Researchers identify mechanism behind structural birth defects in fetuses of mothers with diabetes

Finding a precise mechanism behind birth defects in fetuses of periconceptually diagnosed patients with diabetes is a step closer in identifying preventative measures

With more than three million women of birthing age in the US and more than sixty million worldwide with diabetes, it is essential to know how diabetes can affect mother and baby both pre and post-birth. Insulin and blood sugar checks are a big part of controlling hyperglycemia and keeping things in check during pregnancy. Even with continued control, maternal diabetes can still cause severe and permanent damage to the fetus and long-term damage to the baby post-birth.  300,000 to 400,000 fetuses per year from mothers with diabetes develop neural tube defects; a neural tube defect is when the tissue that eventually forms the brain and spinal cord fails to form correctly; this can lead to miscarriages during pregnancy or severe profound disabilities post-birth. Studies have highlighted issues that can occur with fetuses and babies’ long term after being born from mothers with diabetes. For example, the EVOLVE study highlighted congenital malformations or perinatal and neonatal death due to specific basal insulins. In another study, adverse maternal and neonatal outcomes in pregnant women with abnormal glucose metabolism highlighted adverse outcomes when glucose is abnormal in pregnant diabetic mothers. Many studies have highlighted metabolic issues that may arise post-birth to offspring born from mothers with diabetes.

Research has been done to identify the mechanism behind the many structural congenital disabilities that can arise when women with diabetes conceive. This study was done at the University of Maryland School of Medicine in rat models.  Folate supplement it’s currently the only method of neural tube defect prevention, but it only prevents up to 70% of neural tube defects, according to studies. After discovering the mechanism of neural tube defects in diabetic mothers, the objective of this study is to use this knowledge to discover other therapeutic preventatives to stop neural tube defects. This study used rodent models of diabetic embryopathy to conclude that maternal diabetes induces explicitly neural tube defects by altering kinase activation and gene expression. However, the molecular events leading to downstream hyperglycemia and failed neurulation are still unknown. 

Research showed that the neural tube tissue in 8-day old mice from mothers with diabetes contained staining signals specific markers of premature aging in comparison; these same markers were not found in the mice offspring from mothers without diabetes. Researchers then found out that the cells from the mice with the premature aging markers secreted a host of other chemical signals that led to neighboring cells dying. The mice were then treated with rapamycin, the mechanistic target of rapamycin (mTOR) acts to inhibit premature senescence and reduce neural tube defect formation. Embryos from diabetic dams (pregnant female mice) treated with rapamycin had a significantly lower neural tube defect incidence than those embryos from diabetic dams that did not undergo a rapamycin treatment course. Rapamycin caused the senescent cells to behave like normal cells in the rat models. 

In conclusion, a mechanism has been studied and found for causing neural tube defect formation in diabetic dams if rate models. But, unfortunately, the drug used to treat and cause these cells that are otherwise senescent in the diabetic mother-born dams is much too dangerous and toxic for human subjects. Therefore, more studies will need to be done to identify a medication that can prevent premature aging and apoptosis of neighboring cells, leading to neural tube defects for human fetuses and babies. Furthermore, more studies should be done to identify if this exact mechanism that causes neural tube defects causes congenital disabilities of the heart and kidneys in fetuses born from mothers with diabetes. Mothers with diabetes have five times the congenital disability rate than those mothers without diabetes, so it’s imperative to find preventative medicine and mechanisms to decrease the congenital disability rates and increase healthier births in mothers with diabetes.

Practice Pearls:

• 300,000 to 400,000 fetuses per year from mothers with diabetes develop neural tube defects
• Research showed that the neural tube tissue in 8-day old mice from mothers with diabetes contained staining signals specific markers of premature aging in comparison; these same markers were not found in the mice offspring from mothers without diabetes. Researchers then found out that the cells from the mice with the premature aging markers secreted a host of other chemical signals that led to neighboring cells dying.
• Embryos from diabetic dams (pregnant female mice) that were treated with rapamycin had a significantly lower neural tube defect incidence vs. embryos from diabetic dams that did not undergo rapamycin treatment course

1. Xu, C., et al.(2021) Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin. Science Advances.org/10.1126/sciadv.abf5089.
2. Li MF, Ma L, Yu TP, Zhu Y, Chen MY, Liu Y, Li LX. Adverse maternal and neonatal outcomes in pregnant women with abnormal glucose metabolism. Diabetes Res Clin Pract. 2020 Mar;161:108085. doi: 10.1016/j.diabres.2020.108085. Epub 2020 Feb 13. PMID: 32061817.

Erica Hicks, PharmD Candidate 2022, South College School of Pharmacy