New research findings on novel anti-diabetes mechanism could lead to next generation of therapies

In a joint study, scientists from The Scripps Research Institute and the Dana-Farber Cancer Institute at Harvard University have uncovered a novel mechanism that dramatically increases insulin sensitivity and reduces the risk of developing type 2 diabetes and cardiovascular disease.

These findings offer a potent new target in the continuing search for new and improved anti-diabetic treatments. Currently, nearly 24 million children and adults in the United States have some form of the disease, according to the America Diabetes Association.

The new study, which focuses on controlling a fat-regulating protein known as PPARy, was published July 22, 2010, in the journal Nature (Volume 466, Issue 7304).

"The field has become interested in finding drugs that can promote increased insulin sensitization but not activate the classical fat cell generating pathway of PPAR?," said Patrick R. Griffin, chairman of the department of molecular therapeutics at Scripps Florida who headed up the Scripps Research part of the study. "We examined the mechanism of action of compounds that bind to PPAR? that improve insulin sensitivity but have minimal induction of fat. It was clear from the studies that these compounds have a unique but overlapping mechanism with the class of drugs used clinically that target PPAR?."

Adipose or fat tissue lies at the center of the metabolic syndrome, a cluster of risk factors that increases the possibility of type 2 diabetes, as well as stroke, coronary artery disease, even certain cancers. Of those risk factors, excessive body fat is considered the most problematic. PPAR? can be considered the master gene of fat cell biology because it drives the conversion of cellular precursors into fat cells.

The collaborative studies showed obesity causes a modification on PPAR? that leads to alterations in the expression of a number of genes, including a reduction in the production of an insulin-sensitizing protein (adiponectin). This leads to an increase in insulin resistance. The reprogramming of genes controlled by PPAR? occurs when it undergoes phosphorylation (a phosphate group is added to a protein) by the cdk5 kinase, an enzyme that is involved in a number of important sensory pathways and that can be activated by pro-inflammatory proteins.