, Volume 62, Issue 10, pp 1463–1480 | Cite as

Metabolic and Additional Vascular Effects of Thiazolidinediones

  • Fabrice M. A. C MartensEmail author
  • Frank L. J. Visseren
  • Jacinthe Lemay
  • Eelco J. P. de Koning
  • Ton J. Rabelink
Review Article


Several cardiovascular risk factors (dyslipidaemia, hypertension, glucose intolerance, hypercoagulability, obesity, hyperinsulinaemia and low-grade inflammation) cluster in the insulin resistance syndrome. Treatment of these individual risk factors reduces cardiovascular complications. However, targeting the underlying pathophysiological mechanisms of the insulin resistance syndrome is a more rational treatment strategy to further improve cardiovascular outcome.

Our understanding of the so-called cardiovascular dysmetabolic syndrome has been improved by the discovery of nuclear peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. As transcription factors, PPARs regulate the expression of numerous genes and affect glycaemic control, lipid metabolism, vascular tone and inflammation. Activation of the subtype PPAR-γ improves insulin sensitivity. Expression of PPAR-γ is present in several cell types involved in the process of atherosclerosis. Thus, modulation of PPAR-γ activity is an interesting therapeutic approach to reduce cardiovascular events.

Thiazolidinediones are PPAR-γ agonists and constitute a new class of pharmacological agents for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Two such compounds are currently available for clinical use: rosiglitazone and pioglitazone. Thiazolidinediones improve insulin sensitivity and glycaemic control in patients with type 2 diabetes. In addition, improvement in endothelial function, a decrease in inflammatory conditions, a decrease in plasma levels of free fatty acids and lower blood pressure have been observed, which may have important beneficial effects on the vasculature.

Several questions remain to be answered about PPAR-γ agonists, particularly with respect to the role of PPAR-γ in vascular pathophysiology. More needs to be known about the adverse effects of thiazolidinediones, such as hepatotoxicity, increased low-density lipoprotein cholesterol levels and increased oedema. The paradox of adipocyte differentiation with weight gain concurring with the insulin-sensitising effect of thiazolidinediones is not completely understood. The decrease in blood pressure induced by thiazolidinedione treatment seems incompatible with an increase in the plasma volume, and the discrepancy between the stimulation of the expression of CD36 and the antiatherogenic effects of the thiazolidinediones also needs further explanation. Long-term clinical trials of thiazolidinediones with cardiovascular endpoints are currently in progress.

In conclusion, studying the effects of thiazolidinediones may shed more light on the mechanisms involved in the insulin resistance syndrome. Furthermore, thiazolidinediones could have specific, direct effects on processes involved in the development of vascular abnormalities.


Insulin Resistance Rosiglitazone Pioglitazone Glycaemic Control Thiazolidinediones 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37(12): 1595–607PubMedCrossRefGoogle Scholar
  2. 2.
    Fagan TC, Deedwania PC. The cardiovascular dysmetabolic syndrome. Am J Med 1998; 105(1A): S77–82CrossRefGoogle Scholar
  3. 3.
    Meigs JB. Invited commentary: insulin resistance syndrome?. Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 2000; 152(10): 908–11PubMedCrossRefGoogle Scholar
  4. 4.
    Mudaliar S, Henry R. New Oral Therapies For Type 2 Diabetes Mellitus: The Glitazones or Insulin Sensitizers. Annu Rev Med 2001; 52: 239–57PubMedCrossRefGoogle Scholar
  5. 5.
    Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitis: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998; 316(7134): 823–8PubMedCrossRefGoogle Scholar
  6. 6.
    Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet 1999; 354(9173): 141–8PubMedCrossRefGoogle Scholar
  7. 7.
    Lemberger T, Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol 1996; 12: 335–63PubMedCrossRefGoogle Scholar
  8. 8.
    Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990; 347(6294): 645–50PubMedCrossRefGoogle Scholar
  9. 9.
    Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83(6): 835–9PubMedCrossRefGoogle Scholar
  10. 10.
    Willson TM, Brown PJ, Sternbach DD, et al. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000; 43(4): 527–50PubMedCrossRefGoogle Scholar
  11. 11.
    Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000; 49(10): 497–505PubMedCrossRefGoogle Scholar
  12. 12.
    Loviscach M, Rehman N, Carter L, et al. Distribution of peroxisome proliferator-activated receptors (PPARs) in human skeletal muscle and adipose tissue: relation to insulin action. Diabetologia 2000; 43(3): 304–11PubMedCrossRefGoogle Scholar
  13. 13.
