Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mutated protein combination tied to excessive sugar production

19.05.2003


Study identifies potential target for diabetes drugs



Researchers at Dana-Farber Cancer Institute have traced runaway sugar production in the liver – an important feature of diabetes – to flaws in a two-protein combination at the heart of a molecular switch that responds to insulin.

The findings, to be posted by the journal Nature on its Web site on May 18, suggest that drugs designed to block the interaction of the two switch proteins might be effective in treating diabetes, and with few side effects.


Building on their discovery of this master switch in fall 2001, scientists led by Dana-Farber’s Bruce Spiegelman, PhD, found that two previously known proteins in mice must “dock,” one on top of the other, to enable the switch to turn on genes that initiate the liver’s sugar-making process. Furthermore, when mutations cause a flaw in one of the proteins, the switch no longer can respond to insulin, the hormone that normally regulates sugar manufacture in the liver.

“The actual molecular connections between the proteins are potential targets for diabetic therapy,” says Spiegelman, the paper’s senior author. It may be possible to design an oral drug that could block the joining of the two proteins – PGC-1alpha and FOXO1 – when the switch is stuck in the “on” position.

The liver’s manufacture of sugar from raw materials, a process called gluconeogenesis, is designed to provide the body (especially the brain) with necessary glucose when the person has been fasting and isn’t obtaining the sugar from food. Glucagon and glucocorticoid hormones initiate the process on by sending signals to liver cells, triggering activity (DNA transcription) in genes that set gluconeogenesis in motion.

Insulin, produced in the pancreas, has the opposite effect, turning off gluconeogenesis when normal feeding resumes. Insulin activates the insulin receptors on liver cells’ surfaces, which send signals into the cells’ nuclei where they are received by the switch made up of the PGC-1alpha and FOXO1 proteins.

FOXO1 protein, known as a transcription factor, binds directly to the DNA molecules of the gluconeogenesis genes, causing them to copy their genetic blueprints into RNA. PGC-1alpha does not directly bind to the DNA, but instead docks onto the FOXO1 protein. Together, “they area a powerful, insulin-sensitive switch” for gluconeogenesis, says Spiegelman. “PGC-1 provides the horsepower, and FOXO1 is the insulin-sensitive receiver” of signals.

In a series of experiments with transgenic mice, Spiegelman and his colleagues showed that if a mutation occurs in the gene producing FOXO1, it results in an abnormal FOXO1 protein that no longer is sensitive to insulin. Consequently, the switch fails and the liver overproduces glucose, which spills into the blood and can damage vital organs and nerves.

In his previous Nature paper [Sept. 13, 2001] Spiegelman demonstrated that the PGC-1alpha protein was the long-sought switch for gluconeogenesis, but how that protein worked with FOXO1 wasn’t clear. At the time, Spiegelman suggested that blocking PGC-1alpha might be a new therapeutic strategy. He now says that targeting just the combination of PGC-1alpha and FOXO1 would be a more finely pointed tool with fewer unwanted effects.

“What’s exciting about this paper is that is unifies two fields,” commented Spiegelman, who is also a professor of cell biology at Harvard Medical School. “One was the discovery of the signaling pathway from the insulin receptor to the FOXO1 protein – and this was found in worms. The other was the work that led to the identification of PGC-1alpha as the switch for gluconeogenesis. Now we know that it is the complex of PGC-1alpha and FOXO1 that is important.”



The research was funded in part by the National Institutes of Health.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Bill Schaller | EurekAlert!
Further information:
http://www.dfci.harvard.edu/

More articles from Health and Medicine:

nachricht PET imaging tracks Zika virus infection, disease progression in mouse model
20.09.2017 | US Army Medical Research Institute of Infectious Diseases

nachricht 'Exciting' discovery on path to develop new type of vaccine to treat global viruses
18.09.2017 | University of Southampton

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

Im Focus: Silencing bacteria

HZI researchers pave the way for new agents that render hospital pathogens mute

Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Molecular Force Sensors

20.09.2017 | Life Sciences

Producing electricity during flight

20.09.2017 | Power and Electrical Engineering

Tiny lasers from a gallery of whispers

20.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>