Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Joslin Researchers Discover a Surprising Culprit in the Search for Causes of Diabetic Birth Defects

07.03.2007
Protein Makes It Possible for High Blood Glucose to Enter Embryonic Cells

Over the past several years, Joslin Investigator Mary R. Loeken, Ph.D., and her colleagues at Joslin Diabetes Center have unlocked several mysteries behind what puts women with diabetes more at risk of having a child with birth defects. Even though those risks have decreased significantly over the years, thanks in part to advancements at Joslin, women with diabetes still are two to five times more likely than the general population to have a baby with birth defects, especially of the heart and spinal cord, organs that form within the first few weeks of pregnancy.

In past work, Dr. Loeken and her research team were able to establish through their studies in mice that the mother’s high blood glucose levels are the cause of these defects. This is one of the reasons why women with diabetes who are planning a pregnancy are encouraged to have their blood glucose levels under good control prior to conception. The Joslin researchers also have shown that the damage occurs because the extra glucose in the mother’s blood inhibits the expression of embryonic genes that control essential developmental processes.

Now, in this latest study done in mice, Dr. Loeken and her colleagues have discovered that the protein called glucose transporter 2 (Glut2) makes it possible for the high concentrations of glucose to get into the embryonic cells efficiently when the mother’s blood glucose concentrations are high. Also involved in the study was Rulin Li, Ph.D., a former postdoctoral fellow at Joslin. The study, supported by the National Institutes of Health, will appear in the March print edition of Diabetologia and was published online by the journal on Jan. 18.

“Glut2 is a gene that we wouldn’t have expected to be switched on in early embryonic development,” said Dr. Loeken, Investigator in the Section on Developmental and Stem Cell Biology and Associate Professorof Medicine at Harvard Medical School. “Yet our research in mice shows that the expression of this gene in the early embryo enables the cells to absorb glucose about two to three times faster when the mother’s glucose levels are elevated, while other glucose transporters would be saturated at normal glucose concentrations. This makes the embryo very susceptible to the malformations that high glucose levels cause, such as neural tube defects.”

Researchers so far have identified 14 different glucose transporters, a class of proteins that sit on the membranes of cells and enable the cells to absorb glucose. Each type plays a different role in glucose uptake and is found in different cell types. “We knew that the embryo expresses a variety of glucose transporters that bring necessary glucose into the developing cells,” said Dr. Loeken, “but what caught my eye was that one of them was Glut2.” This protein, Dr. Loeken explained, is what is known as a high-Km glucose transporter, that is, it works efficiently only when glucose levels are high. Low-Km glucose transporters, on the other hand, become saturated at these higher levels and no longer work efficiently to get glucose into the cells.

Low Km transporters can be thought of like a narrow doorway into a room that will only allow one person to pass at a time, whereas a high Km transporter is like a wide-open door that will allow several people to pass at a time, explained Dr. Loeken. When very few people need to get through the doors at a time, the narrow doors will work just as well as the wide-open doors, but if a crowd needs to get through the doors, the narrow doors will be saturated, the wide open doors will allow the people to go through at a high rate, and the concentration of people in the room will be very high.

“After birth, the Glut2 transporter is expressed on insulin-producing beta cells of the pancreas and in the liver, the tissues that receive blood carrying high concentrations of glucose absorbed from the intestine after a meal,” said Dr. Loeken. “It makes sense that Glut2 would be expressed in the pancreas where the high glucose level signals the beta cells to release insulin, and in the liver, where it signals the liver to store the glucose. In a normal pregnancy, the glucose in the mother’s blood that circulates to the uterus would never be as high as the blood that flows by the pancreas and the liver, and the embryo would not be exposed to high concentrations of glucose. Therefore, Glut2 won’t work any better than the other glucose transporters to absorb glucose. But glucose concentrations can be very high during a diabetic pregnancy, and if this highly efficient glucose transport is functioning, the embryo cells act like a glucose sponge, absorbing glucose at a much higher rate than normal.”

Using mice that lacked Glut2 genes, which were developed by one of the study’s co-authors, Bernard Thorens, Ph.D., of the Center for Integrated Genomics at the University of Lausanne in Switzerland, Joslin researchers found that only embryos carrying normal Glut2 genes developed malformations when the mothers were diabetic, whereas embryos that lacked Glut2 genes were protected from malformations during diabetic pregnancy. “This shows that the high-transport Glut2 transporter was responsible for getting higher concentrations of glucose in the cell and causing the malformations.” The embryos were examined on the 10th day of gestation. The time span in the mice, Dr. Loeken explained, is comparable to about the fourth or fifth weeks of a human pregnancy, which is about the time a woman may discover that she is pregnant.

The Joslin researchers were also surprised to find that there were fewer embryos recovered on day 10 of gestation if they lacked the Glut2 genes, whether or not the mothers were diabetic, suggesting that there is a survival advantage in having the Glut2 transporter. “Recent research by our collaborator, Dr. Thorens, has shown that Glut2 is also a transporter for glucosamine, an amino sugar that serves important functions in the synthesis of proteins,” said Dr. Loeken. “Since glucosamine is synthesized in the liver, which the early embryo still lacks, it must get it from its mother’s circulation. Although we don’t know for sure, Glut2 could be needed by the embryo for glucosamine transport.”

Putting these findings together, Dr. Loeken said, “The early embryo must express Glut2 for some reason, because fewer embryos survived early development if they lacked this transporter. Perhaps it is because it is needed to transport glucosamine. However, because this transporter, which works so well after birth to allow the pancreas to produce insulin and the liver to store glucose, also makes the early embryo take up glucose very efficiently when glucose concentrations are high, as can occur during diabetic pregnancy, this explains why the embryo is so sensitive to the mother’s hyperglycemia.

“While it is too early yet to give any clinical recommendations to patients based on these new findings, the research does suggest that once the glucose reaches the concentration where the Glut2 transporter functions efficiently, that is probably sufficient to cause malformations,” said Dr. Loeken. “The best we can do now to prevent malformations in diabetic pregnancy is to help a woman establish good blood glucose control before she becomes pregnant, so that she will be better able make sure her glucose levels are as close to normal during pregnancy,” she added.

Working with high-risk maternal-fetal medicine specialists at Beth Israel Deaconess Medical Center, Joslin’s medical staff has established a Diabetes and Pregnancy Program to help women with diabetes and women at risk for developing the disease to get the care they need to minimize these risks and give birth to healthy babies. More information about this program can be found by clicking on the following link: http://www.joslin.org/754_880.asp

Marjorie Dwyer | EurekAlert!
Further information:
http://www.joslin.org/754_880.asp
http://www.joslin.harvard.edu

More articles from Life Sciences:

nachricht Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside

nachricht Chlamydia: How bacteria take over control
28.03.2017 | Julius-Maximilians-Universität Würzburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Researchers create artificial materials atom-by-atom

28.03.2017 | Physics and Astronomy

Researchers show p300 protein may suppress leukemia in MDS patients

28.03.2017 | Health and Medicine

Asian dust providing key nutrients for California's giant sequoias

28.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>