    Marx N, Libby P, Plutzky J. Peroxisome proliferator-activated receptors (PPARs) and their role in the vessel wall: possible mediators of cardiovascular risk? J Cardiovasc Risk 2001; 8(4): 203–10PubMedCrossRefGoogle Scholar
  14. 14.
    Elangbam CS, Tyler RD, Lightfoot RM. Peroxisome proliferator-activated receptors in atherosclerosis and inflammation-an update. Toxicol Pathol 2001; 29(2): 224–31PubMedCrossRefGoogle Scholar
  15. 15.
    Dubois M, Pattou F, Kerr-Conte J, et al. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in normal human pancreatic islet cells. Diabetologia 2000; 43(9): 1165–9PubMedCrossRefGoogle Scholar
  16. 16.
    Moore KJ, Rosen ED, Fitzgerald ML, et al. The role of PPARgamma in macrophage differentiation and cholesterol uptake. Nat Med 2001; 7(1): 41–7PubMedCrossRefGoogle Scholar
  17. 17.
    Forman BM, Tontonoz P, Chen J, et al. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995; 83(5): 803–12PubMedCrossRefGoogle Scholar
  18. 18.
    Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47(4): 507–14PubMedCrossRefGoogle Scholar
  19. 19.
    Chaiken RL, Eckert-Norton M, Pasmantier R, et al. Metabolic effects of darglitazone, an insulin sensitizer, in NIDDM subjects. Diabetologia 1995; 38(11): 1307–12PubMedCrossRefGoogle Scholar
  20. 20.
    Suter SL, Nolan JJ, Wallace P, et al. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 1992; 15(2): 193–203PubMedCrossRefGoogle Scholar
  21. 21.
    Sironi AM, Vichi S, Gastaldelli A, et al. Effects of troglitazone on insulin action and cardiovascular risk factors in patients with non-insulin-dependent diabetes. Clin Pharmacol Ther 1997; 62(2): 194–202PubMedCrossRefGoogle Scholar
  22. 22.
    Maggs DG, Buchanan TA, Burant CF, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128(3): 176–85PubMedGoogle Scholar
  23. 23.
    Raman P, Judd RL. Role of glucose and insulin in thiazolidinedione-induced alterations in hepatic gluconeogenesis. Eur J Pharmacol 2000; 409(1): 19–29PubMedCrossRefGoogle Scholar
  24. 24.
    Zierath JR, Ryder JW, Doebber T, et al. Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARgamma agonist) action. Endocrinology 1998; 139(12): 5034–41PubMedCrossRefGoogle Scholar
  25. 25.
    Preininger K, Stingl H, Englisch R, et al. Acute troglitazone action in isolated perfused rat liver. Br J Pharmacol 1999; 126(1): 372–8PubMedCrossRefGoogle Scholar
  26. 26.
    Tanaka T, Itoh H, Doi K, et al. Down regulation of peroxisome proliferator-activated receptorgamma expression by inflammatory cytokines and its reversal by thiazolidinediones. Diabetologia 1999; 42(6): 702–10PubMedCrossRefGoogle Scholar
  27. 27.
    Hallakou S, Doare L, Foufelle F, et al. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 1997; 46(9): 1393–9PubMedCrossRefGoogle Scholar
  28. 28.
    Hallakou S, Foufelle F, Doare L, et al. Pioglitazone-induced increase of insulin sensitivity in the muscles of the obese Zucker fa/fa rat cannot be explained by local adipocyte differentiation. Diabetologia 1998; 41(8): 963–8PubMedCrossRefGoogle Scholar
  29. 29.
    Matsuhisa M, Shi ZQ, Wan C, et al. The effect of pioglitazone on hepatic glucose uptake measured with indirect and direct methods in alloxan-induced diabetic dogs. Diabetes 1997; 46(2): 224–31PubMedCrossRefGoogle Scholar
  30. 30.
    Szalkowski D, White-Carrington S, Berger J, et al. Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. Endocrinology 1995; 136(4): 1474–81PubMedCrossRefGoogle Scholar
  31. 31.
    Shimaya A, Kurosaki E, Shioduka K, et al. YM268 increases the glucose uptake, cell differentiation, and mRNA expression of glucose transporter in 3T3-L1 adipocytes. Horm Metab Res 1998; 30(9): 543–8PubMedCrossRefGoogle Scholar
  32. 32.
    Arakawa K, Ishihara T, Aoto M, et al. Actions of novel anti-diabetic thiazolidinedione, T-174, in animal models of non-insulin-dependent diabetes mellitus (NIDDM) and in cultured muscle cells. Br J Pharmacol 1998; 125(3): 429–36PubMedCrossRefGoogle Scholar
  33. 33.
