Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Future diabetes drugs may target new protein interaction

03.03.2005


Proteins also link cellular aging and response to calorie restriction in mammals

In the March 3 issue of Nature, Johns Hopkins researchers report that two proteins best known for very different activities actually come together to turn the liver into a sugar-producing factory when food is scarce. Because the liver’s production of sugar is a damaging problem in people with diabetes, the proteins’ interaction might be a target for future drugs to fight the disease, the researchers say. Under normal circumstances, the liver’s production of sugar is a back-up plan that enables survival during food shortages; the brain and certain other critical organs rely on sugar -- specifically glucose -- for the energy to function. In people with diabetes, however, the liver doesn’t sense the incoming calories, and it keeps making glucose when it shouldn’t.

The researchers discovered that, in fasting mice, the liver’s production of sugar kicked into high gear because amounts and activities of the two proteins, called sirtuin1 and PGC1-alpha, increased when dietary calories weren’t available. Once mice were fed, levels of the two proteins went down and sugar production ceased. "It isn’t a coincidence," says Pere Puigserver, Ph.D., an assistant professor of cell biology at the Johns Hopkins University School of Medicine’s Institute for Basic Biomedical Sciences. "The two proteins actually bind to each other, and without sirtuin1, PGC1 can’t make glucose."



A current diabetes-fighting drug, metformin, blocks steps in the glucose-making process, but the new research identifies a critical regulatory step the researchers say could be targeted as well. PGC1, which Puigserver isolated and cloned in 1998 as a postdoctoral fellow at Harvard, controls gene expression in the liver and other tissues. In the liver, it triggers the conversion of fats into sugar, particularly when access to food is limited. But no one knew exactly how it was controlled or what else it might need in order to launch the sugar-making process.

Sirtuin1, like its sirtuin relatives, is best known for removing molecular "decorations" on proteins that help organize DNA and restrict access to genes. It turns out that sirtuin1 also removes these decorations from PGC1, and then remains bound to PGC1 as it starts up the sugar-making process, the researchers found. "Because both proteins are required for the liver to make sugar, targeting sirtuin1 in a very specific way might help control sugar production in people with diabetes," says Puigserver. "Sirtuin1 interacts with many different proteins, and it’s just this one interaction you would want to prevent."

But, he says, PGC1 has an unusually close relationship with sirtuin1 that may make for relatively easy picking. PGC1, unlike the vast majority of proteins, only uses sirtuin1 to remove its "decorations," called acetyl groups. Most other proteins can have the groups plucked off by a number of different enzymes. "PGC1 is a ’clean’ target for sirtuin1," says Puigserver. "If sirtuin1 isn’t available, PGC1 becomes covered in acetyl groups, and the acetyl-covered PGC1 can’t make sugar."

In their experiments, graduate student Joseph Rodgers also discovered that the livers of fasted mice first developed high levels of a chemical called pyruvate, which is a starting material for making glucose, and then accumulated high levels of sirtuin1 protein. (Rodgers will receive the Nupur Dinesh Thekdi Research Award on April 14 for this work as part of the School of Medicine’s 28th annual Young Investigators’ Day celebration.) "When there’s no incoming food, muscles make lactate and alanine and send them to the liver to be converted into pyruvate and glucose," says Puigserver. "It appears, from our work, as though the pyruvate then triggers increased production of sirtuin1, which in turn lets PGC1 start converting the pyruvate into the glucose the body needs to survive."

The relationship between sirtuin1 and PGC1 also connects processes involved in cellular aging and responding to calorie intake in mammals for the first time. In bacteria and yeast, the equivalent of sirtuin1 is already known to help slow processes linked to cellular aging when food is scarce, an effect that extends the single-celled organism’s lifespan. "We now know that sirtuin1 is directly involved in the response to calorie restriction in mammals and in processes involved in cellular aging," says Puigserver. "But we still don’t know whether sirtuin1’s activity affects lifespan in mammals."

There is a precarious anecdotal link, however. In 2003, other scientists reported that a compound found in red wine activated yeast’s sirtuin1-equivalent and extended the organism’s lifespan. Moving up the food chain, decades of reports have shown that drinking moderate amounts of red wine is associated with a longer life for people.

But at this point, knowing for sure whether sirtuin1 helps extend lifespan (an organism issue) or is merely involved in cellular aging (a cell-by-cell issue) in mammals will take much more work. Sirtuin1’s potential as a target for treating diabetes is much closer, says Puigserver.

The researchers are now probing the pyruvate-sirtuin1 connection more closely and looking for more details of the sirtuin1-PGC1 interaction. Also on the to-do list: examining sirtuin1 and PGC1 in other tissues, particularly muscle and fat, two other energy-producing tissues in mammals.

The study was funded by the Ellison Medical Foundation, the American Federation for Aging Research, and start-up funds from the Department of Cell Biology at the Johns Hopkins School of Medicine.

Authors on the paper are Rodgers, Puigserver and C. Lerin of Johns Hopkins; and Wilhelm Haas, Steven Gygi and Bruce Spiegelman of Harvard Medical School.

Joanna Downer | EurekAlert!
Further information:
http://www.jhmi.edu
http://www.nature.com./nature

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>