Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

International Journal of Obesity volume 27, pages 147–161 (2003)Cite this article

Abstract

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the PPAR family. The endogenous activators of all members of the PPAR family are a variety of fatty acids, which suggests that the PPARs are highly involved in lipid metabolism. In the present paper, the current understanding of the involvement of PPARγ in adipocyte proliferation and adipose tissue formation is extensively reviewed, and it is stressed that PPARγ seems to be a major regulator in the differentiation of adipocytes. Thiazoledinediones (TZDs) are a group of PPARγ-agonists used in the treatment of type 2 diabetes (T2D) since 1997. They are characterized by their ability to decrease insulin resistance, and have been suggested to slow down the progression of insulin resistance. Treatment with TZD requires several weeks of treatment to decrease plasma glucose levels, but in addition they markedly decrease plasma triglycerides and free fatty acids. A major drawback of treatment with TZD is body fat gain, but some evidence suggests that the fat is redistributed in a favourable direction, that is, from visceral to subcutaneous depots. However, the effect of long-term treatment on weight gain following TZD treatment is unknown, and it may be questioned whether the use of these ‘adipogenic compounds’ is appropriate, considering that excess body fat is almost a prerequisite for the development of type 2 diabetes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Issemann I, Green S . Activation of a member of the steroid-hormone receptor superfamily by peroxisome proliferators. Nature 1990; 347: 645–650.

    CAS  PubMed  Google Scholar 

  2. Knopp RH . Drug treatment of lipid disorders. N Engl J Med 1999; 341: 498–511.

    CAS  PubMed  Google Scholar 

  3. Hansen JB et al. Peroxisome proliferator-activated receptor delta (PPARdelta)-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signaling. J Biol Chem 2001; 276: 3175–3182.

    CAS  PubMed  Google Scholar 

  4. Peters JM et al. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta). Mol Cell Biol 2000; 20: 5119–5128.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bastie C, Luquet S, Holst D, Jehl-Pietri C, Grimaldi PA . Alterations of peroxisome proliferator-activated receptor delta activity affect fatty acid-controlled adipose differentiation. J Biol Chem 2000; 275: 38768–38773.

    CAS  PubMed  Google Scholar 

  6. Leibowitz MD et al. Activation of PPAR delta alters lipid metabolism in db/db mice. FEBS Lett 2000; 473: 333–336.

    CAS  PubMed  Google Scholar 

  7. Oliver Jr WR et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 2001; 98: 5306–5311.

    CAS  PubMed  Google Scholar 

  8. Ren DL, Collingwood TN, Rebar EJ, Wolffe AP, Camp HS . PPAR gamma knockdown by engineered transcription factors: exogenous PPAR gamma 2 but not PPAR gamma 1 reactivates adipogenesis. Genes Develop 2002; 16: 27–32.

    CAS  PubMed  Google Scholar 

  9. VidalPuig A et al. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. J Clin Invest 1996; 97: 2553–2561.

    CAS  Google Scholar 

  10. VidalPuig AJ 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: 2416–2422.

    CAS  Google Scholar 

  11. Auboeuf D et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans—no alteration in adipose tissue of obese and NIDDM patients. Diabetes 1997; 46: 1319–1327.

    CAS  PubMed  Google Scholar 

  12. Mukherjee R, Jow L, Croston GE, Paterniti JR . Identification characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPAR gamma 2 versus PPAR gamma 1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 1997; 272: 8071–8076.

    CAS  PubMed  Google Scholar 

  13. Kruszynska YT et al. Skeletal muscle peroxisome proli-ferator-activated receptor-gamma expression in obesity and non-insulin-dependent diabetes mellitus. J Clin Invest 1998; 101: 543–548.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Loviscach M et al. Distribution of peroxisome proliferator-activated receptors (PPARs) in human skeletal muscle and adipose tissue: relation to insulin action. Diabetologia 2000; 43: 304–311.

    CAS  PubMed  Google Scholar 

  15. Forman BM et al. 15-Deoxy-delta(12,14)-prostaglandin J(2) is a ligand for the adipocyte determination factor ppar-gamma. Cell 1995; 83: 803–812.

    CAS  PubMed  Google Scholar 

  16. Kliewer SA et al. A prostaglandin J(2) metabolite binds peroxisome proliferator-activated receptor-gamma and promotes adipocyte differentiation. Cell 1995; 83: 813–819.

