Skip to main content
SpringerLink
Log in

PPAR-gamma agonisti nella terapia del diabete mellito e di altre malattie endocrino-metaboliche

  • Published:
L’Endocrinologo Aims and scope

Riassunto

Gli agonisti dei fattori di trascrizione peroxisome prolife rator-activated receptor (PPAR)-gamma sono una nuova classe di farmaci insulino-sensibilizzanti, che comprende il pioglitazone e il rosiglitazone, con molteplici effetti sul tessuto adiposo, sul sistema cardiovascolare e sul metabolismo. L’impiego di questi farmaci in pazienti con diabete tipo 2 determina effetti benefici sul compenso glicemico, sulla dislipidemia e su alcuni indicatori di rischio cardiovascolare. Per le azioni insulinosensibilizzante, anti-infiammatoria e anti-proliferativa questi farmaci sono anche di potenziale utilità nella terapia di condizioni associate a insulino-resistenza e di alcune forme neoplastiche. Ad oggi, tuttavia, non è approvato l’impiego dei tiazolidinedioni per indicazioni diverse dal trattamento del diabete mellito tipo 2. I PPAR-gamma agonisti sono in genere ben tollerati, anche se è consigliato il monitoraggio della funzionalità epatica e la massima cautela in soggetti cardiopatici per la possibilità di precipitare uno scompenso cardiaco in seguito a ritenzione di liquidi.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Bibliografia

  1. DiRenzo J, Soderstrom M, Kurokawa R, Ogliastro MH, Ricote M, Ingrey S, Horlein A, Rosenfeld MG, Glass CK. Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. Mol Cell Biol 17: 2166, 1997.

    PubMed Central  PubMed  CAS  Google Scholar 

  2. Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med 10: 355, 2004.

    Article  PubMed  CAS  Google Scholar 

  3. Rangwala SM, Lazar MA. Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci 25: 331, 2004.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4: 611, 1999.

    Article  PubMed  CAS  Google Scholar 

  6. Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams RL, Umpleby AM, Thomas EL, Bell JD, Dixon AK, Dunne F, Boiani R, Cinti S, Vidal-Puig A, Karpe F, Chatterjee VK, O’Rahilly S. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 52: 910, 2003.

    Article  PubMed  CAS  Google Scholar 

  7. Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, McKeon C, Darlington GJ, Spiegelman BM. Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell 3: 151, 1999.

    Article  PubMed  CAS  Google Scholar 

  8. Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, Ide T, Kubota N, Terauchi Y, Tobe K, Miki H, Tsuchida A, Akanuma Y, Nagai R, Kimura S, Kadowaki T. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 276: 41245, 2001.

    Article  PubMed  CAS  Google Scholar 

  9. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50: 2094, 2001.

    Article  PubMed  CAS  Google Scholar 

  10. Hsueh WA, Law R. The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease. Am J Cardiol 92: 3J, 2003.

    Article  PubMed  CAS  Google Scholar 

  11. Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 87: 2784, 2002.

    Article  PubMed  CAS  Google Scholar 

  12. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 101: 1354, 1998.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Reusch JE, Regensteiner JG, Watson PA. Novel actions of thiazolidinediones on vascular function and exercise capacity. Am J Med 115 Suppl 8A: 69S, 2003.

    Article  PubMed  CAS  Google Scholar 

  14. Lebovitz HE. Rationale for and role of thiazolidinediones in type 2 diabetes mellitus. Am J Cardiol 90: 34G, 2002.

    Article  PubMed  CAS  Google Scholar 

  15. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 351: 1106, 2004.

    Article  PubMed  Google Scholar 

  16. Freed MI, Ratner R, Marcovina SM, Kreider MM, Biswas N, Cohen BR, Brunzell JD; Rosiglitazone Study 108 investigators. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus. Am J Cardiol 90: 947, 2002.

    Article  PubMed  CAS  Google Scholar 

  17. Sakamoto J, Kimura H, Moriyama S, Odaka H, Momose Y, Sugiyama Y, Sawada H. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 278: 704, 2000.

