New research could help sufferers avoid harmful side effects linked to some controversial drugs for diabetes. The study, published in the July 22 Nature, examines the action of rosiglitazone, whose brand name is Avandia, and other antidiabetic drugs. The work uncovers a mechanism that could lead scientists to eliminate some of the risks associated with the drugs, including heart attack and stroke.
“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,” said Bruce Spiegelman, the Stanley J. Korsmeyer professor of cell biology and medicine at HMS and the Dana-Farber Cancer Institute.
The research comes during a period of intense debate about the side effects of thiazolidinediones, the class of compound to which Avandia belongs. The medication has been the subject of numerous lawsuits and an investigation by the Food and Drug Administration, which ruled in July that Avandia could remain on the market but would be subject to new restrictions.
Thiazolidinediones act on a master regulatory protein called PPAR-gamma, primarily in fat cells, which governs genes involved in the body’s response to insulin. A high-fat diet can alter the function of PPAR-gamma and disrupt insulin response, a cause of diabetes.
Avandia was thought to work by stimulating or “agonizing” the PPAR-gamma receptor, causing it to rev up some genes and dampen the activity of others. But Spiegelman’s team discovered a new explanation for the role of thiazolidinediones in countering insulin resistance. They found that obesity in mice caused the activation of a protein kinase—a molecular switch—called cdk5, resulting in a chemical change in PPAR-gamma. It was this chemical change, known as phosphorylation, that was blocked by the medications and led to most of the drugs’ benefits. The finding suggests the most damaging function of Avandia is not needed for its beneficial effects.
“Agonism [of the PPAR-gamma receptor] may not be therapeutically necessary and likely results in a lot of the toxicities,” said Spiegelman.
The study included findings from patients treated with Avandia in a German clinical trial. It showed that improvements in insulin sensitivity were closely linked with decreased phosphorylation of PPAR-gamma.
HMS dean Jeffrey Flier said in a comment on the study, “I think this is a really important finding and potentially very timely in light of the current discussions about Avandia.
“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.”
For more information, students may contact Bruce Spiegelman at bruce_spiegelman@dfci.harvard.edu.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The National Institutes of Health, Deutsche Forschungsgemeinschaft, and the clinical research group Atherobesity; the authors are solely responsible for the content of this work.