    Lee MK, Miles PD, Khoursheed M, et al. Metabolic effects of troglitazone on fructose-induced insulin resistance in the rat. Diabetes 1994; 43(12): 1435–9PubMedCrossRefGoogle Scholar
  34. 34.
    Miles PD, Romeo OM, Higo K, et al. TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes 1997; 46(11): 1678–83PubMedCrossRefGoogle Scholar
  35. 35.
    Miles PD, Higo K, Romeo OM, et al. Troglitazone prevents hyperglycemia-induced but not glucosamine-induced insulin resistance. Diabetes 1998; 47(3): 395–400PubMedCrossRefGoogle Scholar
  36. 36.
    Kraegen EW, James DE, Jenkins AB, et al. A potent in vivo effect of ciglitazone on muscle insulin resistance induced by high fat feeding of rats. Metabolism 1989; 38(11): 1089–93PubMedCrossRefGoogle Scholar
  37. 37.
    Prigeon RL, Kahn SE, Porte Jr D. Effect of troglitazone on B cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 1998; 83(3): 819–23PubMedCrossRefGoogle Scholar
  38. 38.
    Fonseca VA, Valiquett TR, Huang SM, et al. Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. The Troglitazone Study Group. J Clin Endocrinol Metab 1998; 83(9): 3169–76PubMedCrossRefGoogle Scholar
  39. 39.
    Spencer CM, Markham A. Troglitazone. Drugs 1997; 54(1): 89–101PubMedCrossRefGoogle Scholar
  40. 40.
    Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998; 338(13): 867–72PubMedCrossRefGoogle Scholar
  41. 41.
    Nolan JJ, Jones NP, Patwardhan R, et al. Rosiglitazone taken once daily provides effective glycaemic control in patients with Type 2 diabetes mellitus. Diabetes Med 2000; 17(4): 287–94CrossRefGoogle Scholar
  42. 42.
    Wolffenbuttel BH, Gomis R, Squatrito S, et al. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. Diabetes Med 2000; 17(1): 40–7CrossRefGoogle Scholar
  43. 43.
    Wolffenbuttel BH, Sels JP, Huijberts MS. Rosiglitazone. Expert Opin Pharmacother 2001; 2(3): 467–78PubMedCrossRefGoogle Scholar
  44. 44.
    Einhorn D, Rendell M, Rosenzweig J, et al. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 2000; 22(12): 1395–409PubMedCrossRefGoogle Scholar
  45. 45.
    Aronoff S, Rosenblatt S, Braithwaite S, et al. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000; 23(11): 1605–11PubMedCrossRefGoogle Scholar
  46. 46.
    Nolan JJ, Ludvik B, Beerdsen P, et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331(18): 1188–93PubMedCrossRefGoogle Scholar
  47. 47.
    Berkowitz K, Peters R, Kjos SL, et al. Effect of troglitazone on insulin sensitivity and pancreatic beta-cell function in women at high risk for NIDDM. Diabetes 1996; 45(11): 1572–9PubMedCrossRefGoogle Scholar
  48. 48.
    Chawla A, Schwarz EJ, Dimaculangan DD, et al. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 1994; 135(2): 798–800PubMedCrossRefGoogle Scholar
  49. 49.
    Sandouk T, Reda D, Hofmann C. The antidiabetic agent pioglitazone increases expression of glucose transporters in 3T3-F442A cells by increasing messenger ribonucleic acid transcript stability. Endocrinology 1993; 133(1): 352–9PubMedCrossRefGoogle Scholar
  50. 50.
    Vidal-Puig AJ, Considine RV, Jimenez-Linan M, et al. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 1997; 99(10): 2416–22PubMedCrossRefGoogle Scholar
  51. 51.
    Miles PD, Barak Y, He W, et al. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest 2000; 105(3): 287–92PubMedCrossRefGoogle Scholar
  52. 52.
    Fajas L, Debril MB, Auwerx J. Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis. J Mol Endocrinol 2001; 27(1): 1–9PubMedCrossRefGoogle Scholar
  53. 53.
    Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994; 79(7): 1147–56PubMedCrossRefGoogle Scholar
  54. 54.
    Takamura T, Nohara E, Nagai Y, et al. Stage-specific effects of a thiazolidinedione on proliferation, differentiation and PPARgamma mRNA expression in 3T3-L1 adipocytes. Eur J Pharmacol 2001; 422(1–3): 23–9PubMedCrossRefGoogle Scholar
  55. 55.
    Torti FM, Torti S V, Larrick JW, et al. Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor beta. J Cell Biol 1989; 108(3): 1105–13PubMedCrossRefGoogle Scholar
  56. 56.
    Hofmann C, Lorenz K, Braithwaite SS, et al. Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 1994; 134(1): 264–70PubMedCrossRefGoogle Scholar
  57. 57.
