Biological Characterization of a Heterodimer-Selective Retinoid X Receptor Modulator: Potential Benefits for the Treatment of Type 2 Diabetes

• DOI: 10.1210/en.2005-0690
• Publication Date: 2005-11-04T01:29:31Z
• Authors: Mark D. Leibowitz; Robert J. Ardecky; Marcus F. Boehm; Carol L. Broderick; Mark A. Carfagna; Diane L. Crombie; Jennifer D’Arrigo; Garrett J. Etgen; Margaret M. Faul; Timothy A. Grese; Henry Havel; Nancy I. Hein; Richard A. Heyman; Diane Jolley; Kay Klausing; Sha Liu; Dale E. Mais; Christopher M. Mapes; Keith B. Marschke; Pierre-Yves Miche...; Chahrzad Montrose...; Kathleen M. Ogilvie; Bernadette Pascual; Deepa Rungta; John S. Tyhonas; Mary S. Urcan; Marilyn Wardlow; Nathan Yumibe; Anne Reifel-Miller
• Keywords: Retinoid X receptor; Rosiglitazone; Thiazolidinedione; Pioglitazone

Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARγ rosiglitazone, produce insulin sensitization in rodent models of resistance type 2 diabetes. In sharp contrast to TZDs that significant increases body weight gain, RXR agonists reduce gain food consumption. Unfortunately, also suppress thyroid hormone axis generally hypertriglyceridemia. Heterodimer-selective modulators have been identified that, rodents, retain metabolic benefits with reduced side effects. These bind specifically high affinity are homodimer partial agonists. Although activate many heterodimer partners, these selectively RXR:PPARα RXR:PPARγ, but not RXR:RARα, RXR:LXRα, RXR:LXRβ, or RXR:FXRα. We report vivo characterization one modulator, LG101506 (LG1506). Zucker fatty (fa/fa) rats, LG1506 is a potent sensitizer enhances insulin-sensitizing activities rosiglitazone. Administration reduces both consumption blocks TZD-induced when coadministered does significantly nor it elevate triglycerides Sprague Dawley rats. However, produces unique pattern elevation elevates high-density lipoprotein cholesterol humanized apolipoprotein A-1-transgenic mice. Therefore, selective promising approach for developing improved therapies diabetes, although additional studies needed understand strain-specific effects on triglycerides.