Current opinion in investigational drugs (London, England : 2000)Nov 8, 2006

Insulin resistance and drugs that improve insulin sensitivity through PPAR

Updated Apr 3, 2026

Abstract

Thiazolidinediones (TZDs) act as insulin sensitizers and may provide multiple additional health benefits.

PPARalpha activation enhances the breakdown of fatty acids and reduces inflammation.
PPARgamma is crucial for the formation and function of fat cells and the storage of fatty acids.
TZDs, which target PPARgamma, reduce free fatty acids by inhibiting fat breakdown in fat tissue.
Current insulin sensitizers under investigation include partial PPARgamma agents and dual PPARalpha/PPARgamma agents.
TZDs have properties that may reduce inflammation, oxidative stress, and blood clotting, alongside their insulin-sensitizing effects.
There is potential for early initiation of TZD therapy in type 2 diabetes, especially for patients with cardiovascular risk.

Simplified

Drugs that reverse insulin resistance are of importance as insulin resistance is frequently associated with type 2 diabetes. The three peroxisome proliferator-activated receptors (PPARs) PPARalpha, PPAR90 and PPARgamma are essential for the actions of the many insulin sensitizers. PPARalpha activation enhances free fatty acid oxidation and potentiates anti-inflammatory effects, while PPARgamma is essential for normal adipocyte differentiation and proliferation, as well as fatty acid uptake and storage. Thiazolidinediones (TZDs) are selective ligands of PPARgamma and act as insulin sensitizers. TZDs also suppress free fatty acids via the inhibition of lipolysis in adipose tissue. Insulin sensitizers currently under development include partial PPARgamma agonists and antagonists, and dual PPARalpha/PPARgamma agonists. Given that TZDs show anti-inflammatory, anti-oxidant and antiprocoagulant properties in addition to their insulin sensitizing and antilipotoxic properties, a case may be made for initiating TZD therapy early in the treatment of type 2 diabetes, particularly in those patients at risk of cardiovascular disease. TZDs may also be an important therapeutic option in the treatment of metabolic syndrome.

Insulin resistance and drugs that improve insulin sensitivity through PPAR

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