    CAS  PubMed  Google Scholar 

  17. Kliewer SA et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 1997; 94: 4318–4323.

    CAS  PubMed  Google Scholar 

  18. Nagy L, Tontonoz P, Alvarez JGA, Chen HW, Evans RM . Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR gamma. Cell 1998; 93: 229–240.

    CAS  PubMed  Google Scholar 

  19. Desvergne B, Wahli W . Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999; 20: 649–688.

    CAS  PubMed  Google Scholar 

  20. Willson TM, Lambert MH, Kliewer SA . Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001; 70: 341–367.

    CAS  PubMed  Google Scholar 

  21. Ibrahimi A et al. Evidence for a common mechanism of action for fatty acids and thiazolidinedione antidiabetic agents on gene expression in preadipose cells. Mol Pharmacol 1994; 46: 1070–1076.

    CAS  PubMed  Google Scholar 

  22. Oberfield JL et al. A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation. Proc Natl Acad Sci USA 1999; 96: 6102–6106.

    CAS  PubMed  Google Scholar 

  23. Wright HM et al. A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem 2000; 275: 1873–1877.

    CAS  PubMed  Google Scholar 

  24. Camp HS, Chaudhry A, Leff T . A novel potent antagonist of peroxisome proliferator-activated receptor gamma blocks adipocyte differentiation but does not revert the phenotype of terminally differentiated adipocytes. Endocrinology 2001; 142: 3207–3213.

    CAS  PubMed  Google Scholar 

  25. Mukherjee R et al. A selective peroxisome proliferator-activated receptor-gamma (PPAR gamma) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes. Mol Endocr 2000; 14: 1425–1433.

    CAS  Google Scholar 

  26. Morrison RF, Farmer SR . Role of PPAR gamma in regulating a cascade expression of cyclin-dependent kinase inhibitors p18(INK4c), and p21(Waf1/Cip1), during adipogenesis. J Biol Chem 1999; 274: 17088–17097.

    CAS  PubMed  Google Scholar 

  27. Morrison RF, Farmer SR . Hormonal signaling and transcriptional control of adipocyte differentiation. J Nutr 2000; 130: 3116S–3121S.

    CAS  PubMed  Google Scholar 

  28. Kim JB, Wright HM, Wright M, Spiegelman BM . ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. Proc Natl Acad Sci USA 1998; 95: 4333–4337.

    CAS  PubMed  Google Scholar 

  29. Soukas A, Socci ND, Saatkamp BD, Novelli S, Friedman JM . Distinct transcriptional profiles of adipogenesis in vivo and in vitro. J Biol Chem 2001; 276: 34167–34174.

    CAS  PubMed  Google Scholar 

  30. Takamura T, Nohara E, Nagai Y, Kobayashi K . Stage-specific effects of a thiazolidinedione on proliferation, differentiation and PPAR gamma mRNA expression in 3T3-L1 adipocytes. Eur J Pharmacol 2001; 422: 23–29.

    CAS  PubMed  Google Scholar 

  31. Vernochet C et al. PPARgamma-dependent and PPARgamma-independent effects on the development of adipose cells from embryonic stem cells. FEBS Lett 2002; 510: 94–98.

    CAS  PubMed  Google Scholar 

  32. Tontonoz P, Hu E, Spiegelman BM . Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994; 79: 1147–1156.

    CAS  PubMed  Google Scholar 

  33. Hu E, Tontonoz P, Spiegelman BM . Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha. Proc Natl Acad Sci USA 1995; 92: 9856–9860.

    CAS  PubMed  Google Scholar 

  34. Kubota N et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999; 4: 597–609.

    CAS  PubMed  Google Scholar 

  35. Barak Y et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 1999; 4: 585–595.

    CAS  PubMed  Google Scholar 

  36. Rosen ED et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999; 4: 611–617.

    CAS  PubMed  Google Scholar 

  37. Gurnell M et al. A dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutant is a constitutive repressor and inhibits PPARgamma-mediated adipogenesis. J Biol Chem 2000; 275: 5754–5759.

    CAS  PubMed  Google Scholar 

  38. Young PW et al. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J Pharmacol Exp Ther 1998; 284: 751–759.

    CAS  PubMed  Google Scholar 

  39. Werman A et al. Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin. J Biol Chem 1997; 272: 20230–20235.

    CAS  PubMed  Google Scholar 

  40. Hu E, Kim JB, Sarraf P, Spiegelman BM . Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science 1996; 274: 2100–2103.