    Okuno A, Tamemoto H, Tobe K, et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998; 101(6): 1354–61PubMedCrossRefGoogle Scholar
  58. 58.
    Montague CT, O’Rahilly S. The perils of portliness: causes and consequences of visceral adiposity. Diabetes 2000; 49(6): 883–8PubMedCrossRefGoogle Scholar
  59. 59.
    Niesler CU, Urso B, Prins JB, et al. IGF-I inhibits apoptosis induced by serum withdrawal, but potentiates TNF-alpha-induced apoptosis, in 3T3-L1 preadipocytes. J Endocrinol 2000; 167(1): 165–74PubMedCrossRefGoogle Scholar
  60. 60.
    Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001; 409(6818): 307–12PubMedCrossRefGoogle Scholar
  61. 61.
    Sreenan S, Keck S, Fuller T, et al. Effects of troglitazone on substrate storage and utilization in insulin-resistant rats. Am J Physiol 1999; 276 (6 Pt 1): E1119–29PubMedGoogle Scholar
  62. 62.
    Shimabukuro M, Zhou YT, Lee Y, et al. Troglitazone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats. J Biol Chem 1998; 273(6): 3547–50PubMedCrossRefGoogle Scholar
  63. 63.
    Fonseca V, Rosenstock J, Patwardhan R, et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000; 283(13): 1695–702PubMedCrossRefGoogle Scholar
  64. 64.
    Rebrin K, Steil GM, Getty L, et al. Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 1995; 44(9): 1038–45PubMedCrossRefGoogle Scholar
  65. 65.
    Michaud SE, Renier G. Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. Diabetes 2001; 50(3): 660–6PubMedCrossRefGoogle Scholar
  66. 66.
    Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 1998; 14(4): 263–83PubMedCrossRefGoogle Scholar
  67. 67.
    Martin G, Schoonjans K, Staels B, et al. PPARgamma activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes. Atherosclerosis 1998; 137: S75–80PubMedCrossRefGoogle Scholar
  68. 68.
    Tontonoz P, Nagy L, Alvarez JG, et al. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998; 93(2): 241–52PubMedCrossRefGoogle Scholar
  69. 69.
    Aitman TJ, Glazier AM, Wallace CA, et al. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nat Genet 1999; 21(1): 76–83PubMedCrossRefGoogle Scholar
  70. 70.
    Miyaoka K, Kuwasako T, Hirano K, et al. CD36 deficiency associated with insulin resistance. Lancet 2001; 357(9257): 686–7PubMedCrossRefGoogle Scholar
  71. 71.
    Wolfrum C, Borrmann CM, Borchers T, et al. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors al. Proc Natl Acad Sci U S A 2001; 98(5): 2323–8PubMedCrossRefGoogle Scholar
  72. 72.
    Glorian M, Duplus E, Beale EG, et al. A single element in the phosphoenolpyruvate carboxykinase gene mediates thiazolidinedione action specifically in adipocytes. Biochimie 2001; 83(10): 933–43PubMedCrossRefGoogle Scholar
  73. 73.
    Yamauchi T, Kamon J, Waki H, et al. The mechanisms by which both heterozygous PPARgamma deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 2001; 276(44): 41245–54PubMedCrossRefGoogle Scholar
  74. 74.
    Maeda N, Takahashi M, Funahashi T, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001; 50(9): 2094–9PubMedCrossRefGoogle Scholar
  75. 75.
    Stephens JM, Lee J, Pilch PF. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem 1997; 272(2): 971–6PubMedCrossRefGoogle Scholar
  76. 76.
    Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997; 389(6651): 610–4PubMedCrossRefGoogle Scholar
  77. 77.
    Zhang B, Berger J, Hu E, et al. Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha. Mol Endocrinol 1996; 10(11): 1457–66PubMedCrossRefGoogle Scholar
  78. 78.
    Feinstein R, Kanety H, Papa MZ, et al. Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 1993; 268(35): 26055–8PubMedGoogle Scholar
  79. 79.
    Fukuzawa M, Satoh J, Qiang X, et al. Inhibition of tumor necrosis factor-alpha with anti-diabetic agents. Diabetes Res Clin Pract 1999; 43(3): 147–54PubMedCrossRefGoogle Scholar
  80. 80.
    Peraldi P, Xu M, Spiegelman BM. Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J Clin Invest 1997; 100(7): 1863–9PubMedCrossRefGoogle Scholar
  81. 81.
    Iwata M, Haruta T, Usui I, et al. Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator—activated receptor-gamma. Diabetes 2001; 50(5): 1083–92PubMedCrossRefGoogle Scholar
  82. 82.
