Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Mutated protein combination tied to excessive sugar production


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:

More articles from Health and Medicine:

nachricht NIH scientists describe potential antibody treatment for multidrug-resistant K. pneumoniae
14.03.2018 | NIH/National Institute of Allergy and Infectious Diseases

nachricht Researchers identify key step in viral replication
13.03.2018 | University of Pittsburgh Schools of the Health Sciences

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: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

Im Focus: Surveying the Arctic: Tracking down carbon particles

Researchers embark on aerial campaign over Northeast Greenland

On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...

Im Focus: Unique Insights into the Antarctic Ice Shelf System

Data collected on ocean-ice interactions in the little-researched regions of the far south

The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...

Im Focus: ILA 2018: Laser alternative to hexavalent chromium coating

At the 2018 ILA Berlin Air Show from April 25–29, the Fraunhofer Institute for Laser Technology ILT is showcasing extreme high-speed Laser Material Deposition (EHLA): A video documents how for metal components that are highly loaded, EHLA has already proved itself as an alternative to hard chrome plating, which is now allowed only under special conditions.

When the EU restricted the use of hexavalent chromium compounds to special applications requiring authorization, the move prompted a rethink in the surface...

Im Focus: Radar for navigation support from autonomous flying drones

At the ILA Berlin, hall 4, booth 202, Fraunhofer FHR will present two radar sensors for navigation support of drones. The sensors are valuable components in the implementation of autonomous flying drones: they function as obstacle detectors to prevent collisions. Radar sensors also operate reliably in restricted visibility, e.g. in foggy or dusty conditions. Due to their ability to measure distances with high precision, the radar sensors can also be used as altimeters when other sources of information such as barometers or GPS are not available or cannot operate optimally.

Drones play an increasingly important role in the area of logistics and services. Well-known logistic companies place great hope in these compact, aerial...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

International Virtual Reality Conference “IEEE VR 2018” comes to Reutlingen, Germany

08.03.2018 | Event News

Latest News

Wandering greenhouse gas

16.03.2018 | Earth Sciences

'Frequency combs' ID chemicals within the mid-infrared spectral region

16.03.2018 | Physics and Astronomy

Biologists unravel another mystery of what makes DNA go 'loopy'

16.03.2018 | Life Sciences

Science & Research
Overview of more VideoLinks >>>