Science

Study raises hope for safer diabetes drugs

CHICAGO (Reuters) - A new understanding of the link between diabetes and obesity may help scientists design safer drugs to lower blood sugar levels, U.S. researchers said on Wednesday.

The researchers had believed the embattled drug Avandia (rosiglitazone) and its rival Actos (pioglitazone) 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," Dr. Bruce Spiegelman of Dana-Farber Cancer Institute in Boston, who worked on the study published online today in Nature, said in a statement.

Avandia and Actos, both widely used to offset obesity-related changes in insulin response, both also 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.

PPAR-gamma, found mostly in fat cells, 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 mice, they found that obesity activates a molecular switch called cdk5, which causes a chemical change in PPAR-gamma, triggering resistance to insulin and increasing blood sugar levels.

In vitro studies should 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," Dr. Spiegelman said

He thinks drug companies might be able to design more selective diabetes drugs that treat insulin resistance without stimulating PPAR-gamma, which he thinks is responsible for the side effects seen with Actos and Avandia.

Nature;466,451-456.

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