    De Vos P, Lefebvre AM, Miller SG, et al. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest 1996; 98(4): 1004–9PubMedCrossRefGoogle Scholar
  83. 83.
    Clarkson P, Celermajer DS, Donald AE, et al. Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol 1996; 28(3): 573–9PubMedCrossRefGoogle Scholar
  84. 84.
    Brown AA, Hu FB. Dietary modulation of endothelial function: implications for cardiovascular disease. Am J Clin Nutr 2001; 73(4): 673–86PubMedGoogle Scholar
  85. 85.
    Baron AD. Vascular reactivity. Am J Cardiol 1999; 84(1A): J25–7CrossRefGoogle Scholar
  86. 86.
    Standl E, Schnell O. A new look at the heart in diabetes mellitus: from ailing to failing. Diabetologia 2000; 43(12): 1455–69PubMedCrossRefGoogle Scholar
  87. 87.
    Fujishima S, Ohya Y, Nakamura Y, et al. Troglitazone, an insulin sensitizer, increases forearm blood flow in humans. Am J Hypertens 1998; 11(9): 1134–7PubMedCrossRefGoogle Scholar
  88. 88.
    Garg R, Kumbkarni Y, Aljada A, et al. Troglitazone reduces reactive oxygen species generation by leukocytes and lipid peroxidation and improves flow-mediated vasodilatation in obese subjects. Hypertension 2000; 36(3): 430–5PubMedCrossRefGoogle Scholar
  89. 89.
    Avena R, Mitchell ME, Nylen ES, et al. Insulin action enhancement normalizes brachial artery vasoactivity in patients with peripheral vascular disease and occult diabetes. J Vasc Surg 1998; 28(6): 1024–31PubMedCrossRefGoogle Scholar
  90. 90.
    Inoguchi T, Li P, Yu HY, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000; 49(11): 1939–45PubMedCrossRefGoogle Scholar
  91. 91.
    Kotchen TA, Zhang HY, Reddy S, et al. Effect of pioglitazone on vascular reactivity in vivo and in vitro. Am J Physiol 1996; 270 (3 Pt 2): R660–6PubMedGoogle Scholar
  92. 92.
    Zhang F, Sowers JR, Ram JL, et al. Effects of pioglitazone on calcium channels in vascular smooth muscle. Hypertension 1994; 24(2): 170–5PubMedCrossRefGoogle Scholar
  93. 93.
    Buchanan TA, Meehan WP, Jeng YY, et al. Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. J Clin Invest 1995; 96(1): 354–60PubMedCrossRefGoogle Scholar
  94. 94.
    Hattori Y, Hattori S, Kasai K. Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells. Hypertension 1999; 33(4): 943–8PubMedCrossRefGoogle Scholar
  95. 95.
    Yoshizumi M, Perrella MA, Burnett Jr JC, et al. Tumour necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res 1993; 73(1): 205–9PubMedCrossRefGoogle Scholar
  96. 96.
    Wang P, Ba ZF, Chaudry IH. Administration of tumor necrosis factor-alpha in vivo depresses endothelium-dependent relaxation. Am J Physiol 1994; 266 (6 Pt 2): H2535–41PubMedGoogle Scholar
  97. 97.
    Nakamura M, Yoshida H, Arakawa N, et al. Effects of tumor necrosis factor-alpha on basal and stimulated endothelium-dependent vasomotion in human resistance vessel. J Cardiovasc Pharmacol 2000; 36(4): 487–92PubMedCrossRefGoogle Scholar
  98. 98.
    Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103(13): 1813–8PubMedCrossRefGoogle Scholar
  99. 99.
    Libby P. Changing concepts of atherogenesis. J Intern Med 2000; 247(3): 349–58PubMedCrossRefGoogle Scholar
  100. 100.
    Pickup JC, Mattock MB, Chusney GD, et al. NIDDM as a dis- ease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 1997; 40(11): 1286–92PubMedCrossRefGoogle Scholar
  101. 101.
    Margaglione M, Cappucci G, Colaizzo D, et al. C-reactive protein in offspring is associated with the occurrence of myocardial infarction in first-degree relatives. Arterioscler Thromb Vasc Biol 2000; 20(1): 198–203PubMedCrossRefGoogle Scholar
  102. 102.
    Fichtischerer S, Rosenberger G, Walter DH, et al. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000; 102(9): 1000–6CrossRefGoogle Scholar
  103. 103.
    Neve BP, Corseaux D, Chinetti G, et al. PPARalpha Agonists Inhibit Tissue Factor Expression in Human Monocytes and Macrophages. Circulation 2001; 103(2): 207–12PubMedCrossRefGoogle Scholar
  104. 104.
