Acta Diabetologica

, Volume 46, Issue 1, pp 27–33 | Cite as

Effect of pioglitazone and rosiglitazone on mediators of endothelial dysfunction, markers of angiogenesis and inflammatory cytokines in type-2 diabetes

  • Sudarshan K. Vijay
  • Manish Mishra
  • Hemant Kumar
  • K. TripathiEmail author
Original Article


The purpose of this study was to assess the effects of PPAR-γ agonists (pioglitazone and rosiglitazone) on mediators of endothelial dysfunction and markers of angiogenesis in patients with type-2 diabetes. Pioglitazone group showed favorable reductions in serum total cholesterol, triglycerides, LDL cholesterol, VLDL cholesterol and increase in HDL cholesterol as compared to rosiglitazone group, after 16 weeks of treatment and also with control group. There was significant reduction of CRP level in pioglitazone and rosiglitazone group. The level of serum TNF-α decreased significantly in pioglitazone and mildly decreased in rosiglitazone group. The level of VEGF, IL-8 and Angiogenin were increased in pioglitazone than rosiglitazone group. There were no significant changes observed in the serum angiogenin and IL-8 levels in the control group. Pioglitazone and rosiglitazone therapy in type-2 diabetes subjects have additional benefits of reducing mediators of endothelial dysfunction. Increase in angiogenesis markers in patients receiving pioglitazone could have variable effects in diabetic nephropathy and retinopathy as there may be increased vascular neogenesis. Pioglitazone has advantage over rosiglitazone in lowering lipid and proinflammatory cytokines.


PPAR-γ agonists Diabetic nephropathy Diabetic retinopathy Vascular neogenesis 



Authors Mr. Manish Mishra and Mr. Hemant Kumar are thankful to UGC, India, for financial support. Authors are also thankful to Dr. R. K. Singh, Department of Biochemistry and Radheyshyam Maurya, Department of Medicine for their support and help.


