Researchers have discovered a new molecular link between obesity and the way diabetes drugs work , which may lead to the development of safer medications for diabetes.
Scientists from Dana-Farber Cancer Institute and The Scripps Research Institute, led by Dr. Bruce Spiegelman, conducted the above study.
"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," Nature quoted Spiegelman as saying.
The drugs act on a master regulatory protein called PPAR-gamma, primarily in fat cells, which governs genes involved in the body's response to insulin.
Obesity resulting from a high-fat diet alters the function of PPAR-gamma and disrupts the expression of those insulin response genes, including adipsin and adiponectin.
Avandia and Actos work by binding to PPAR-gamma and reversing the gene expression changes.
The drugs were believed to work by stimulating or "agonizing" the PPAR-gamma receptor, causing it to rev up some genes and dampen the activity of others.
However, in the new study, researchers say that they have identified "an entirely new and surprising mechanism by which PPAR-gamma can control whole-body insulin sensitivity."
They found that it is mainly through this mechanism that the diabetes drugs counteract insulin resistance - not their agonist effect on PPAR-gamma.
Moreover, they say, agonism of PPAR-gamma may be largely responsible for the harmful drug side effects.
The newly identified pathway linking obesity and insulin response involves cdk5, a protein kinase, or molecular "switch."
When cdk5 is activated by the development of obesity in mice, it causes a chemical change in PPAR-gamma called phosphorylation.
In contrast to agonism of PPAR-gamma, phosphorylation has a narrow effect, disrupting a smaller set of genes that lead to insulin resistance.
In addition to agonizing PPAR-gamma, Avandia and Actos also block the phosphorylation of PPAR-gamma by cdk5.
It's this latter effect that accounts for most of the drugs' anti-diabetic benefits, the authors contend.
The study has been published in the latest issue of Nature.