The prevalence of obesity, impaired glucose tolerance, and type 2 diabetes mellitus is escalating at an alarming rate. If current trends continue, 33% of adults in the United States may have diabetes by the year 2050, 1 a prediction that underscores the need for new, effective, and safe strategies for prevention and treatment. Recently, Choi et al. 2 reported findings that may enable the development of safer antidiabetic agents that target peroxisome-proliferator–activated receptor γ (PPARγ), a nuclear receptor and transcription factor that regulates the expression of hundreds of genes and has a fundamental role in adipocyte differentiation.

Synthetic activators of PPARγ, called thiazoli-dinediones, are one of the few classes of drugs that act primarily as effective insulin sensitizers, thereby reducing plasma insulin levels and, theoretically, the complications associated with hyperinsulinemia. The efficacy of thiazolidinediones was thought to result from altered transcriptional activity of PPARγ, although the glucose-lowering effects of different PPARγ ligands do not correspond with changes in the expression of genes regulated by PPARγ. 3 Side effects of thiazolidinediones include weight gain, fluid retention, congestive heart failure, and bone fractures4 (Fig. 1). Since such side effects have become more evident, the use of these drugs has become controversial. Earlier this year, the Food and Drug Administration severely restricted the use of one of the most commonly prescribed thiazolidinediones, rosiglitazone, because of an associated increase in the rates of complications from cardiovascular causes.