Idealized PPARγ-Based Therapies: Lessons from Bench and Bedside

The incidence of type 2 (T2D) diabetes and other chronic conditions associated with insulin resistance is increasing at an alarming rate, underscoring the need for effective and safe therapeutic strategies. Peroxisome-proliferator-activated receptor gamma (PPAR gamma) has emerged as a critical regulator of glucose homeostasis, lipid homeostasis, and vascular inflammation. Currently marketed drugs targeting this receptor, the thiazolidinediones (TZDs), have proven benefits on insulin resistance and hyperglycemia associated with T2D. Unfortunately, they have been associated with long-term unfavorable effects on health, such as weight gain, plasma volume expansion, bone loss, cardiovascular toxicity, and possibly cancer, and these safety concerns have led to reduced interest for many PPAR gamma ligands. However, over the last years, data from human genetic studies, animal models, and studies with ligands have increased our understanding of PPAR gamma's actions and provided important insights into how ligand development strategies could be optimized to increase effectiveness and safety of PPAR gamma-based therapies.