    Article  PubMed  CAS  Google Scholar 

  18. Prigeon RL, Kahn SE, Porte D Jr. Effect of troglitazone on B cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 83: 819, 1998.

    PubMed  CAS  Google Scholar 

  19. Wallace TM, Levy JC, Matthews DR. An increase in insulin sensitivity and basal beta-cell function in diabetic subjects treated with pioglitazone in a placebo-controlled randomized study. Diabet Med 21: 568, 2004.

    Article  PubMed  CAS  Google Scholar 

  20. Juhl CB, Hollingdal M, Porksen N, Prange A, Lonnqvist F, Schmitz O. Influence of rosiglitazone treatment on beta-cell function in type 2 diabetes: evidence of an increased ability of glucose to entrain high-frequency insulin pulsatility. J Clin Endocrinol Metab 88: 3794, 2003.

    Article  PubMed  CAS  Google Scholar 

  21. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51: 2796, 2002.

    Article  PubMed  CAS  Google Scholar 

  22. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O’Keefe M, Ghazzi MN; PCOS/Troglitazone Study Group. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86: 1626, 2001.

    PubMed  CAS  Google Scholar 

  23. Brettenthaler N, De Geyter C, Huber PR, Keller U. Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J Clin Endocrinol Metab 89: 3835, 2004.

    Article  PubMed  CAS  Google Scholar 

  24. Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke RW. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 79: 562, 2003.

    Article  PubMed  Google Scholar 

  25. Arioglu E, Duncan-Morin J, Sebring N, Rother KI, Gottlieb N, Lieberman J, Herion D, Kleiner DE, Reynolds J, Premkumar A, Sumner AE, Hoofnagle J, Reitman ML, Taylor SI. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 133: 263, 2000.

    Article  PubMed  CAS  Google Scholar 

  26. Laviola, L., N. Pannacciulli, S. Martemucci, F. Logoluso, G. De Pergola, R. Giorgino, F. Giorgino. Il pioglitazone migliora le caratteristiche cliniche e metaboliche dell’insulino-resistenza in un soggetto con sindrome di Dunnigan. Il Diabete 16: 17, 2004.

    Google Scholar 

  27. Sutinen J, Hakkinen AM, Westerbacka J, Seppala-Lindroos A, Vehkavaara S, Halavaara J, Jarvinen A, Ristola M, Yki-Jarvinen H. Rosiglitazone in the treatment of HAART-associated lipodystrophy—a randomized double-blind placebo-controlled study. Antivir Ther 8: 199, 2003.

    PubMed  CAS  Google Scholar 

  28. Grommes C, Landreth GE, Heneka MT. Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol 5: 419, 2004.

    Article  PubMed  CAS  Google Scholar 

  29. Demetri GD, Fletcher CD, Mueller E, Sarraf P, Naujoks R, Campbell N, Spiegelman BM, Singer S. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. Proc Natl Acad Sci U S A 96: 3951, 1999.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Debrock G, Vanhentenrijk V, Sciot R, Debiec-Rychter M, Oyen R, Van Oosterom A. A phase II trial with rosiglitazone in liposarcoma patients. Br J Cancer 89: 1409, 2003.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA, Evans RM. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 4: 1058, 1998.

    Article  PubMed  CAS  Google Scholar 

  32. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure: A consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 27: 256, 2004.

    Article  PubMed  CAS  Google Scholar 

  33. Bluher M, Lubben G, Paschke R. Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Diabetes Care 26: 825, 2003.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento dell’Emergenza e dei Trapianti di Organi, — Sezione di Medicina Interna, Endocrinologia e Malattie Metaboliche, Università degli Studi di Bari, Piazza Giulio Cesare 11, 70124, Bari, Italia

    Francesco Giorgino & Luigi Laviola

Authors
  1. Francesco Giorgino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luigi Laviola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Giorgino.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Giorgino, F., Laviola, L. PPAR-gamma agonisti nella terapia del diabete mellito e di altre malattie endocrino-metaboliche. L’Endocrinologo 6, 81–88 (2005). https://doi.org/10.1007/BF03345935

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03345935

Search

Navigation