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Resolving the PPARgamma paradox

Researchers at the Dana-Farber Cancer Institute and Scripps Florida have found an alternative mechanism by which peroxisome proliferation-activated receptor-g agonists exert their antidiabetic effects.1 By blocking phosphorylation of the protein, these compounds actually may improve insulin sensitivity independent of receptor agonism.

The findings offer a reason for drug companies to take a fresh look at antidiabetic compounds that may have been previously dismissed due to their reduced agonistic activity but now may be seen to offer therapeutic benefits with the potential for fewer side effects than marketed peroxisome proliferation-activated receptor-g (PPARG; PPARg) agonists.

Indeed, the alternative mechanism may explain how partial PPARg agonists in clinical development, including InteKrin Therapeutics Inc.'s INT131, can exhibit potent antidiabetic effects similar to those of full agonists such as GlaxoSmithKline plc's Avandia rosiglitazone and Takeda Pharmaceutical Co. Ltd.'s Actos pioglitazone.

Avandia and Actos are marketed to treat type 2 diabetes and had combined worldwide sales of over $4.5 billion in 2009. However, patients taking these thiazolidinedione (TZD) drugs can experience side effects such as weight gain and edema. An FDA advisory panel recently

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