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
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