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Scientists find unsuspected molecular link between obesity and insulin resistance
Date:7/21/2010

ange in PPAR-gamma called phosphorylation. In contrast to agonism of PPAR-gamma, phosphorylation has a narrow effect, disrupting a smaller set of genes that lead to insulin resistance.

In addition to agonizing PPAR-gamma, Avandia and Actos also block the phosphorylation of PPAR-gamma by cdk5. It's this latter effect that accounts for most of the drugs' anti-diabetic benefits, the authors contend. "Agonism may not be therapeutically necessary and likely results in a lot of the toxicities," Spiegelman said.

The strength of various drugs' agonist effects on PPAR-gamma doesn't correlate with how well they work, the researchers observe; instead, it is their ability to block cdk5 phosphorylation that counts. In support of this assertion, the paper describes the researchers' findings from patients treated with Avandia in a German clinical trial. It showed that improvements in insulin sensitivity were tightly correlated with decreased phosphorylation of PPAR-gamma.

"I think this is a really important finding, and potentially very timely in light of the current discussions about Avandia," commented Jeffrey Flier, MD, Dean of the Harvard Medical School, a leading researcher in obesity, insulin resistance, and diabetes.

"It may motivate pharmaceutical companies to take another look at compounds acting through PPAR-gamma that were taken to various stages of development but put on hold because they did not demonstrate strong agonism of PPAR-gamma," Flier said. "People may have been focusing on the wrong outcomes."

Avandia and Actos belong to a relatively new class of compounds called thiazolidinediones, the first medications that can reverse insulin resistance. They have been widely used to treat Type 2 diabetes since being approved in 1999. However, in recent years they have been linked in some patients to heart attacks, heart failure, and strokes. Thousands of lawsuits have been filed against the maker of Avandia, and the US Food a
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Contact: Teresa Herbert
teresa_herbert@dfci.harvard.edu
617-632-4090
Dana-Farber Cancer Institute
Source:Eurekalert

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