The thiazolidinediones exert their insulin sensitising effect by binding to the nuclear receptors (transcription factors) peroxisome proliferator activated receptor (PPAR) γ and, to varying degrees, to PPARα. Several different genes are activated by thiazolidinediones, many of which contribute to the increase in insulin sensitivity (eg. an increase in glucose uptake and utilisation, a decrease in gluconeogenesis and in insulin-antagonistic cytokines, such as tumour necrosis factor α). Activation of other genes indirectly reduces insulin resistance by, for example, increasing free fatty acid (FFA) uptake and oxidation resulting in lower circulating FFA levels. The action of thiazolidinediones at PPARγ is generally responsible for their insulin sensitising effects while action at PPARα contributes to their lipid lowering effects. Therefore, the relative affinities of the different thiazolidinediones for PPARγ and PPARα will also lead to a different spectrum of actions for each agent.
Willson TM, Brown PJ, Sternbach DD, Henke BRThe PPARs: from orphan receptors to drug discovery. J Med Chem2000;43:527-50.
2.
Rosen ED, Spiegelman BMPPARγ: a nuclear regulator of metabolism, differentiation, and cell growth . J Biol Chem2001;276:37731-4.
3.
Auwerx J.PPARγ, the ultimate thrifty gene. Diabetologia1999;42:1033-49.
4.
Schoonjans K. , Staels B., Auwerx J.Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res1996;37:907-25.
5.
Mori H., Ikegami H., Kawaguchi Y. et al. The Pro12--->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. Diabetes2001;50:891-4.
6.
Barroso I., Gurnell M., Crowley VEF et al. Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature1999;402:880-3.
7.
Sakamoto J., Kimura H., Moriyama S. et al. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun2000;278:704-11.
8.
Campbell IWAntidiabetic drugs present and future: will improving insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus?Drugs2000;60:1017-28.
9.
El-Kebbi IM, Roser S., Pollet RJRegulation of glucose transport by pioglitazone in cultured muscle cells. Metabolism1994;43:953-9.
10.
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 . Endocrinology1993;133:352-9.
11.
Hofmann C., Lorenz K., Colca JRGlucose transport deficiency in diabetic animals is corrected by treatment with the oral antihyperglycemic agent pioglitazone. Endocrinology1991;129:1915-25.
12.
Hayakawa T. , Shiraki T., Morimoto T. et al. Pioglitazone improves insulin signalling defects in skeletal muscle from Wistar fatty (fa/fa) rats. Biochem Biophys Res Commun1996;223:439-44.
13.
Smith U., Gogg S., Johansson A., Olausson T., Rotter V., Svalstedt B.Thiazolidinediones (PPARγ agonists) but not PPARα agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes. FASEB J2001;15: 215-20.
14.
Hofmann CA, Edwards CWI, Hillman RM et al. Treatment of insulin-resistant mice with the oral antidiabetic agent pioglitazone: elevation of liver GLUT 2 and phosphoenolpyruvate carboxykinase expression. Endocrinology1992;130:735-40.
15.
Hofmann C., Lorenz K., Williams D., Palazuk BJ, Colca JRInsulin sensitisation in diabetic rat liver by an antihyperglycemic agent . Metabolism1995;44:384-9.
16.
Sugiyama Y. , Shimura Y., Ikeda H.Effects of pioglitazone on hepatic and peripheral insulin resistance in Wistar fatty rats. Arzneimittelforschung1990;40:436-40.
17.
Nishimura Y. , Inoue Y., Takeuchi H., Oka Y.Acute effects of pioglitazone on glucose metabolism in perfused rat liver. Acta Diabetol1997;34:206-10.
18.
Hallakou S. , Doare L., Foufelle F. et al. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes1997; 46:1393-9.
19.
Swanson ML, Bleasdale JEAntidiabetic agent pioglitazone increases insulin receptors on 3T3-L1 adipocytes . Drug Dev Res1995;35:69-82.
20.
Murase K., Odaka H., Suzuki N., Tayuki N., Ikeda H.Pioglitazone time-dependently reduces tumour necrosis factor-α level in muscle and improves metabolic abnormalities in Wistar fatty rats . Diabetologia1998; 41:257-64.
21.
Miyazaki Y. , Mahankali A., Matsuda M. et al. Improved glycaemic control and enhanced insulin sensitivity in Type 2 diabetic subjects treated with pioglitazone . Diabetes Care2001;24:710-9.
22.
Yamasaki Y. , Kawamori R., Wasada T. et al. Pioglitazone (AD-4833) ameliorates insulin resistance in patients with NIDDM. Tohuku J Exp Med1997;183:173-83.
23.
Roden M., Price TB, Perseghin G. et al. Mechanism of free fatty-acid-induced insulin resistance in humans . J Clin Invest1996;97:2859-65.
24.
Rebrin K., Steil GM, Getty L., Bergman RNFree fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes1995;44:1038-45.
Carey GBMechanisms regulating adipocyte lipolysis. Adv Exp Med Biol1998;441:157-70.
29.
Engfeldt P. , Arner P., Bolinder J., Ostman J.Phosphodiesterase activity in human subcutaneous adipose tissue in insulin- and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab1982;55:983-8.
30.
Tang Y., Osawa H., Onuma H., Nishimiya T., Ochi M., Makino H.Improvement in insulin resistance and the restoration of reduced phosphodiesterase 3B gene expression by pioglitazone in adipose tissue of obese diabetic KKAy mice. Diabetes1999;48:1830-5.
31.
Kletzien RF , Clarke SD, Ulrich RGEnhancement of adipocyte differentiation by an insulin sensitising agent. Mol Pharmacol1992;41:393-8.
32.
King ABA comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones. Diabetes Care2000;23:557.
