Fresh Air For Avandia

By shedding light on how a beleaguered class of antidiabetic drugs exerts its effects, a new study could help chemists design better next-generation medications.

Many patients with type 2 diabetes rely on drugs such as Avandia (rosiglitazone maleate) and Actos (pioglitazone hydrochloride) to increase their bodies’ sensitivity to insulin. Both drugs activate a transcription factor protein called peroxisome proliferator-activated receptor γ (PPARγ), which is a master regulator of cellular metabolism. Many pharmaceutical companies have searched for molecules that activate PPARγ, but most efforts were shelved because of side effects such as weight gain. Avandia itself is under fire because of heart risks (see page 32).

But the antidiabetic effects of Avandia and other PPARγ activators may in fact have little to do with their PPARγ-activating properties, according to a team led by biochemists Bruce M. Spiegelman of the Dana-Farber Cancer Institute of Harvard Medical School and Patrick R. Griffin of Scripps Florida, with physician Matthias Blüher of the University of Leipzig, in Germany. Instead, these researchers say the molecules’ therapeutic benefits can be traced to their ability to prevent a kinase enzyme from placing a phosphate group on PPARγ (Nature 2010, 466, 451). In fact, stimulating PPARγ might even be the reason for the side effects, Spiegelman says. “It ought to be possible to improve this class of drugs by dialing in the ability to inhibit the phosphorylation while dialing out receptor activation,” he says.

Originally, the team was intrigued by a paradox about PPARγ-targeted drugs, Spiegelman explains. Some weak PPARγ activators were just as good as very strong activators at improving cells’ response to insulin. The new study offers an explanation: Strong and weak PPARγ activators are equally good at blocking PPARγ phosphorylation. On the basis of hydrogen-deuterium exchange experiments, the researchers suggest the compounds work by freezing PPARγ into a position that makes phosphorylation difficult.

Further tying phosphorylation inhibition to drug efficacy, in a small number of patients who received Avandia, the team found that lower levels of PPARγ phosphorylation in fat tissue correlated with better antidiabetic effects.

“For years, scientists have known that it was possible to identify ligands that retained the beneficial antidiabetic actions of PPARγ drugs like rosiglitazone while dialing out the weight gain and other side effects,” says Steven A. Kliewer of the University of Texas Southwestern Medical Center, an expert in PPAR receptors. “However, pharmaceutical companies were hesitant to pursue these compounds in the absence of any molecular understanding of why they worked,” he says. “Hopefully this study will reignite interest in PPARγ as a drug discovery target.”