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Mary Loeken Part 3, Understanding Diabetes Birth Defects

Jan 12, 2018
 

In part 3 of this Exclusive Interview, Dr. Mary Loeken talks with Diabetes in Control Publisher Steve Freed during the ADA meeting in San Diego, CA about how diabetes causes birth defects.

Mary Loeken, PhD is an Associate Professor of Medicine at Harvard Medical School and an Investigator at Joslin Diabetes Center.

Transcript of this video segment:

Steve: How has your research contributed to the understanding of how maternal diabetes causes birth defects?

Dr. Loeken: One of the things we showed with the mice is that high glucose levels seem to be teratogens and we did this by either only raising glucose levels in the mouse on a particular day of pregnancy, which actually corresponds in the women to about 4 weeks of pregnancy based on the last menstrual period or about the time she recognizes she is pregnant. Glucose above a certain level was sufficient to cause malformations.  Also, in our diabetic model if we used a drug to cause excretion of glucose in the urine without changing any of the other metabolic disturbances of diabetes, that prevented the malformations.  That shows that elevated glucose is essential and it is the cause of malformations. Another thing that we showed is it is known that there are families of transporters that are responsible for getting nutrients into the cells, including glucose transporters. Most of the glucose transporters throughout our body work very well when glucose levels are in pretty much normal range, 5.5 mmol, or 100 mg/dL. However, the embryo, in addition to expressing those glucose transporters, expresses the glucose transporter called Glut2, that is also expressed on pancreatic beta cells in the liver. Those tissues see higher glucose concentrations than our peripheral blood normally sees after a meal.  Expressing Glut2 is very important for releasing insulin after a meal and storing glucose in the liver after a meal.  We didn’t know at first why the embryo would express Glut2 because it would not function very well as the glucose transporter in non-diabetic pregnancies, but in the diabetic pregnancies it could make the embryo just like a glucose sponge, take up glucose really well when it is at high concentrations. We showed by using mice embryos that had mutations in the Glut2 gene – they either had one copy or zero copies of Glut2 – they were protected from the mother’s high glucose levels. That indicates that we know that Glut2 takes up glucose very well, when glucose levels are about 3-fold higher than normal, about 300 mg/dL or about 15 mmol.  If we can keep glucose levels below those levels, you still may be getting more glucose in the embryo cells, but not be acting like the glucose sponge. So, I would say we want to strive not just to achieve good HbA1c levels, but monitoring glucose to keep those excursions away from the maximum uptake rate for Glut2.

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