    CAS  PubMed  Google Scholar 

  41. Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK . Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem 1997; 272: 5128–5132.

    CAS  PubMed  Google Scholar 

  42. Camp HS, Tafuri SR . Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase. J Biol Chem 1997; 272: 10811–10816.

    CAS  PubMed  Google Scholar 

  43. Yang W et al. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J Biol Chem 2001; 276: 38341–38344.

    CAS  PubMed  Google Scholar 

  44. Camp HS, Whitton AL, Tafuri SR . PPARgamma activators down-regulate the expression of PPARgamma in 3T3-L1 adipocytes. FEBS Lett 1999; 447: 186–190.

    CAS  PubMed  Google Scholar 

  45. Hauser S et al. Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. J Biol Chem 2000; 275: 18527–18533.

    CAS  PubMed  Google Scholar 

  46. Lefebvre AM et al. Depot-specific differences in adipose tissue gene expression in lean and obese subjects. Diabetes 1998; 47: 98–103.

    CAS  Google Scholar 

  47. Hotta K et al. Relationships of PPARgamma and PPARgamma2 mRNA levels to obesity, diabetes and hyperinsulinaemia in rhesus monkeys. Int J Obes Relat Metab Disord 1998; 22: 1000–1010.

    CAS  PubMed  Google Scholar 

  48. Edvardsson U et al. Rosiglitazone (BRL49653) a PPARgamma-selective agonist, causes peroxisome proliferator-like liver effects in obese mice. J Lipid Res 1999; 40: 1177–1184.

    CAS  PubMed  Google Scholar 

  49. Memon RA et al. Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice. Endocrinology 2000; 141: 4021–4031.

    CAS  PubMed  Google Scholar 

  50. Park KS et al. PPAR-gamma gene expression is elevated in skeletal muscle of obese and type II diabetic subjects. Diabetes 1997; 46: 1230–1234.

    CAS  PubMed  Google Scholar 

  51. Rieusset J et al. Insulin acutely regulates the expression of the peroxisome proliferator-activated receptor-gamma in human adipocytes. Diabetes 1999; 48: 699–705.

    CAS  PubMed  Google Scholar 

  52. Lapsys NM et al. Expression of genes involved in lipid metabolism correlate with peroxisome proliferator-activated receptor gamma expression in human skeletal muscle. J Clin Endocrinol Metab 2000; 85: 4293–4297.

    CAS  PubMed  Google Scholar 

  53. Rousseau V et al. Developmental and nutritional changes of ob and PPAR gamma 2 gene expression in rat white adipose tissue. Biochem J 1997; 321(Pt 2): 451–456.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ribot J, Rantala M, Kesaniemi YA, Palou A, Savolainen MJ . Weight loss reduces expression of SREBP1c/ADD1 and PPARgamma2 in adipose tissue of obese women. Pflugers Arch 2001; 441: 498–505.

    CAS  PubMed  Google Scholar 

  55. Nisoli E et al. Induction of fatty acid translocase/CD36, peroxisome proliferator-activated receptor-gamma2, leptin, uncoupling proteins 2 and 3, and tumor necrosis factor-alpha gene expression in human subcutaneous fat by lipid infusion. Diabetes 2000; 49: 319–324.

    CAS  PubMed  Google Scholar 

  56. Zierath JR et al. Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARgamma agonist) action. Endocrinology 1998; 139: 5034–5041.

    CAS  PubMed  Google Scholar 

  57. Hallakou S, Foufelle F, Doare L, Kergoat M, Ferre P . 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: 963–968.

    CAS  PubMed  Google Scholar 

  58. Way JM et al. Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues. Endocrinology 2001; 142: 1269–1277.

    CAS  PubMed  Google Scholar 

  59. Jiang G et al. Potentiation of insulin signaling in tissues of zucker obese rats after acute and long-term treatment with PPARgamma agonists. Diabetes 2002; 51: 2412–2419.

