After screening hundreds of compounds for their effects on fat development, researchers have discovered that an ingredient found in some plants fights diabetes in mice without some of the side effects attributed to other antidiabetes drugs. The chemical they pinpointed, known as harmine, was first isolated more than 150 years ago from plants traditionally included in ritual and medicinal preparations around the world, the team reports in the May issue of the journal Cell Metabolism, published by Cell Press.

The work suggests a new approach for treating insulin resistance that might complement the use of preexisting drugs and, more generally, provides validation for fat cell screens as a promising strategy for identifying new metabolic drugs, according to the researchers.

While harmine itself has effects on the central nervous system that may preclude its use, "it may eventually be possible to separate the nervous system and metabolic effects of harmine through optimization of the chemical structure," said Peter Tontonoz, a Howard Hughes Medical Institute investigator at the University of California, Los Angeles. Harmine has been known to induce hallucinations, convulsions, and tremors.

The principal class of drugs prescribed for obesity-related diabetes, called thiazolidinediones or TZDs, work through a counterintuitive mechanism: they restore insulin sensitivity by activating a central promoter of fat tissue production called peroxisome proliferator-activated receptor (PPAR).

"The current explanation for this paradoxical mode of action is the idea that the body needs a place to store lipids," Tontonoz said. "If the body becomes less able to store lipids in fat, it may deposit in other tissues," where it can spur disease.

Despite their efficacy, the development and clinical use of TZDs is limited by adverse effects such as fluid retention, weight gain, congestive heart failure, liver toxicity, and potential cance
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Contact: Erin Doonan
edoonan@cell.com
617-397-2802
Cell Press
8-May-2007