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new england journal



review article

drug therapy

Hannele Yki-Järvinen, M.D., F.R.C.P.
From the Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki. Address reprint requests to Dr. Yki-Järvinen at the Division of Diabetes, Department of Medicine, P.O. Box 340, 00029 HUS Helsinki, Finland, or at ykijarvi@cc.helsinki.fi. N Engl J Med 2004;351:1106-18.
Copyright © 2004 Massachusetts Medical Society.


nsulin resistance both precedes and predicts type 2 diabetes mellitus.1 Although exercise and weight loss ameliorate insulin resistance and may in some cases prevent or delay onset of the disease,2 therapy that combats insulin resistance in those who fail to change their lifestyle is needed. Currentpharmacologic approaches are unsatisfactory in improving such consequences of insulin resistance as hyperglycemia, diabetic dyslipidemia, abnormal coagulation and fibrinolysis, and hypertension,3 each of which may require the use of at least one medication. Thus, the development of drugs targeted to reverse insulin resistance is important. The insulin-sensitizing thiazolidinediones, which are selectiveligands of the nuclear transcription factor peroxisome-proliferator–activated receptor g (PPARg),4 are the first drugs to address the basic problem of insulin resistance in patients with type 2 diabetes. Furthermore, this class of agents may have a role in treating patients with nondiabetic insulin-resistant conditions. This review briefly describes the current understanding of the mechanisms ofaction of thiazolidinediones and focuses on their use as hypoglycemic therapies in patients with type 2 diabetes.

the su perfamily of peroxisome-proliferator– activated receptors
The peroxisome-proliferator–activated receptors (PPARs) are a subfamily of the 48member nuclear-receptor superfamily5 and regulate gene expression in response to ligand binding.6,7 Various fatty acids serve as endogenousligands for PPARs, whereas some members of the superfamily (farnesoid X receptors) bind bile acids and others (liver X receptors) bind oxysterols.5 Three PPARs, designated PPARa, PPARd (also known as PPARb), and PPARg, have been identified to date. After ligand binding, PPARs undergo specific conformational changes that allow for the recruitment of one coactivator protein or more.8 Ligands differin their ability to interact with coactivators, which explains the various biologic responses observed.6,7,9-11 PPARs regulate gene transcription by two mechanisms (Fig. 1). Transactivation is DNAdependent and involves binding to PPAR response elements of target genes and heterodimerization with the retinoid X receptor.8 A second mechanism, transrepression, may explain the antiinflammatoryactions of PPARs. It involves interfering with other transcription-factor pathways in a DNA-independent way.9 PPARa is expressed predominantly in the liver, heart, and muscle, as well as in the vascular wall.7 Fibrates such as fenofibrate, bezafibrate, ciprofibrate, and gemfibrozil act as full or partial PPARa agonists. In general, PPARa activation enhances free fatty acid oxidation, controls expressionof multiple genes regulating lipoprotein concentrations, and has antiinflammatory effects (Fig. 2). PPARa agonists prevent or retard atherosclerosis in mice and humans.12-14 PPARd is expressed in many tissues, with the highest expression in the skin, brain, and adipose tissue. In mice in which PPARd is ablated (PPARd null mice),15 these tissues display alterations such as delayed wound closureand diminished myelination.


n engl j med 351;11


september 9, 2004

Downloaded from www.nejm.org by ROBERT G. REPPAS on April 17, 2008 . Copyright © 2004 Massachusetts Medical Society. All rights reserved.

drug therapy

PPARg is expressed most abundantly in adipose tissue but is also found in pancreatic beta cells, vascular endothelium, and macrophages.8,16 Its...
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