    CAS  PubMed  Google Scholar 

  60. Boden G . Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46: 3–10.

    CAS  Google Scholar 

  61. Yakubu-Madus FE, Stephens TW, Johnson WT . Lipid lowering explains the insulin sensitivity enhancing effects of a thiazolidinedione, 5-(4-(2-(2-phenyl-4-oxazolyl)ethoxy)benzyl)-2,4 thiazolidinedione. Diabetes Obes Metab 2000; 2: 155–163.

    CAS  PubMed  Google Scholar 

  62. de Souza CJ et al. Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 2001; 50: 1863–1871.

    CAS  PubMed  Google Scholar 

  63. Chao L et al. Adipose tissue is required for the antidiabetic, but not for the hypolipidaemic, effect of thiazolidinediones. J Clin Invest 2000; 106: 1221–1228.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Yamauchi T et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 2001; 276: 41245–41254.

    CAS  PubMed  Google Scholar 

  65. Pickavance LC, Buckingham RE, Wilding JP . Insulin-sensitizing action of rosiglitazone is enhanced by preventing hyperphagia. Diabetes Obes Metab 2001; 3: 171–180.

    CAS  PubMed  Google Scholar 

  66. Pickavance LC, Tadayyon M, Widdowson PS, Buckingham RE, Wilding JP . Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution. Br J Pharmacol 1999; 128: 1570–1576.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Danforth Jr E . Failure of adipocyte differentiation causes type II diabetes mellitus? Nat Genet 2000; 26: 13.

    CAS  PubMed  Google Scholar 

  68. Arioglu E et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 2000; 133: 263–274.

    CAS  PubMed  Google Scholar 

  69. Burant CF et al. Troglitazone action is independent of adipose tissue. J Clin Invest 1997; 100: 2900–2908.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hallakou S et al. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 1997; 46: 1393–1399.

    CAS  PubMed  Google Scholar 

  71. Okuno A 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: 1354–1361.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Miles PD, Barak Y, He W, Evans RM, Olefsky JM . Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest 2000; 105: 287–292.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Deeb SS et al. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998; 20: 284–287.

    CAS  Google Scholar 

  74. Masugi J, Tamori Y, Mori H, Koike T, Kasuga M . Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis. Biochem Biophys Res Commun 2000; 268: 178–182.

    CAS  PubMed  Google Scholar 

  75. Hara K et al. The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun. 2000; 271: 212–216.

    CAS  PubMed  Google Scholar 

  76. Altshuler D et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76–80.

    CAS  PubMed  Google Scholar 

  77. Ek J et al. Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant Caucasians. Diabetologia 2001; 44: 1170–1176.

    CAS  PubMed  Google Scholar 

  78. Ek J et al. Homozygosity of the Pro12Ala variant of the peroxisome proliferation-activated receptor-gamma2 (PPAR-gamma2): divergent modulating effects on body mass index in obese and lean Caucasian men. Diabetologia 1999; 42: 892–895.

    CAS  Google Scholar 

  79. Beamer BA et al. Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. Diabetes 1998; 47: 1806–1808.

    CAS  Google Scholar 

  80. Barroso I et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999; 402: 880–883.

    CAS  PubMed  Google Scholar 

  81. Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn CR . Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med 1998; 339: 953–959.

    CAS  Google Scholar 

  82. Schmitz OE, Brock B, Madsbad S, Beck-Nielsen H . [Thiazolidinediones--a new class of oral antidiabetics]. Ugeskr Laeger 2001; 163: 6106–6111.

    CAS  PubMed  Google Scholar 

  83. Zinman B . PPAR gamma agonists in type 2 diabetes: how far have we come in ‘preventing the inevitable’? A review of the metabolic effects of rosiglitazone. Diabetes Obes Metab 2001; 3 (Suppl 1): S34–S43.

    CAS  PubMed  Google Scholar 

  84. Unger RH, Orci L . Diseases of liporegulation: new perspective on obesity and related disorders. FASEB J 2001; 15: 312–321.

    CAS  PubMed  Google Scholar 

  85. Bedoucha M, Atzpodien E, Boelsterli UA . Diabetic KKAy mice exhibit increased hepatic PPARgamma1 gene expression and develop hepatic steatosis upon chronic treatment with antidiabetic thiazolidinediones. J Hepatol 2001; 35: 17–23.

    CAS  PubMed  Google Scholar 

  86. Camp HS et al. Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone. Diabetes 2000; 49: 539–547.

    CAS  PubMed  Google Scholar 

  87. Malinowski JM, Bolesta S . Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review. Clin Ther 2000; 22: 1151–1168.

