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 Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>