Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mouse with designer liver has enhanced glucose tolerance and improved insulin response

13.04.2005


Liver-specific knock out mouse has improved liver function



A collaborative effort led by The Burnham Institute’s Gen-Sheng Feng has created a mouse with improved glucose tolerance and insulin activity in the liver, and generated new findings about insulin-signaling in the liver that could prove useful in understanding the pathogenesis of type 2 diabetes. These results, to be published by Nature Medicine in May, were made available to the scientific community by advance posting online at the journal’s website on April 10th.

The liver plays a major role in the uptake of glucose from the bloodstream, its storage, and regulation. Insulin resistance in the liver is a crucial factor in the development of hyperglycemia and hypertriglyceridemia in individuals who suffer type 2-diabetes. Precisely how insulin-initiated signals are modulated in liver cells for glucose uptake and metabolism is unknown.


Gen-Sheng Feng, Ph.D., a Professor in The Burnham Institute’s Signal Transduction Program, has focused his efforts on a recently discovered protein called Gab1. Gab1 has a structure that is similar to other proteins in a family known as Insulin Receptor-Signaling, or IRS, proteins. IRS proteins relay signals initiated by insulin receptors and thus play a critical role in insulin regulation inside cells. Biochemical studies on Gab1 in cell cultures suggested that Gab1 is also involved in insulin signaling, but it is not clear how Gab1 acts to control insulin activity in the liver.

To learn how Gab1 functions in the liver, Feng used a highly advanced genetic engineering technology, called tissue-specific gene deletion, to create a mouse in which the Gab1 gene was deleted, or "knocked out", from the liver, and only the liver. Offsprings were termed "LGKO" for liver-Gab1 knockout mice.

Dr. Feng’s laboratory, in collaboration with Drs. Andrea Hevener and Jerrold Olefsky at the University of California, San Diego, conducted a thorough investigation of the glucose metabolism and insulin activity in this newly-created mouse strain. Interestingly, the LGKO mice had reduced blood glucose levels and lower levels of serum insulin. The mice retained triglycerides in the liver with a commensurate decrease of circulating triglycerides in the bloodstream. Insulin response to glucose load was diminished in LGKO mice, thus glucose tolerance in the liver was significantly improved in the absence of Gabl protein.

The Feng team conducted biochemical analyses on the LGKO mice, homing in on enzymatic pathways critical to insulin response in cells. Upon stimulation with insulin, they found an elevated level of Akt/PkB kinase, an enzyme needed for insulin signaling, and elevated activity of IRS proteins. There was no activation of another enzyme, Erk, which is elevated in normal liver in reaction to insulin stimulation. Dr. Feng concluded that the function of Gab1 in normal liver cells is to promote signaling in the Erk pathway, which reduces insulin response signals flowing through IRS and Akt proteins.

"We propose that Gab1 acts as a negative regulator on insulin signal strength in the liver," said Dr. Feng. "In this work, by making a new liver-specific gene knockout mouse model, we found a novel balancing mechanism for control of liver insulin signaling. Our observation might be instrumental for understanding better the pathogenesis of type II diabetes and designing anti-diabetes drugs."

Co-authors on this study from Dr. Feng’s laboratory were Emilie Bard-Chapeau, Ph.D., and Shinong Long, Ph.D., postdoctoral fellows, and Eric Zhang, graduate student in the Burnham Institute-UCSD’s joint graduate training program in Molecular Pathology.

Jerrold Olefsky, Ph.D. and Andrea Hevener, Ph.D. are Professor and Adjunct Associate Professor, respectively, in the Department of Medicine at the University of Calfornia, San Diego.

Nancy Beddingfield | EurekAlert!
Further information:
http://www.burnham.org

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

17.01.2017 | Materials Sciences

Smart homes will “LISTEN” to your voice

17.01.2017 | Architecture and Construction

VideoLinks
B2B-VideoLinks
More VideoLinks >>>