Findings suggest that PPAR-gamma agonism may be the cause of side effects.

Researchers have identified a new link between obesity and insulin response involving cdk5, a protein kinase. This pathway better explains how drugs like GlaxoSmithKline’s Avandia and Takeda’s Actos work against diabetes, the team from Dana-Farber Cancer Institute and The Scripps Research Institute adds. Details are published in the July 22 issue of Nature.

The study, carried out in mice, suggests that cdk5 is activated by the development of obesity. It causes phosphorylation of PPR-gamma, which governs genes involved in the body’s response to insulin. Obesity resulting from a high-fat diet alters the function of PPAR-gamma and disrupts the expression of those insulin-response genes including adipsin and adiponectin.

Avandia and Actos, known generically as rosiglitazone and pioglitazone, respectively, are known to work by binding to PPAR-gamma and reversing the gene-expression changes. The drugs were believed to work by agonizing the PPAR-gamma receptor, causing it to rev up some genes and dampen the activity of others.

In the Nature report, however, the researchers say that cdk5’s phosphorylation of PPAR-gamma effects a narrower set of insulin-resistance genes than agonization of PPAR-gamma. They thus attribute the antidiabetic benefits of Avandia and Actos to their ability to block the phosphorylation of PPAR-gamma by cdk5.

In fact, they suggest that the agonization of PPAR-gamma may be the culprit behind some of the side effects that have been linked to these therapeutics. “Agonism may not be therapeutically necessary and likely results in a lot of the toxicities,” says Bruce Spiegelman, Ph.D., of Dana-Farber and senior author of the Nature paper.

The strength of various drugs’ agonist effects on PPAR-gamma doesn’t correlate with how well they work, the researchers observe. In their study, they looked at patients treated with Avandia in a German clinical trial. They found 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,” comments Jeffrey Flier, M.D., dean of Harvard Medical School, in reference to growing concerns about Avandia’s cardiovascular risks. “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. People may have been focusing on the wrong outcomes.”

Dr. Spiegelman adds, “Our findings strongly suggest that good and bad effects of these drugs can be separated by designing second-generation drugs that focus on the newly uncovered mechanism.”

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 1999. However, in recent years they have been linked in some patients to heart attacks, heart failure, and strokes.

GSK today said that it would halt enrollment of additional patients into its postmarketing trial with Avandia. Those currently receiving the drug in the study will continue to do so until FDA makes a final decision. In July two FDA advisory panels voted 20–12 in favor of keeping Avandia on the market but on the condition that its label be revised to reflect cardiovascular risk factors and/or restrictions.

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