  1. 1.
    Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW (1999) C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arteriocler Thromb Vasc Biol 19:972–978Google Scholar
  2. 2.
    Verma S, Buchanan MR, Anderson TJ (2003) Endothelial function testing as a biomarker of vascular disease. Circulation 108:2054–2059PubMedCrossRefGoogle Scholar
  3. 3.
    Verma S, Kuliszewski MA, Li SH, Szmitko PE, Zucco L, Wang CH, Badiwala MV, Mickle DA, Weisel RD, Fedak PW, Stewart DJ, Kutryk MJ (2004) C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation 109:2058–2067PubMedCrossRefGoogle Scholar
  4. 4.
    Verma S, Li SH, Badiwala MV, Weisel RD, Fedak PW, Li RK, Dhillon B, Mickle DA (2002) Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation 105:1890–1896PubMedCrossRefGoogle Scholar
  5. 5.
    Wang CH, Li SH, Weisel RD, Fedak PW, Dumont AS, Szmitko P, Li RK, Mickle DA, Verma S (2003) C-reactive protein upregulates angiotensin type-1 receptors in vascular smooth muscle. Circulation 107:1783–1790PubMedCrossRefGoogle Scholar
  6. 6.
    Rask-Madsen C, Domínguez H, Ihlemann N, Hermann T, Køber L, Torp-Pedersen C (2003) Tumor necrosis factor-alpha inhibits insulin’s stimulating effect on glucose uptake and endothelial dependent vasodilatation in humans. Circulation 108:1815–1821PubMedCrossRefGoogle Scholar
  7. 7.
    Peraldi P, Spiegelman B (1998) TNF-alpha and Insulin resistance: Summary and future prospects. Mol Cell Biochem 182:169–175PubMedCrossRefGoogle Scholar
  8. 8.
    McNeill KL, Fontana L, Russell-Jones DL, Rajman I, Ritter JM, Chowienczyk PJ (2000) Inhibitory effects of low density lipoproteins from men with type-2 diabetes on endothelium dependent relaxation. J Am Coll Cardiol 35:1622–1627PubMedCrossRefGoogle Scholar
  9. 9.
    Ginsberg HN (1991) Lipoprotein physiology in nondiabetic and diabetic status: relationship to atherogenesis. Diabetes Care 14:839–855PubMedCrossRefGoogle Scholar
  10. 10.
    Stitt AW, McGoldrick C, Rice-McCaldin A, McCance DR, Glenn JV, Hsu DK, Liu FT, Thorpe SR, Gardiner TA (2005) Impaired retinal angiogenesis in diabetes: role of advanced glycation end products and galectin-3. Diabetes 54:785–794PubMedCrossRefGoogle Scholar
  11. 11.
    Currie CJ, Morgan CL, Peters JR (1998) The epidemiology and cost of inpatient care for peripheral vascular disease, infection, neuropathy and ulceration in diabetes. Diabetes Care 21:42–48PubMedCrossRefGoogle Scholar
  12. 12.
    Abaci A, Oğuzhan A, Kahraman S, Eryol NK, Unal S, Arinç H, Ergin A (1999) Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 99:2239–2242PubMedGoogle Scholar
  13. 13.
    Favard C, Ortega N, Bayard F, Plouet J (1996) Vascular endothelial growth factor and retinal neovascularisation : a new therapeutic approach for diabetic retinopathy. Diabetes Metab 22:368–373Google Scholar
  14. 14.
    Sharma NK, Gardiner TA, Archer DB (1985) A morphologic and autoradiographic study of cell death and regeneration in the retinal microvasculature of normal and diabetic rats. Am J Opthalmol 100:51–60Google Scholar
  15. 15.
    Mizutani M, Kern TS, Lorenzi M (1996) Accelerated death of retinal microvasculature cells in human and experimental diabetic retinopathy. J Clin Invest 97:2883–2890PubMedCrossRefGoogle Scholar
  16. 16.
    Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidediones is a high affinity ligand for perroxisome proliferators activated receptor gamma. J Biol Chem 270:12953–12956PubMedCrossRefGoogle Scholar
  17. 17.
    Barbier O, Torra IP, Duguay Y, Blanquart C, Fruchart JC, Glineur C, Staels B (2002) Pleiotropic actions of peroxisome proliferators activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 22:717–726PubMedCrossRefGoogle Scholar
  18. 18.
    Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJ, GLAI Study Investigators (2005) A Comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type-2 diabetes and dyslipidemia. Diabetes Care 28:1547–1554PubMedCrossRefGoogle Scholar
  19. 19.
    Boyle PJ, King AB, Olansky L, Marchetti A, Lau H, Magar R, Martin J (2002) Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records. Clin Ther 24:378–396PubMedCrossRefGoogle Scholar
  20. 20.
    Khan MA, St Peter JV, Xue JL (2002) A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care 25:708–711PubMedCrossRefGoogle Scholar
  21. 21.
    Sakamoto J, Kimura H, Moriyama S, Odaka H, Momose Y, Sugiyama Y, Sawada H (2000) Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 278:704–711PubMedCrossRefGoogle Scholar
  22. 22.
    Cabrero A, Cubero M, Llaverías G, Jové M, Planavila A, Alegret M, Sánchez R, Laguna JC, Carrera MV (2003) Differential effects of peroxisome proliferator-activated receptor activators on the mRNA levels of genes involved in lipid metabolism in primary human monocyte-derived macrophages. Metabolism 52:652–657PubMedCrossRefGoogle Scholar
  23. 23.
    Ridker PM, Hennekens CH, Buring JE, Rifai N (2000) C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836–843PubMedCrossRefGoogle Scholar
  24. 24.
    Lukacs NW, Strieter RM, Chensue SW, Widmer M, Kunkel SL (1995) TNF-alpha mediates recruitment of neutrophils and Eosinophils during airway inflammation. J Immunol 154:5411–5417PubMedGoogle Scholar
  25. 25.
    Wang TD, Chen WJ, Lin JW, Chen MF, Lee YT (2004) Effects of rosiglitazone on endothelial function, c-reactive protein and components of the metabolic syndrome in non diabetic patients with the metabolic syndrome. Am J Cardiol 93:362–365PubMedCrossRefGoogle Scholar
  26. 26.
    Jiang C, Ting AT, Seed B (1998) PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 39:82–86Google Scholar
  27. 27.
    Peraldi P, Xu M, Spiegelman BM (1997) Thiazolidinediones block tumour necrosis factor-alpha- induced inhibition of insulin signalling. J Clin Invest 100:1863–1869PubMedCrossRefGoogle Scholar
  28. 28.
    Chiarelli F, Spagnoli A, Basciani F, Tumini S, Mezzetti A, Cipollone F, Cuccurullo F, Morgese G, Verrotti A (2000) Vascular endothelial growth factor in children, adolescents and young adults with type-1 diabetes mellitus: relation to glycemic control and microvascular complications. Diabet Med 17:650–656PubMedCrossRefGoogle Scholar
  29. 29.
    Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312PubMedCrossRefGoogle Scholar
  30. 30.
    Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA, Evans RM (1998) Activatots of nuclear receptor PPAR-γ enhance colon polyp formation. Nat Med 4:1058–1061PubMedCrossRefGoogle Scholar
  31. 31.
    Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerx J (1998) Activation of peroxisome proliferator activated receptor-γ promotes the development of colon tumors in C57BL/6 J-APC Min/t mice. Nat Med 4:1053–1057PubMedCrossRefGoogle Scholar
  32. 32.
    Yamakawa K, Hosoi M, Koyama H, Tanaka S, Fukumoto S, Morii H, Nishizawa Y (2000) Peroxisone proliferator activated receptor-gamma agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells. Biochem Biopsy Res Comm 271:571–574CrossRefGoogle Scholar
  33. 33.
    Baba T, Shimada K, Neugebauer S, Yamada D, Hashimoto S, Watanabe T (2001) The oral insulin sensitizer, thiazolidinedione increases plasma vascular endothelial growth level in type 2 diabetic patients. Diabetes Care 24:953–954PubMedCrossRefGoogle Scholar
  34. 34.
    Emoto M, Anno T, Sato Y, Tanabe K, Okuya S, Tanizawa Y, Matsutani A, Oka Y (2001) Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3–L1 adipocytes. Diabetes 50:1166–1170PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Sudarshan K. Vijay
    • 1
  • Manish Mishra
    • 1
  • Hemant Kumar
    • 1
  • K. Tripathi
    • 1
    Email author
  1. 1.Department of Medicine, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia

Personalised recommendations