The Insulin-sensitizers Troglitazone And Rosiglitazone Alter Lipid Bilayer Properties

Abstract

Thiazolidinediones are widely used to treat hyperglycemia in patients suffering from type 2 diabetes. Three thiazolinediones - troglitazone (Resulin), rosiglitazone (Avandia), and pioglitazone (Actos) - have been marketed; troglitazone was subsequently withdrawn due to hepatotoxicity. The thiazolidinediones are selective peroxizome-proliferator receptor gamma (PPARγ) agonists and they increase insulin sensitivity. They also have been found to have anti-oxidant, anti-inflammatory, anti-atherosclerotic and cardiovascular effects, but PPARγ activation alone does not account for all their actions. All three derivatives, with troglitazone being the most potent, modulate L-type calcium and delayed-rectifier potassium Kv1.3 channels by a seemingly PPARγ-independent mechanism. This could result from the adsorption of amphiphilic molecules to the membrane, which can alter bilayer properties such as thickness, intrinsic curvature and elastic moduli, and thus membrane protein function. We therefore set out to determine whether the amphiphilic troglitazone and rosiglitazone alter lipid bilayer properties. Using gramicidin channels as probes, where we monitor the changes in channel lifetime and rate of appearance, we tested and compared the effects of troglitazone and rosiglitazone on channels of different lengths in DOPC bilayers. Troglitazone or rosiglitazone did not alter gramicidin channel conductances, suggesting that direct interactions are not involved. In contrast, the lifetimes of both channels increased with similar relative changes for both the shorter and the longer channels. Consistent with their effects on calcium and potassium channels troglitazone is more potent than rosiglitazone. Our results show that both troglitazone and rosiglitazone affect bulk membrane properties at the concentrations where they modulate other ion channels.