Navigation Links
New twist in diabetes drugs could reduce life-threatening side effects
Date:9/9/2011

Researchers from Dana-Farber Cancer Institute in Boston and the Scripps Research Institute in Jupiter, Fla., report they have created prototype drugs having powerful anti-diabetic effects, yet apparently free at least in mice of dangerous side effects plaguing some current diabetes medications.

The researchers say that their "proof-of-principle" findings could lead to safer medications for Type 2 diabetes, which affects more than 25 million children and adults in the United States. Their findings are being published Sept. 4 by the journal Nature as an advanced online publication and later in a print edition.

One of the drug prototypes proved capable of reducing disease symptoms in diabetes-prone mice without triggering weight gain or fluid retention, potential side effects of current drugs such as rosiglitazone (Avandia) and pioglitazone (Actos) that can have had fatal consequences in some patients.

Bruce Spiegelman, PhD, of Dana-Farber and Patrick Griffin, PhD, of Scripps led the scientific group that developed a series of related compounds and tested them in overfed and genetically obese mice. While these novel compounds would not be suitable for use in human patients, the scientists say the results showed that they had succeeded in building selective anti-diabetic molecules that minimize the risk of severe side effects.

"This insight shows how you can make new compounds that appear to be safer, but you don't know for sure until a drug is developed that you can give to patients," says Spiegelman.

Avandia and Actos are members of a drug class called thiazolidinediones (TZD) that have proven to be effective, oral diabetes drugs and are well tolerated by most patients. In a minority of patients, however, Avandia and Actos have been linked to cardiac complications, including fatal heart attacks and loss of bone density. The drugs are under close scrutiny by federal regulators, and are prescribed cautiously by physicians.

TZD drugs target a metabolic "master regulator" of fat cell development, called PPAR-gamma, which is a transcription factor controlling the behavior of a host of genes and proteins related to diabetes. Spiegelman's lab discovered the role of PPAR-gamma as a regulator of fat cell development in 1994. The new experimental compounds also target PPAR-gamma, but through a different mechanism discovered this past year.

Actos and Avandia are so-called "agonists" of PPAR-gamma. That is, they bind to the molecule, like a key fitting into a lock, and activate it. When activated, PPAR-gamma causes changes in an unknown number of "downstream" genes and proteins. This cascade treats diabetes by improving cells' response to insulin and helping the body to control blood sugar. However, the researchers believe this series of molecular events initiated by PPAR-gamma agonism also causes the harmful fluid retention, weight gain, and loss of bone density.

Until recently, it had been assumed that Avandia and Actos worked exclusively by agonizing PPAR-gamma. But in 2010, Spiegelman and Griffin reported that they had discovered a second, unsuspected effect of the drugs on PPAR-gamma. The TZD drugs, they said, also block a process called phosphorylation, by a molecule known as Cdk5, that modifies PPAR-gamma in a manner that is entirely separate from agonism. This mechanism, they said, might in fact be more critical to combating diabetes and, to their surprise, apparently seemed not to cause the worrisome side effects.

In the new report, the team describes the development of synthetic small molecules "that bind tightly to PPAR-gamma yet are completely devoid of classical agonism, and effectively inhibit phosphorylation."

These findings suggested that it might be possible to develop new diabetes drugs that work entirely by blocking the phosphorylation of PPAR-gamma, thus separating wanted from unwanted effects.

Griffin, who heads Scripps' Department of Molecular Therapeutics, and his team devised a plan for concocting the prototype drugs. They searched the literature for compounds known to bind with PPAR-gamma, and chose one to serve as a scaffold which they modified in hundreds of ways. The researchers sifted through these modifications until they found several that blocked phosphorylation of PPAR-gamma.

The most effective of these candidates, labeled SR1664, was tested in cultured cells and insulin-resistant mice in the Spiegelman laboratory. It was found to have potent anti-diabetic properties but caused no fluid retention or weight gain. When compared with Avandia, SR1664 showed equivalent anti-diabetic effects, confirming the scientists' hypothesis that diabetes can be treated by drugs that target PPAR-gamma but don't agonize the molecule.

These studies illustrate that the development of entirely new classes of PPAR-gamma-targeted drugs is feasible, concludes Spiegelman, who is the Stanley J. Korsmeyer Professor of Cell Biology and Medicine at Harvard Medical School, and his colleagues.


'/>"/>

Contact: Teresa Herbert
teresa_herbert@dfci.harvard.edu
Dana-Farber Cancer Institute
Source:Eurekalert

Related medicine news :

1. A New Twist On Convert to Purchase
2. New twist on potential malaria drug target acts by trapping parasites in cells
3. eMindful Provides a New Twist on Chocolate for Members of Boston's Beacon Hill Village
4. Shape matters: The corkscrew twist of H. pylori enables it to set up shop in the stomach
5. Innovative Twist 'n Shake Jar Mixes Probiotics and Prebiotics
6. MIT researchers discover an unexpected twist in cancer metabolism
7. Tumor metastasis with a twist
8. Experts Call for Twist on Football Helmet Design
9. Neighborhood socioeconomic status and diabetes
10. NACDD Receives Two-Year Grant From Merck & Co., Inc. to Improve Diabetes Education
11. International Diabetes Federation awards $2 million to 9 global diabetes research projects
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/26/2016)... ... June 26, 2016 , ... ... have been diagnosed with endometriosis. These women need a treatment plan to not ... comprehensive approach that can help for preservation of fertility and ultimately achieving a ...
(Date:6/25/2016)... ... June 25, 2016 , ... First Choice Emergency Room ... Dr. Sesan Ogunleye, as the Medical Director of its new Mesquite-Samuell Farm facility. ... of our new Mesquite location,” said Dr. James M. Muzzarelli, Executive Medical Director of ...
(Date:6/24/2016)... ... 24, 2016 , ... A recent article published June 14 on ... article goes on to state that individuals are now more comfortable seeking to undergo ... such as calf and cheek reduction. The Los Angeles area medical group, Beverly Hills ...
(Date:6/24/2016)... ... ... Global law firm Greenberg Traurig, P.A. announced that 20 Florida attorneys are recognized ... this recognition are considered among the top 2 percent of lawyers practicing within the ... this year’s Legal Elite Hall of Fame: Miami Shareholders Mark D. Bloom, Burt ...
(Date:6/24/2016)... ... June 24, 2016 , ... EB Medicine presented ... in Emergency Medicine conference in Ponte Vedra Beach, FL. The awards honor the ... Emergency Medicine Practice and Pediatric Emergency Medicine Practice. , “With this award, ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... , June 24, 2016 Dehaier Medical ... the "Company"), which develops, markets and sells medical devices ... , signed a strategic cooperation agreement with Hongyuan ... "Hongyuan Supply Chain") on June 20, 2016, to develop ... the strategic cooperation agreement, Dehaier will leverage Hongyuan Supply ...
(Date:6/24/2016)... , June 24, 2016 Research and ... Market for Companion Diagnostic Tests" report to their offering. ... for Companion Diagnostics The World Market for ... personalized medicine diagnostics. Market analysis in the report includes the ... Market (In Vitro Diagnostic Kits) by Region (N. America, EU, ...
(Date:6/24/2016)... 24, 2016   Pulmatrix, Inc ., (NASDAQ: ... inhaled drugs, announced today that it was added to ... its comprehensive set of U.S. and global equity ... an important milestone for Pulmatrix," said Chief Executive Officer ... of our progress in developing drugs for crucial unmet ...
Breaking Medicine Technology: