The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction

Abstract

Aims/hypothesis: Although retinoid X receptor (RXR) and peroxisome proliferator activated receptor-gamma (PPARgamma) agonists have antidiabetic effects in hyperinsulinaemic animals, little information exists on their effects after pancreatic beta-cell failure. Thus, we examined if RXR and PPARgamma agonists alter distinct metabolic pathways in animals suffering from impaired insulin secretion.

Methods: Adverse side effects and antidiabetic responses were measured in db/db mice treated from 14-16 weeks of age with the RXR agonist, LG100268, and/or the PPARgamma agonists, BRL49653 or GW1929.

Results: In animals treated with LG100268 or BRL49653, serum glucose, glycohaemoglobin and the cardiovascular risk factor, fibrinogen, decreased to the same extent. Both of these agonists were equally effective at increasing insulin accumulation in beta cells, although neither agent had an effect on serum insulin concentrations. In contrast, the RXR agonist was less effective than the PPARgamma agonists at lowering serum triglycerides and non-esterified fatty acids and increasing interscapular brown fat and body weight. Further, LG100268 increased serum alkaline phosphatase and liver mass, hepatic fat accumulation, lauric acid hydroxylase activity, catalase-immunostaining and peroxisomal number more than the PPARgamma agonists. Moreover, co-treatment with the RXR and PPARgamma agonists reduced glucose, triglycerides, non-esterified fatty acids and cholesterol more than either agent alone.

Conclusion/interpretation: These data suggest 1) RXR and PPARgamma agonists decrease islet degeneration, cardiovascular risk and cachexia during later stages of diabetes, 2) RXR agonists are less effective than PPARgamma agonists at decreasing serum lipids and causing weight gain and 3) RXR agonists have a more pronounced effect on liver metabolism (e.g. peroxisome accumulation and hepatomegaly) than PPARgamma agonists.