SBH's TZD, BRL 49653 (rosiglitazone), was used in LGND's Nature paper showing that Targretin and LGD1268 could synergize with it:
Nature 1997 Mar 27;386(6623):407-410
Sensitization of diabetic and obese mice to insulin by retinoid X receptor
agonists.
Mukherjee R, Davies PJ, Crombie DL, Bischoff ED, Cesario RM, Jow L, Hamann LG, Boehm MF, Mondon CE,
Nadzan AM, Paterniti JR Jr, Heyman RA
Department of Cardiovascular Research, Ligand Pharmaceuticals, San Diego, California 92121, USA.
Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the
orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate
transcription. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We
demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating
RXR: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for
antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of
noninsulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease
hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. This antidiabetic activity can be further enhanced by combination
treatment with PPARgamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPARgamma heterodimer is a
single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARgamma
dimer with rexinoids may provide a new and effective treatment for NIDDM.
PMID: 9121558, UI: 97238686 |
