Navigation Links
Mayo-led research team develop agents that keep insulin working longer
Date:5/7/2010

JACKSONVILLE, Fla. More than half a century after researchers identified a promising way to treat diabetes based on blocking the breakdown of insulin in the body, a research team led by a scientist at the Mayo Clinic campus in Florida have developed potent molecules that can do just that.

The researchers say their findings, published in the May issue of PLoS ONE, could lay the foundation for a new class of drugs for treating diabetes. The tiny molecules they developed work by inhibiting a powerful molecular machine known as insulin-degrading enzyme (IDE) from chewing up the insulin hormone. That keeps insulin in the body longer to help remove glucose (simple food sugar) from the blood.

The discovery may lead to drugs that diabetics can use to help insulin work better and longer, says the study's lead researcher, Malcolm Leissring, Ph.D., from Mayo Clinic's Department of Neuroscience. Diabetes affects over 200 million people worldwide, and the incidence is growing at an alarming rate, so new treatments are greatly needed, he says.

IDE is a protease, an enzyme that chops proteins or peptides into smaller pieces. According to Dr. Leissring, inhibitors have been developed for practically all biomedically important proteases in the body. "It was very surprising that IDE inhibitors had not been developed before, particularly given IDE's special relationship with insulin, a very important hormone," he says.

This was especially puzzling because IDE was discovered more than 60 years ago. In fact, finding an IDE inhibitor was a major goal of diabetes research in the 1950s. In a landmark study, one group of early researchers managed to purify a naturally occurring IDE inhibitor, and showed that it made insulin more effective at lowering blood glucose in animals, precisely the desired effect for treating diabetes. However, the composition of the agent was never determined.

The research team initially tried to find IDE inhibitors using sophisticated technologies. They used robots to test hundreds of thousands of compounds at the Laboratory for Drug Discovery in Neurodegeneration (LDDN), a part of Brigham and Women's Hospital and Harvard Medical School. Surprisingly, these modern methods did not identify any good inhibitors, Dr. Leissring says.

"Our robots wound up being powerless for tackling this particular problem," he says. "Ironically, it was an old-fashioned method that made this breakthrough possible."

The old-fashioned approach involved using a technology invented in 1950 to figure which peptide sequence among trillions of possible combinations IDE chops up most efficiently. Benjamin Turk, Ph.D., of Yale University School of Medicine, conducted this critical step. Then, a team of chemists led by Gregory Cuny, Ph.D., director of Medicinal Chemistry at the LDDN, generated a compound that contained the preferred peptide sequence, together with a special chemical group that binds to zinc. The resulting compound is called "Ii1" (IDE inhibitor 1).

Ii1 is about a million times more potent than any previous IDE inhibitors, but additional work will be needed to turn it into a drug suitable for therapeutic use, Dr. Leissring says. In a key step towards this goal, Dr. Leissring, together with Wei-Jen Tang, Ph.D., and other colleagues from the University of Chicago, solved the 3-dimensional crystal structure of Ii1 bound to IDE. This crystal structure will facilitate the development of inhibitors that are more stable in the body than Ii1 is predicted to be.

The structure of IDE is unlike other proteases, the researchers say. It is shaped like a hinged clamshell that opens and shuts, like the well-known video game protagonist, Pac-Man.

The researchers found from their crystal structure that the Ii1 peptide acts like a magnetic latch that holds the clamshell shut. "Think of a coin purse that uses a magnet at the top to keep the purse from opening up," Dr. Leissring says. "Ii1 is analogous to the magnetic latch, holding the two halves of IDE closed."

If IDE is inhibited, insulin remains in the body longer. Normally, about half of the insulin produced by the pancreas is immediately destroyed by the liver; no one knows why this occurs but it may be a way to regulate how much insulin enters the bloodstream, he says.

IDE inhibitors would slow the rate of this initial destruction. However, according to a surprising finding from the study, they would also help prevent degradation of insulin at the "destination" cells that are responsible for removing sugar from the bloodstream. "When insulin reaches cells, it is normally destroyed very rapidly by IDE. We show that when you stop that process with an IDE inhibitor, insulin stays around longer inside the cell, allowing the hormone to function more efficiently," Dr. Leissring says.

IDE inhibitors may also be beneficial for other diseases besides diabetes, the researchers suggest. "Insulin is involved in a surprisingly wide range of important processes, including memory and cognition, so IDE inhibitors may turn out to have multiple uses. They also will be very valuable as tools for basic research," says Dr. Leissring.


'/>"/>

Contact: Kevin Punsky
punsky.kevin@mayo.edu
904-953-2299
Mayo Clinic
Source:Eurekalert

Related medicine news :

1. New research identifies modifiable risk factors for heart disease
2. Nuvo Research announces early redemption of 5% convertible debentures
3. Researcher to track spread of disease, malware and power outages
4. UCSF Researchers Identify Regulator of Human Sperm Cells
5. Octapharma Accepting Applications for Research Grants Through March 31
6. Valentine Tailgate Party for the Girls with Festive Ideas from Beauty Research
7. New Research Shows Genes of Pregnant Women and Their Fetuses Can Increase the Risk of Preterm Labor
8. University of Maryland chemist receives Astellas Award for blindness prevention research
9. Developing a cyberinfrastructure for comparative effectiveness in cancer research
10. Women should be allowed to eat, drink during labor: Queens University researcher
11. Parkinsons disease research uncovers social barrier
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/29/2016)... ... April 29, 2016 , ... Shamangelic Healing, Sedona ... Onnit brand Alpha BRAIN and New Mood Daily-Stress Formula for brain optimization and ... products to the store is just one more way Shamangelic Healing supports people’s ...
(Date:4/29/2016)... ... 29, 2016 , ... On Tuesday, April 26, 2016 members of the HomeTown ... of Gov. Nathan Deal on SB 258, the “Rural Health Care Relief” Bill. , ... 70% tax credit to individuals and corporations which donate directly to a “rural hospital” ...
(Date:4/29/2016)... ... April 29, 2016 , ... ... author of best seller "LOVE, MEDICINE and MIRACLES") addresses touchy topics related to ... and podcasted thereafter . Dr. Bernie Siegel, author of a plethora of ...
(Date:4/29/2016)... ... April 29, 2016 , ... Conditions were ideal for ... Island Park on Sunday, with sunny skies, a light breeze and temperatures in the ... , The 5k Run and Walk and 1-mile walk were held to ...
(Date:4/29/2016)... ... 29, 2016 , ... A new study by a Johns ... hernia have better survival rates if surgery is performed early. Approximately one in ... diaphragm fails to form completely, letting abdominal organs into the chest cavity and ...
Breaking Medicine News(10 mins):
(Date:4/27/2016)... 2016  Bayer Animal Health today announced that ... University of Florida College of Veterinary Medicine, is ... Communication Award (BECA). Brittany was selected from entries ... total of $70,000 in scholarship funds through the ... has provided a total of $232,500 in scholarship ...
(Date:4/27/2016)... , April 27, 2016 ... USD 2.14 billion by 2022, according to a ...      (Logo: http://photos.prnewswire.com/prnh/20150105/723757 ) , ... affecting the efficiency and accuracy delivered by the ... demand for novel urinalysis instruments and consumables. For ...
(Date:4/26/2016)... 2016 Hill-Rom Holdings, Inc. (NYSE: HRC ... the Deutsche Bank 41 st Annual Health Care Conference ... You are invited to listen to the live discussion ... it directly at http://edge.media-server.com/m/p/mr4uxgas . A recorded replay of ... the live event and accessible at the links above until ...
Breaking Medicine Technology: