werner, C.H. Kamani, C. Gensch, M. Böhm, U. Laufs, The peroxisome proliferator-activated receptor-gamma agonist pioglitazone increases number and function of endothelial progenitor cells in patients with coronary artery disease and normal glucose tolerance. Diabetes 56, 2609–2615 (2007)CrossRefPubMedGoogle Scholar
  28. 28.
    M. Hristov, C. Fach, C. Becker, N. Heussen, E.A. Liehn, R. Blindt, P. Hanrath, C. Weber, Reduced numbers of circulating endothelial progenitor cells in patients with coronary artery disease associated with long-term statin treatment. Atherosclerosis 192, 413–420 (2007)CrossRefPubMedGoogle Scholar
  29. 29.
    R.R. Holman, S.K. Paul, M.A. Bethel, D.R. Matthews, H.A. Neil, 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008)CrossRefPubMedGoogle Scholar
  30. 30.
    T. Thum, D. Fraccarollo, M. Schultheiss, S. Froese, P. Galuppo, J.D. Widder, D. Tsikas, G. Ertl, J. Bauersachs, Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes 56, 666–674 (2007)CrossRefPubMedGoogle Scholar
  31. 31.
    Y.H. Chen, S.J. Lin, F.Y. Lin, T.C. Wu, C.R. Tsao, P.H. Huang, P.L. Liu, Y.L. Chen, J.W. Chen, High glucose impairs early and late endothelial progenitor cells by modifying nitric oxide-related but not oxidative stress-mediated mechanisms. Diabetes 56, 1559–1568 (2007)CrossRefPubMedGoogle Scholar
  32. 32.
    G. Zhou, R. Myers, Y. Li, Y. Chen, X. Shen, J. Fenyk-Melody, M. Wu, J. Ventre, T. Doebber, N. Fujii, N. Musi, M.F. Hirshman, L.J. Goodyear, D.E. Moller, Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001)PubMedGoogle Scholar
  33. 33.
    N. Musi, M.F. Hirshman, J. Nygren, M. Svanfeldt, P. Bavenholm, O. Rooyackers, G. Zhou, J.M. Williamson, O. Ljunqvist, S. Efendic, D.E. Moller, A. Thorell, L.J. Goodyear, Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51, 2074–2081 (2002)CrossRefPubMedGoogle Scholar
  34. 34.
    P.E. Jennings, Vascular benefits of gliclazide beyond glycemic control. Metabolism 49, 17–20 (2000)CrossRefPubMedGoogle Scholar
  35. 35.
    K. Ukinc, S. Eminagaoglu, H.O. Ersoz, C. Erem, C. Karahan, A.B. Hacihasanoglu, M. Kocak, A novel indicator of widespread endothelial damage and ischemia in diabetic patients: ischemia-modified albumin. Endocrine 26, (2009) [Epub ahead of print]Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Lu-lu Chen
    • 1
  • Yun-fei Liao
    • 1
  • Tian-shu Zeng
    • 1
  • Fan Yu
    • 1
  • Hui-qing Li
    • 1
  • Yong Feng
    • 2
  1. 1.Department of Endocrinology, Union HospitalHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Orthopedics, Union HospitalHuazhong University of Science and TechnologyWuhanChina

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