    Marx N, Mackman N, Schonbeck U, et al. PPARalpha Activators Inhibit Tissue Factor Expression and Activity in Human Monocytes. Circulation 2001; 103(2): 213–9PubMedCrossRefGoogle Scholar
  105. 105.
    Pasceri V, Wu HD, Willerson JT, et al. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation 2000; 101(3): 235–8PubMedCrossRefGoogle Scholar
  106. 106.
    Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998; 391(6662): 79–82PubMedCrossRefGoogle Scholar
  107. 107.
    Jackson SM, Parhami F, Xi XP, et al. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler Thromb Vasc Biol 1999; 19(9): 2094–104PubMedCrossRefGoogle Scholar
  108. 108.
    Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391(6662): 82–6PubMedCrossRefGoogle Scholar
  109. 109.
    Nagy L, Tontonoz P, Alvarez JG, et al. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998; 93(2): 229–40PubMedCrossRefGoogle Scholar
  110. 110.
    Chawla A, Barak Y, Nagy L, et al. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001; 7(1): 48–52PubMedCrossRefGoogle Scholar
  111. 111.
    Marx N, Sukhova G, Murphy C, et al. Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma (PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am J Pathol 1998; 153(1): 17–23PubMedCrossRefGoogle Scholar
  112. 112.
    Thieringer R, Fenyk-Melody JE, et al. Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol 2000; 164(2): 1046–54PubMedGoogle Scholar
  113. 113.
    Moore KJ, Fitzgerald ML, Freeman MW. Peroxisome proliferator-activated receptors in macrophage biology: friend orfoe? Curr Opin Lipidol 2001; 12(5): 519–27PubMedCrossRefGoogle Scholar
  114. 114.
    Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000; 106(4): 523–31PubMedCrossRefGoogle Scholar
  115. 115.
    Abumrad N, Harmon C, Ibrahimi A. Membrane transport of long-chain fatty acids: evidence for a facilitated process. J Lipid Res 1998; 39(12): 2309–18PubMedGoogle Scholar
  116. 116.
    Febbraio M, Podrez EA, Smith JD, et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest 2000; 105(8): 1049–56PubMedCrossRefGoogle Scholar
  117. 117.
    Chinetti G, Lestavel S, Bocher V, et al. PPAR-alpha and PPARgamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 2001; 7(1): 53–8PubMedCrossRefGoogle Scholar
  118. 118.
    Plutzky J. Peroxisome proliferator-activated receptors in endothelial cell biology. Curr Opin Lipidol 2001; 12(5): 511–8PubMedCrossRefGoogle Scholar
  119. 119.
    Aitman TJ. CD36, insulin resistance, and coronary heart disease. Lancet 2001; 357(9257): 651–2PubMedCrossRefGoogle Scholar
  120. 120.
    Takano H, Nagai T, Asakawa M, et al. Peroxisome proliferator-activated receptor activators inhibit lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal rat cardiac myocytes. Circ Res 2000; 87(7): 596–602PubMedCrossRefGoogle Scholar
  121. 121.
    Ginsberg HN, Huang LS. The insulin resistance syndrome: impact on lipoprotein metabolism and atherothrombosis. J Cardiovasc Risk 2000; 7(5): 325–31PubMedGoogle Scholar
  122. 122.
    Kraegen EW, Cooney GJ, Ye J, et al. Triglycerides, fatty acids and insulin resistance—hyperinsulinemia. Exp Clin Endocrinol Diabetes 2001; 109(4): S516–26PubMedCrossRefGoogle Scholar
  123. 123.
    Fontbonne A, Eschwege E, Cambien F, et al. Hyper-triglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes: results from the 11-year follow-up of the Paris Prospective Study. Diabetologia 1989; 32(5): 300–4PubMedCrossRefGoogle Scholar
  124. 124.
    Laakso M, Lehto S, Penttila I, et al. Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes. Circulation 1993; 88 (4 Pt 1): 1421–30PubMedCrossRefGoogle Scholar
  125. 125.
    Syvanne M, Taskinen MR. Lipids and lipoproteins as coronary risk factors in non-insulin-dependent diabetes mellitus. Lancet 1997; 350 Suppl. 1: SI20–3PubMedGoogle Scholar
  126. 126.
    Yamasaki Y, Kawamori R, Wasada T, et al. Pioglitazone (AD-4833) ameliorates insulin resistance in patients with NIDDM. AD-4833 Glucose Clamp Study Group, Japan. Tohoku J Exp Med 1997; 183(3): 173–83PubMedCrossRefGoogle Scholar
  127. 127.
