Joslin Researchers Discover a Surprising Culprit in the Search for Causes of Diabetic Birth Defects: Protein Makes It Possible for High Blood Glucose to Enter Embryonic Cells

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Boston – March 5, 2007 – Over the past severalyears, Joslin Investigator Mary R. Loeken, Ph.D., and her colleaguesat Joslin Diabetes Center have unlocked several mysteries behindwhat puts women with diabetes more at risk of having a child withbirth defects.

Even though those risks have decreased significantlyover the years, thanks in part to advancements at Joslin, women withdiabetes still are two to five times more likely than the generalpopulation to have a baby with birth defects, especially of theheart and spinal cord, organs that form within the first few weeksof pregnancy.

In past work, Dr. Loeken and her research team were able toestablish through their studies in mice that the mother’s highblood glucose levels are the cause of these defects. This is one ofthe reasons why women with diabetes who are planning a pregnancy areencouraged to have their blood glucose levels under good controlprior to conception. The Joslin researchers also have shown that thedamage occurs because the extra glucose in the mother’s bloodinhibits the expression of embryonic genes that control essentialdevelopmental processes.

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

“Glut2 is a gene that we wouldn’t have expected to beswitched on in early embryonic development,” said Dr. Loeken,Investigator in the Section on Developmental and Stem Cell Biologyand Associate Professor of Medicine at Harvard Medical School.“Yet our research in mice shows that the expression of thisgene in the early embryo enables the cells to absorb glucose abouttwo to three times faster when the mother’s glucose levels areelevated, while other glucose transporters would be saturated atnormal glucose concentrations. This makes the embryo verysusceptible to the malformations that high glucose levels cause,such as neural tube defects.”

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

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

“After birth, the Glut2 transporter is expressed oninsulin-producing beta cells of the pancreas and in the liver, thetissues that receive blood carrying high concentrations of glucoseabsorbed from the intestine after a meal,” said Dr. Loeken.“It makes sense that Glut2 would be expressed in the pancreaswhere the high glucose level signals the beta cells to releaseinsulin, and in the liver, where it signals the liver to store theglucose. In a normal pregnancy, the glucose in the mother’sblood that circulates to the uterus would never be as high as theblood that flows by the pancreas and the liver, and the embryo wouldnot be exposed to high concentrations of glucose. Therefore, Glut2won’t work any better than the other glucose transporters toabsorb glucose. But glucose concentrations can be very high during adiabetic pregnancy, and if this highly efficient glucose transportis 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 ofthe study’s co-authors, Bernard Thorens, Ph.D., of the Centerfor Integrated Genomics at the University of Lausanne inSwitzerland, Joslin researchers found that only embryos carryingnormal Glut2 genes developed malformations when the mothers werediabetic, whereas embryos that lacked Glut2 genes were protectedfrom malformations during diabetic pregnancy. “This shows thatthe high-transport Glut2 transporter was responsible for gettinghigher concentrations of glucose in the cell and causing themalformations.” The embryos were examined on the 10th day ofgestation. The time span in the mice, Dr. Loeken explained, iscomparable 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 werefewer embryos recovered on day 10 of gestation if they lacked theGlut2 genes, whether or not the mothers were diabetic, suggestingthat there is a survival advantage in having the Glut2 transporter.“Recent research by our collaborator, Dr. Thorens, has shownthat Glut2 is also a transporter for glucosamine, an amino sugarthat serves important functions in the synthesis of proteins,”said Dr. Loeken. “Since glucosamine is synthesized in theliver, which the early embryo still lacks, it must get it from itsmother’s circulation. Although we don’t know for sure,Glut2 could be needed by the embryo for glucosaminetransport.”

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

“While it is too early yet to give any clinicalrecommendations to patients based on these new findings, theresearch does suggest that once the glucose reaches theconcentration 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 indiabetic pregnancy is to help a woman establish good blood glucosecontrol before she becomes pregnant, so that she will be better ablemake sure her glucose levels are as close to normal duringpregnancy,” she added.

Working with high-risk maternal-fetal medicine specialists at BethIsrael Deaconess Medical Center, Joslin’s medical staff hasestablished a Diabetes and Pregnancy Program to help women withdiabetes and women at risk for developing the disease to get thecare they need to minimize these risks and give birth to healthybabies. More information about this program can be found by clickingon the following link: http://www.joslin.org/754_880.asp

About Joslin Diabetes Center

Joslin Diabetes Center, dedicated to conquering diabetes in all ofits forms, is the global leader in diabetes research, care andeducation. Founded in 1898, Joslin is an independent nonprofitinstitution affiliated with Harvard Medical School. Joslin researchis a team of more than 300 people at the forefront of discoveryaimed at preventing and curing diabetes. Joslin Clinic, affiliatedwith Beth Israel Deaconess Medical Center in Boston, the nationwidenetwork of Joslin Affiliated Programs, and the hundreds of Joslineducational programs offered each year for clinicians, researchersand patients, enable Joslin to develop, implement and shareinnovations that immeasurably improve the lives of people withdiabetes. As a nonprofit, Joslin benefits from the generosity ofdonors in advancing its mission. For more information on Joslin,call 1-800-JOSLIN-1 or visit www.joslin.org.

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