Featured Research

from universities, journals, and other organizations

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

Date:
November 26, 1998
Source:
University Of Pennsylvania Medical Center
Summary:
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.

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.


Story Source:

The above story is based on materials provided by University Of Pennsylvania Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

University Of Pennsylvania Medical Center. "New Findings On Receptor Regulation May Lead To Better Drugs For Diabetes." ScienceDaily. ScienceDaily, 26 November 1998. <www.sciencedaily.com/releases/1998/11/981126104618.htm>.
University Of Pennsylvania Medical Center. (1998, November 26). New Findings On Receptor Regulation May Lead To Better Drugs For Diabetes. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/1998/11/981126104618.htm
University Of Pennsylvania Medical Center. "New Findings On Receptor Regulation May Lead To Better Drugs For Diabetes." ScienceDaily. www.sciencedaily.com/releases/1998/11/981126104618.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Generics Eat Into Pfizer's Sales

Generics Eat Into Pfizer's Sales

Reuters - Business Video Online (July 29, 2014) Pfizer, the world's largest drug maker, cut full-year revenue forecasts because generics could cut into sales of its anti-arthritis drug, Celebrex. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Nigeria Ups Ebola Stakes on 1st Death

Nigeria Ups Ebola Stakes on 1st Death

Reuters - Business Video Online (July 29, 2014) Nigerian authorities have shut and quarantined a Lagos hospital where a Liberian man died of the Ebola virus, the first recorded case of the highly-infectious disease in Africa's most populous economy. David Pollard reports Video provided by Reuters
Powered by NewsLook.com
Running 5 Minutes A Day Might Add Years To Your Life

Running 5 Minutes A Day Might Add Years To Your Life

Newsy (July 29, 2014) According to a new study, just five minutes of running or jogging a day could add years to your life. Video provided by Newsy
Powered by NewsLook.com
Ebola Outbreak Poses Little Threat To U.S.: CDC

Ebola Outbreak Poses Little Threat To U.S.: CDC

Newsy (July 29, 2014) The Ebola outbreak in West Africa poses little threat to Americans, according to officials with the Centers for Disease Control and Prevention. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins