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

November 25, 1998

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 readily to insulin -- they also increase at an accelerated rate. And, TZDs further encourage obesity by repressing the gene for leptin, an important weight-regulation factor. Despite these drawbacks, Lazar concludes, "it may be possible to find drugs that selectively help insulin to lower blood sugar."

His group's recent findings represent an important advance toward that goal. Lazar's team showed that a site in the PPAR-gamma receptor, far removed from the TZD-binding region, strongly affects the receptor's ability to bind the diabetes drug. This distant site, Lazar says, provides an additional target for the next generation of diabetes drugs to hit. If compounds can be found that affect this regulatory site, they may lead to diabetes drugs with fewer side effects, according to Lazar.

Specifically, the researchers discovered that although the regulatory site lies at the opposite end of the receptor from the TZD-binding region, the addition of a phosphate group to that distant site -- called phosphorylation -- reduces, by tenfold, the TZD-binding region's ability to grab a drug molecule. Why this happens remains a mystery, Lazar says, "but somehow one end of the receptor is communicating with the other end."

At any given time, half of the PPAR-gamma receptors in fat cells are phosphorylated, Lazar notes. Thus, "if you remove the phosphate from the others, drugs like Rezulin might work better, " he says. Or, it's possible that by reducing phosphorylation, more of the compound that naturally activates the receptor in the body would bind to it -- and if that happened, maybe some people with adult-onset diabetes wouldn't need TZDs at all.

In addition to offering a way to increase the effectiveness of TZDs, the discovery that phosphorylation alters the binding of TZDs to PPAR-gamma could refine strategies for finding new diabetes medicines. The findings also raise the possibility that PPAR-gamma receptors in different tissues and cell types may have distinct patterns of phosphorylation. If that's the case, Lazar says, scientists may be able to design tissue-specific drugs with fewer side effects and greater efficiency than "all-purpose" TZDs.

Postdoctoral fellow Dalei Shao, PhD, was the lead author on the study, which was funded by the National Institute of Diabetes, Digestive, and Kidney Disease.
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Note: Dr. Lazar can be reached at 215-898-0210 or lazar@mail.med.upenn.edu

The University of Pennsylvania Medical Center's sponsored research ranks third in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation. In federal fiscal year 1997, the medical center received $175 million. News releases from the medical center are available to reporters by direct E-mail, fax, or U.S. mail, upon request. They are also posted to the center's website (http://www.med.upenn.edu); EurekAlert! (http://www.eurekalert.org), a resource sponsored by the American Association for the Advancement of Science; and Newswise (http://www.newswise.com).
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University of Pennsylvania School of Medicine

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