Loeken, Mary R., Ph.D.
Diabetes and Pregnancy
Maternal diabetes increases the risk for congenital malformations, however, until recently, it has not been well understood how they occur. My laboratory showed that diabetic pregnancy-induced congenital malformations result from impaired expression of genes that control essential developmental processes. In recent years, we have elucidated many of the biochemical pathways by which the diabetic environment interferes with the normal expression of embryo genes, and how disrupted gene expression causes congenital malformations.
Using a mouse model of diabetic pregnancy, we found that neural tube defects, one of the most common malformations that can occur in human diabetic pregnancies, were significantly increased, and this resulted from impaired expression of Pax3, a gene that is required for neural tube and neural crest development. Increased glucose metabolism by the embryo, resulting from maternal hyperglycemia, produces oxidative stress, and the oxidative stress inhibits Pax3 gene expression. We also showed that Pax3 is needed during normal development of the neural tube and neural crest to inactivate the cell death protein, p53. Therefore, neural tube and related defects appear to result from excessive cell death during formation of early embryonic structures. The two main questions that my laboratory is asking to further understand these processes are: How does oxidative stress interfere with activation of the Pax3 gene? How does Pax3 inactivate p53? In addition to mouse models, this research employs embryonic stem cell lines. Findings from our research may improve methods to prevent and detect birth defects caused by diabetic pregnancy.
Recently, we have extended our studies in diabetic pregnancy to investigating how type 2 diabetes may be “programmed” in the offspring of diabetic mothers. We hypothesize that exposure of the fetus to elevated glucose concentrations alters expression of genes early during formation of organs that will control glucose levels after birth, such as the pancreas. Results of this research may lead to methods to prevent diabetes in the offspring of diabetic mothers.
Mary Loeken, Ph.D., is an Investigator in the Section on Islet Cell Biology and Regenerative Medicine at Joslin and an Associate Professor of Medicine at Harvard Medical School. She received her doctorate in Reproductive Endocrinology at the University of Maryland School of Medicine and did postdoctoral training at the National Cancer Institute's Laboratory of Molecular Virology before coming to Joslin. In 1992 she was named a Capps Scholar in Diabetes Research at Harvard Medical School, which also awarded her a Scholars in Medicine Award in 1998. She is an expert on the study of birth defects resulting from diabetic pregnancy and has served on study sections for the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, and on the Editorial Board for the journal, Diabetes. She is an Associate Member of the Diabetic Pregnancy Study Group of the European Association for the Study of Diabetes.