New twist in diabetes drugs could reduce life-threatening side effects

Researchers from Dana-Farber Cancer Institute in Boston and the Scripps Research Institute in Jupiter, Fla., report they have created prototype drugs having powerful anti-diabetic effects, yet apparently free – at least in mice – of dangerous side effects plaguing some current diabetes medications.

The researchers say that their “proof-of-principle” findings could lead to safer medications for Type 2 diabetes, which affects more than 25 million children and adults in the United States. Their findings are being published Sept. 4 by the journal Nature as an advanced online publication and later in a print edition.

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.

Bruce Spiegelman, PhD, of Dana-Farber and Patrick Griffin, PhD, of Scripps led the scientific group that developed a series of related compounds and tested them in overfed and genetically obese mice. 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,” says Spiegelman.

Avandia and Actos are members of a drug class called thiazolidinediones (TZD) that have proven to be effective, oral diabetes drugs and are well tolerated by most patients. In a minority of patients, however, Avandia and Actos have been linked to cardiac complications, including fatal heart attacks and loss of bone density. The drugs are under close scrutiny by federal regulators, and are prescribed cautiously by physicians.

TZD drugs target a metabolic “master regulator” of fat cell development, called PPAR-gamma, which is a transcription factor controlling the behavior of a host of genes and proteins related to diabetes. Spiegelman’s lab discovered the role of PPAR-gamma as a regulator of fat cell development in 1994. The new experimental compounds also target PPAR-gamma, but through a different mechanism discovered this past year.

Actos and Avandia are so-called “agonists” of PPAR-gamma. That is, they bind to the molecule, like a key fitting into a lock, and activate it. When activated, PPAR-gamma causes changes in an unknown number of “downstream” genes and proteins. This cascade treats diabetes by improving cells’ response to insulin and helping the body to control blood sugar. However, the researchers believe this series of molecular events initiated by PPAR-gamma agonism also causes the harmful fluid retention, weight gain, and loss of bone density.