    CAS  PubMed  Google Scholar 

  88. Miyazaki Y, Matsuda M, DeFronzo RA . Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care 2002; 25: 517–523.

    CAS  PubMed  Google Scholar 

  89. Belcher G, Matthews DR . Safety and tolerability of pioglitazone. Exper Clin Endocr Diabetes 2000; 108: S267–S273.

    Google Scholar 

  90. Shimizu H et al. Troglitazone reduces plasma leptin concentration but increases hunger in NIDDM patients. Diabetes Care 1998; 21: 1470–1474.

    CAS  PubMed  Google Scholar 

  91. Schwartz MW, Boyko EJ, Kahn SE, Ravussin E, Bogardus C . Reduced insulin secretion: an independent predictor of body weight gain. J Clin Endocrinol Metab 1995; 80: 1571–1576.

    CAS  PubMed  Google Scholar 

  92. Kelly IE, Han TS, Walsh K, Lean ME . Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999; 22: 288–293.

    CAS  PubMed  Google Scholar 

  93. Mori Y et al. Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 1999; 22: 908–912.

    CAS  PubMed  Google Scholar 

  94. Kawai T et al. Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes. Metabolism 1999; 48: 1102–1107.

    CAS  PubMed  Google Scholar 

  95. Miyazaki Y et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). Diabetes 2000; 49 (Suppl 1): A299 (Ref Type: Abstract).

    Google Scholar 

  96. Akazawa S, Sun F, Ito M, Kawasaki E, Eguchi K . Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care 2000; 23, 1067–1071.

    CAS  PubMed  Google Scholar 

  97. Nakamura T et al. Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation—double-blind placebo-controlled trial. Diabetes Res Clin Pract 2001; 54: 181–190.

    CAS  PubMed  Google Scholar 

  98. Montague CT, O'Rahilly S . The perils of portliness: causes and consequences of visceral adiposity. Diabetes 2000; 49: 883–888.

    CAS  Google Scholar 

  99. Yanase T et al. Differential expression of PPAR gamma1 and gamma2 isoforms in human adipose tissue. Biochem Biophys Res Commun 1997; 233: 320–324.

    CAS  PubMed  Google Scholar 

  100. Adams M et al. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 1997; 100: 3149–3153.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Sewter CP, Blows F, Vidal-Puig A, O'Rahilly S . Regional differences in the response of human pre-adipocytes to PPARgamma and RXRalpha agonists. Diabetes 2002; 51: 718–723.

    CAS  PubMed  Google Scholar 

  102. Hauner H, Wabitsch M, Pfeiffer EF . Differentiation of adipocyte precursor cells from obese and nonobese adult women and from different adipose tissue sites. Horm Metab Res Suppl 1988; 19: 35–39.

    CAS  PubMed  Google Scholar 

  103. Miyazaki Y et al. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients. Diabetologia 2001; 44: 2210–2219.

    CAS  PubMed  Google Scholar 

  104. Iwamoto Y et al. Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996; 19: 151–156.

    CAS  PubMed  Google Scholar 

  105. Chilcott J, Tappenden P, Llyod Jones M, Wight JP . A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. Clin Ther 2001; 23: 1792–1823.

    CAS  PubMed  Google Scholar 

  106. Frias JP, Yu JG, Kruszynska YT, Olefsky JM . Metabolic effects of troglitazone therapy in type 2 diabetic, obese, and lean normal subjects. Diabetes Care 2000; 23: 64–69.

    CAS  PubMed  Google Scholar 

  107. Rocchi S et al. A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol Cell 2001; 8: 737–747.

    CAS  PubMed  Google Scholar 

  108. Shimaya A et al. The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice. Metabolism 2000; 49: 411–417.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the help from Gian Francesco Alberto M.D., Department of Internal Medicine, University of Turin.

Author information

Authors and Affiliations

  1. Research Department of Human Nutrition, The Royal Veterinary and Agricultural University, Copenhagen, Denmark

    T M Larsen, S Toubro & A Astrup

Authors
  1. T M Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Toubro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Astrup
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T M Larsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Larsen, T., Toubro, S. & Astrup, A. PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?. Int J Obes 27, 147–161 (2003). https://doi.org/10.1038/sj.ijo.802223

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.802223

Keywords

This article is cited by

Search

Advanced search

Quick links