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Papers In Press, published online ahead of print February 27, 2002
J. Biol. Chem, 10.1074/jbc.C200004200
Submitted on January 3, 2002
Revised on February 15, 2002
Accepted on February 27, 2002

The antidiabetic agent LG100754 sensitizes cells to low concentrations of PPARgamma ligands

Barry Marc Forman

City of Hope National Medical Center, Duarte, CA 91010

Corresponding Author: bmforman{at}earthlink.net

Insulin resistance and non-insulin dependent diabetes mellitus are major causes of morbidity and mortality in industrialized nations. Despite the alarming rise in the prevalence of this disorder, the initial molecular events that promote insulin resistance remain unclear. The data presented here demonstrate that LG100754, an antidiabetic RXR ligand, defines a novel type of nuclear receptor agonist. Surprisingly, LG100754 has minimal intrinsic transcriptional activity; instead it enhances the potency of PPARgamma -RXR heterodimers for PPARgamma ligands. The ability of LG100754 to both increase PPARgamma -sensitivity and relieve insulin resistance implies that a deficiency in endogenous PPARgamma ligands may represent an early step in the development of insulin resistance.


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