Andy, Of course the Nature paper showed that the TZDs and Rexinoids synergize to overcome insulin resistance which is the molecular basis for preventing type II diabetes:
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. |
