New Class of Anti-diabetic Compounds Could Reduce Dangerous Side Effects

Researchers have created prototype drugs that have powerful anti-diabetic effects, yet are apparently free of dangerous side effects found in some current diabetes medications, according to a study published recently in Nature.

Researchers from the Dana-Farber Cancer Institute and the Scripps Research Institute believe their proof-of-principle findings in a mouse model could lead to safer medications for type 2 diabetes, which affects more than 25 million children and adults in the United States alone.

One of the drugs, a new compound known as SR1664, 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 Avandia (rosiglitazone) and Actos (pioglitazone) that can have had fatal consequences in some patients.

“In this study, we demonstrate that we have discovered novel compounds that work effectively through a unique mechanism of action on a well-validated clinical target for diabetes,” Patrick R. Griffin, PhD, professor and chair of the Department of Molecular Therapeutics at Scripps Florida, said in a statement.

“This unique mechanism of action appears to significantly limit side effects associated with marketed drugs. This study is a great example of interdisciplinary, inter-institutional collaboration with chemistry, biochemistry, structural biology, and pharmacology,” added Griffin, one of the leaders of the study.

While these novel compounds would not be suitable for use in human patients, the researchers said the results showed 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,” Bruce Spiegelman, PhD, professor of cell biology at Dana-Farber, another study leader, said in a statement.

Avandia and Actos are thiazolidinediones (TZD) that have proven to be effective and well tolerated by most patients. In a minority of patients, however, Avandia and Actos have been linked to sometimes-fatal cardiac complications and decreased 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.

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

The TZD drugs, they said, also blocked 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. To their surprise, it had the added bonus of apparently not causing the worrisome side effects of existing drugs.

The Nature study suggests 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.

SourcesNew Twist in Diabetes Drugs Could Reduce Life-threatening Side Effects [Dana-Farber Cancer Institute]Scripps Research Scientists Establish New Class of Anti-Diabetic Compound [Scripps Research Institute]Antidiabetic Actions of a Non-agonist PPARγ Ligand Blocking Cdk5-Mediated Phosphorylation [Nature]