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Scientists reduce life-threatening side effects of diabetes drugs



Posted On: Sept. 14, 2011

Washington, Sept 10 (ANI): Prototype drugs having powerful anti-diabetic effects, and yet apparently free - at least in mice - of dangerous side effects plaguing some current diabetes medications have been created.

One of the drug prototypes proved capable of reducing disease symptoms in diabetes-prone mice without triggering weight gain or fluid retention, potential side effects of current drugs such as rosiglitazone (Avandia) and pioglitazone (Actos) that can have had fatal consequences in some patients.

While these novel compounds would not be suitable for use in human patients, the scientists say the results showed that they had succeeded in building selective anti-diabetic molecules that minimize the risk of severe side effects.

"This insight shows how you can make new compounds that appear to be safer, but you don't know for sure until a drug is developed that you can give to patients," said Bruce Spiegelman, PhD, of Dana-Farber Cancer Institute in Boston.

Until recently, it had been assumed that Avandia and Actos worked exclusively by agonizing PPAR-gamma. But in 2010, Spiegelman and Griffin reported that they had discovered a second, unsuspected effect of the drugs on PPAR-gamma.

The TZD drugs, they said, also block a process called phosphorylation, by a molecule known as Cdk5 that modifies PPAR-gamma in a manner that is entirely separate from agonism. This mechanism, they said, might in fact be more critical to combating diabetes - and, to their surprise, apparently seemed not to cause the worrisome side effects.

In the new report, the team describes the development of synthetic small molecules "that bind tightly to PPAR-gamma yet are completely devoid of classical agonism, and effectively inhibit phosphorylation."

These findings suggested that it might be possible to develop new diabetes drugs that work entirely by blocking the phosphorylation of PPAR-gamma, thus separating wanted from unwanted effects.

Their findings are being published Sept. 4 by the journal Nature as an advanced online publication and later in a print edition. (ANI)

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