Reversing the curse on PPARγ
Mitchell A. Lazar
Mitchell A. Lazar
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Commentary

Reversing the curse on PPARγ

Abstract

Thiazolidinediones (TZDs) are the only antidiabetic drugs that reverse insulin resistance. They have been a valuable asset in the treatment of type 2 diabetes, but their side effects have curtailed widespread use in the clinic. In this issue of the JCI, Kraakman and colleagues provide evidence that deacetylation of the nuclear receptor PPARγ improves the therapeutic index of TZDs. These findings should revitalize the quest to employ insulin sensitization as a first-line approach to managing type 2 diabetes.

Authors

Mitchell A. Lazar

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Figure 1

Shifting the balance of benefits and risks of TZD therapy.

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Shifting the balance of benefits and risks of TZD therapy. Kraakman et a...
Kraakman et al. (4) show that mice with the PPARγ-2KR mutation that prevents acetylation maintain the benefit of TZD therapy with fewer risks. If this work translates to humans, it may lead to the resurgence of TZD therapy via drugs that deacetylate PPARγ. It also may be possible to develop SPPARMs that achieve this goal by stabilizing the conformation of deacetylated PPARγ.