    Rosenblatt S, Miskin B, Glazer NB, et al. The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus. Coron Artery Dis 2001; 12(5): 413–23PubMedCrossRefGoogle Scholar
  128. 128.
    Gegick CG, Altheimer MD. Comparison of effects of thiazolidinediones on cardiovascular risk factors: observations from a clinical practice. Endocr Pract 2001; 7(3): 162–9PubMedGoogle Scholar
  129. 129.
    Auwerx J, Schoonjans K, Fruchart JC, et al. Regulation of triglyceride metabolism by PPARs: fibrates and thiazolidinediones have distinct effects. J Atheroscler Thromb 1996; 3(2): 81–9PubMedGoogle Scholar
  130. 130.
    Raskin P, Rendell M, Riddle MC, et al. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001; 24(7): 1226–32PubMedCrossRefGoogle Scholar
  131. 131.
    Boyle PJ, King AB, Olansky L, et al. 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 2002; 24(3): 378–96PubMedCrossRefGoogle Scholar
  132. 132.
    Khan MA, St Peter JV, Xue JL. 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 2002; 25(4): 708–11PubMedCrossRefGoogle Scholar
  133. 133.
    Tack CJ, Smits P, Demacker PN, et al. Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects. Diabetes Care 1998; 21(5): 796–9PubMedCrossRefGoogle Scholar
  134. 134.
    Hirano T, Yoshino G, Kazumi T. Troglitazone and small low-density lipoprotein in type 2 diabetes. Ann Intern Med 1998; 129(2): 162–3PubMedGoogle Scholar
  135. 135.
    Cominacini L, Young MM, Capriati A, et al. Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers. Diabetologia 1997; 40(10): 1211–8PubMedCrossRefGoogle Scholar
  136. 136.
    Cominacini L, Garbin U, Fratta PA, et al. Troglitazone reduces LDL oxidation and lowers plasma E-selectin concentration in NIDDM patients. Diabetes 1998; 47(1): 130–3PubMedCrossRefGoogle Scholar
  137. 137.
    Chen Z, Ishibashi S, Perrey S, et al. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol 2001; 21(3): 372–7PubMedCrossRefGoogle Scholar
  138. 138.
    Mimura K, Umeda F, Hiramatsu S, et al. Effects of a new oral hypoglycaemic agent (CS-045) on metabolic abnormalities and insulin resistance in type 2 diabetes. Diabetes Med 1994; 11(7): 685–91CrossRefGoogle Scholar
  139. 139.
    Colca JR, Dailey CF, Palazuk BJ, et al. Pioglitazone hydrochloride inhibits cholesterol absorption and lowers plasma cholesterol concentrations in cholesterol-fed rats. Diabetes 1991; 40(12): 1669–74PubMedCrossRefGoogle Scholar
  140. 140.
    Ogihara T, Rakugi H, Ikegami H, et al. Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am J Hypertens 1995; 8(3): 316–20PubMedCrossRefGoogle Scholar
  141. 141.
    Sung BH, Izzo JL, Dandona P, et al. Vasodilatory effects of troglitazone improve blood pressure at rest and during mental stress in type 2 diabetes mellitus. Hypertension 1999; 34(1): 83–8PubMedCrossRefGoogle Scholar
  142. 142.
    Ghazzi MN, Perez JE, Antonucci TK, et al. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes 1997; 46(3): 433–9PubMedCrossRefGoogle Scholar
  143. 143.
    Tack CJ, Ong MK, Lutterman JA, et al. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia 1998; 41(5): 569–76PubMedCrossRefGoogle Scholar
  144. 144.
    Kaufman LN, Peterson MM, DeGrange LM. Pioglitazone attenuates diet-induced hypertension in rats. Metabolism 1995; 44(9): 1105–9PubMedCrossRefGoogle Scholar
  145. 145.
    Grinsell JW, Lardinois CK, Swislocki A, et al. Pioglitazone attenuates basal and postprandial insulin concentrations and blood pressure in the spontaneously hypertensive rat. Am J Hypertens 2000; 13 (4 Pt 1): 370–5PubMedCrossRefGoogle Scholar
  146. 146.
    Walker AB, Chattington PD, Buckingham RE, et al. The thiazolidinedione rosiglitazone (BRL-49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats. Diabetes 1999; 48(7): 1448–53PubMedCrossRefGoogle Scholar
  147. 147.
    Zhang HY, Reddy SR, Kotchen TA. Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity. Hypertension 1994; 24(1): 106–10PubMedCrossRefGoogle Scholar
  148. 148.
    Pershadsingh HA, Szollosi J, Benson S, et al. Effects of ciglitazone on blood pressure and intracellular calcium metabolism. Hypertension 1993; 21 (6 Pt 2): 1020–3PubMedCrossRefGoogle Scholar
  149. 149.
