A new understanding of the link between diabetes and obesity may help drug companies design safer versions of treatments like GlaxoSmithKline's Avandia, Reuters cited U.S. researchers as saying today. The researchers had believed Avandia and Takeda Pharmaceutical Co's Actos work by stimulating a protein known as PPAR-gamma. Now the team thinks the drugs also act on the insulin resistance that diabetics develop through a different route. And they think it may be possible to tinker with drugs in this class to overcome some of their side effects. "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," Bruce Spiegelman of Dana-Farber Cancer Institute in Boston, who worked on the study in the journal Nature, said in a statement. Avandia and Actos, known generically as rosiglitazone and pioglitazone, are widely used to offset obesity-related changes in a person's insulin response that lead to diabetes. Both drugs increase the risk of fractures and heart failure, and several reports have linked Avandia with an increased risk of heart attacks and strokes. This month an advisory panel to the U.S. Food and Drug Administration found data that raised concerns about heart attacks associated with Avandia, but not enough to warrant its withdrawal from the market. The drugs act on a protein called PPAR-gamma, found mostly in fat cells, that regulates genes involved in the body's response to insulin. Scientists had believed the drugs work by stimulating PPAR-gamma, causing it to increase the activity of some genes and dampen others. The Dana-Farber researchers and a team from The Scripps Research Institute in California now think the drugs work in a different way. In studies in obese mice, they found obesity activates a molecular switch called cdk5, which causes a chemical change in PPAR-gamma, triggering resistance to insulin and increasing blood sugar levels. They did studies in cells and a test tube and found that drugs like Avandia and Actos block changes in cdk5 in addition to stimulating PPAR-gamma. "That suggested a completely new model for how these drugs were working," Spiegelman said in a telephone interview. He thinks drug companies might be able to design more selective diabetes drugs that treat insulin resistance without stimulating PPAR-gamma, which Spiegelman thinks is responsible for the side effects seen in Actos and Avandia.
