New Findings On Receptor Regulation May Lead To Better Drugs For Diabetes

Promising new treatments for adult-onset diabetes hinge on the action of a single protein: a receptor that controls how cells respond to the hormone insulin.

By binding to the receptor, drugs known as thiazolidinediones (TZDs, for short) raise the body's sensitivity to insulin, allowing it to better regulate its blood sugar levels. Researchers at the University of Pennsylvania Medical Center have now revealed a key step in the regulation of this receptor -- information which could lead to safer and more effective medicines for diabetes. The group's findings appear in the November 26 issue of Nature.

The receptor, called PPAR-gamma, resembles several other receptor proteins that bind to small hormones. In fat cells, this receptor influences a variety of processes, including sugar metabolism and fat cell proliferation, by turning specific genes on and off. Chemicals that can bind to the receptor increase insulin's ability to lower blood sugar in the body.

That action is crucial to controlling adult-onset diabetes, which results not from a lack of insulin, but from the inability of cells to heed insulin's signals, says senior author Mitchell A. Lazar, MD, PhD, professor of medicine and genetics at Penn. More than 15 million Americans are thought to suffer from adult-onset diabetes, which typically develops after age 40. Half are unaware they have the disease, which is also a risk factor for heart disease and stroke.

"The reason this new family of drugs works to control adult-onset diabetes is because they bind to the receptor we worked with," says Lazar, who is also director of Penn's Diabetes Center. Rezulin, manufactured by Parke-Davis, is the only TZD currently on the market; several TZD compounds are in clinical trials and others are at earlier stages of development.

Unfortunately, as Lazar and coworkers discovered in 1996, when TZD activates PPAR-gamma, fat cells not only respond more readil

Contact: Franklin Hoke or Rebecca Harmon
University of Pennsylvania School of Medicine

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