    Knock GA, Mishra SK, Aaronson PI. Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes. Eur J Pharmacol 1999; 368(1): 103–9PubMedCrossRefGoogle Scholar
  150. 150.
    Law RE, Meehan WP, Xi XP, et al. Troglitazone inhibits vascular smooth muscle cell growth and intimai hyperplasia. J Clin Invest 1996; 98(8): 1897–905PubMedCrossRefGoogle Scholar
  151. 151.
    Minamikawa J, Tanaka S, Yamauchi M, et al. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 1998; 83(5): 1818–20PubMedCrossRefGoogle Scholar
  152. 152.
    Takagi T, Akasaka T, Yamamuro A, et al. Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study. J Am Coll Cardiol 2000; 36(5): 1529–35PubMedCrossRefGoogle Scholar
  153. 153.
    Koshiyama H, Shimono D, Kuwamura N, et al. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001; 86(7): 3452–6PubMedCrossRefGoogle Scholar
  154. 154.
    Igarashi M, Takeda Y, Ishibashi N, et al. Pioglitazone reduces smooth muscle cell density of rat carotid arterial intima induced by balloon catheterization. Horm Metab Res 1997; 29(9): 444–9PubMedCrossRefGoogle Scholar
  155. 155.
    Yoshimoto T, Naruse M, Shizume H, et al. Vasculo-protective effects of insulin sensitizing agent pioglitazone in neointimal thickening and hypertensive vascular hypertrophy. Atherosclerosis 1999; 145(2): 333–40PubMedCrossRefGoogle Scholar
  156. 156.
    Goetze S, Xi XP, Kawano H, et al. PPAR gamma-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells. J Cardiovasc Pharmacol 1999; 33(5): 798–806PubMedCrossRefGoogle Scholar
  157. 157.
    Howard G, O’Leary DH, Zaccaro D, et al. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation 1996; 93(10): 1809–17PubMedCrossRefGoogle Scholar
  158. 158.
    Fonseca VA, Reynolds T, Hemphill D, et al. Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus. J Diabet Complications 1998; 12(4): 181–6CrossRefGoogle Scholar
  159. 159.
    Kato K, Satoh H, Endo Y, et al. Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: A possible role for PPAR gamma in endothelial function. Biochem Biophys Res Commun 1999; 258(2): 431–5PubMedCrossRefGoogle Scholar
  160. 160.
    Schwartz S, Raskin P, Fonseca V, et al. Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group. N Engl J Med 1998; 338(13): 861–6PubMedCrossRefGoogle Scholar
  161. 161.
    Pickavance L, Widdowson PS, King P, et al. The development of overt diabetes in young Zucker Diabetic Fatty (ZDF) rats and the effects of chronic MCC-555 treatment. Br J Pharmacol 1998; 125(4): 767–70PubMedCrossRefGoogle Scholar
  162. 162.
    Tafuri SR. Troglitazone enhances differentiation, basal glucose uptake, and Glut1 protein levels in 3T3-L1 adipocytes. Endocrinology 1996; 137(11): 4706–12PubMedCrossRefGoogle Scholar
  163. 163.
    Akazawa S, Sun F, Ito M, et al. Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care 2000; 23(8): 1067–71PubMedCrossRefGoogle Scholar
  164. 164.
    Mori Y, Murakawa Y, Okada K, et al. Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 1999; 22(6): 908–12PubMedCrossRefGoogle Scholar
  165. 165.
    Kelly IE, Han TS, Walsh K, et al. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999; 22(2): 288–93PubMedCrossRefGoogle Scholar
  166. 166.
    Fukunaga Y, Itoh H, Doi K, et al. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 2001; 158(1): 113–9PubMedCrossRefGoogle Scholar
  167. 167.
    Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient taking rosiglitazone. Ann Intern Med 2000; 132(2): 118–21PubMedGoogle Scholar
  168. 168.
    Al Salman J, Arjomand H, Kemp DG, et al. Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann Intern Med 2000; 132(2): 121–4Google Scholar
  169. 169.
    Lebovitz HE, Kreider M, Freed MI. Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction. Diabetes Care 2002; 25(5): 815–21PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Fabrice M. A. C Martens
    • 1
    Email author
  • Frank L. J. Visseren
    • 1
  • Jacinthe Lemay
    • 2
  • Eelco J. P. de Koning
    • 1
  • Ton J. Rabelink
    • 1
  1. 1.Department of Internal Medicine, Section of Vascular Medicine and DiabetologyUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Department of Pharmacology, Faculty of MedicineUniversité de MontréalMontréalCanada

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