In related discoveries with far-reaching implications for treating diabetes and understanding hypertension, University of Utah researchers have learned why thiazolidinediones (TZDs), a major anti-diabetes drug, cause edema and also have found a new pathway critical to fluid metabolism. Identification of this pathway may help understand fundamental mechanisms of blood pressure control.
Using knockout-gene technology, the University of Utah-School of Medicine researchers found that when TZD is activating a nuclear receptor, the peroxisome proliferator-activated receptor gamma, in the collecting duct in the kidney, it serves as a mechanism for fluid retention, or edema. The researchers suggest that the distal nephron, for example the collecting duct, is crucial for regulation of sodium balance and blood pressure. The research is published this week in the Proceedings of the National Academy of Sciences online.
The discoveries may point the way to developing different drugs to treat Type II diabetes and open an entirely new area in the study of hypertension, according to Tianxin Yang, M.D., Ph.D., the two-year study's principal investigator, associate professor of internal medicine at the U medical school, and staff physician at the George E. Wahler Veterans Affairs Medical Center in Salt Lake City.
An estimated 18 million Americans suffer from diabetes. TZD compounds have been shown to be highly effective in lowering blood glucose and lipid levels and in controlling blood pressure.
"It's almost a perfect drug for diabetes," Yang said.
But many diabetics who use TZD eventually have to discontinue the drug because it causes edema. About 1 percent of people who take TZD get pulmonary edema and chronic heart failure, both being potentially life-threatening conditions.
TZD works by activating PPAR-gamma, a receptor that helps sensitize the body to insulin. PPAR is found in muscle, fat, kidney, and heart and controls fatty acid and lipid metabolism. In the kidney, PPAR is found in the collecting duct, a critical site for the control of fluid metabolism.