Study could result in new approach to prevent diabetes-induced birth defects

August 28, 2013, University of Maryland

A research team at the University of Maryland School of Medicine has identified a cell signaling pathway which plays a significant role in causing developmental defects of the fetal spinal cord and brain in babies of women with diabetes. Using an animal model of disease, the team's results point to a potential new therapeutic target for preventing these defects in pregnant women having preexisting diabetes. The results of this study are published in the August 27th issue of Science Signaling.

"Providing the best possible care for women before and during is a significant challenge because the is such a crucial time of development, and many women may not be aware that they are pregnant," says Dean E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers distinguished professor and dean of the School of Medicine. "Prenatal care is especially important for women who have diabetes because research has shown that even transient increases in can lead to serious, and sometimes life-threatening, birth defects."

According to the U.S. Centers for Disease Control and Prevention, approximately 1 in 33 babies in the United States are born with a . Neural tube defects (NTDs), which occur when the fetal does not close completely in the first trimester, are among the most common type of birth defects and affect about 3,000 pregnancies each year. Women with diabetes prior to pregnancy are 3- to 10-times more likely to have a child with NTDs than women without disease. Folic acid (vitamin B; folate) has been shown to prevent NTDs in approximately 70 percent of pregnancies, but is not effective for everyone.

"Recent studies have reported that too much folic acid during pregnancy may increase risk of in offspring later in life, so it has become increasingly important to find additional or adjunctive therapies to prevent NTDs," says Peixin Yang, PhD, associate professor in the Department of Obstetrics, Gynecology and Reproductive Sciences, who led the current study. "For women with diabetes, whose risk of having an infant with a birth defect is much higher than in the general population, having additional preventive methods could significantly improve a baby's development."

Previous work has revealed that a cell signaling pathway which leads to programmed cell death, known as apoptosis, greatly contributes to NTDs. High levels of maternal glucose in diabetic pregnancies lead to abnormal cell death during fetal development. Although much of this work has been conducted in animal models of diabetic pregnancy, and performed by research teams led by Dean Reece, the authors also confirmed that the same pathway is present in human fetal tissues with NTDs.

In the current study, investigators under the direction of Dr. Yang and Dean Reece at the University of Maryland School of Medicine, observed that high levels of glucose initiate the apoptotic pathway by activating a protein called apoptosis signal-regulating kinase 1 (ASK1). Once activated, ASK1 turns on a cell death pathway by activating other pro-cell death proteins. The team found that reducing ASK1 activity, either by deleting the Ask1 gene or by giving diabetic pregnant mice an ASK1 inhibitor, also reduced the incidence of NTDs.

Although the majority of experiments were conducted in an , the team also observed similar expression of ASK1 and other apoptotic proteins in NTDs obtained from human samples. These findings suggest that human NTDs might occur using a similar cell death pathway as in diabetic pregnancy animal models.

One of the most promising results from this study is that the ASK1 inhibitor the team used is a small protein called thioredoxin which people naturally produce. Thioredoxin is thought to act as an antioxidant and has been used commercially as an anti-aging agent in some cosmetics.

"Because thioredoxin is small and naturally-occurring, it may be possible to develop it into a dietary supplement, much like folic acid, which women can take prior to and during pregnancy," says Dr. Yang. "Thioredoxin and folate might even have a combinational effect, providing greater protection for the fetus against NTDs, but also allowing women to take less folic acid, thereby preventing possible folate-induced damage to their children."

More work is needed before trials to test thioredoxin supplements in people could begin. The team does not know exactly how thioredoxin blocks ASK1 activation, or if the antioxidant has any side effects.

"This work contributes greatly to our understanding of how high blood glucose causes birth defects and identifies specific targets that could be exploited to prevent diabetes-induced NTDs," says Dr. Reece. "The findings on thioredoxin's inhibitory effects also have implications for other diseases, such as cancer or kidney disease, which are caused or exacerbated by ."

Explore further: New treatment may work with folic acid to prevent neural tube defects like spina bifida

More information: P Yang et al. Maternal hyperglycemia activates an ASK1-FoxO3a-Caspase 8 pathway that leads to embryonic neural tube defects. Science Signaling. DOI: 10.1126/scisignal.2004020

Related Stories

New treatment may work with folic acid to prevent neural tube defects like spina bifida

August 13, 2013
Researchers at the UCL Institute of Child Health (ICH) are investigating a new treatment that could work alongside folic acid to boost its effectiveness and prevent a greater proportion of neural tube defects – such as ...

Fortifying corn masa flour with folic acid could prevent birth defects, March of Dimes says

June 16, 2011
Fortifying corn masa flour with the B vitamin folic acid could prevent more serious birth defects of the brain and spine in the Hispanic community, according to a March of Dimes commentary published in the American Journal ...

Mouse experiments show fickle functions for folic acid

October 6, 2011
(Medical Xpress) -- Dietary folic acid helps prevent a subset of neurological birth defects in humans -- although the precise mechanism by which it prevents them is unclear. Now, researchers have found that certain genetic ...

Birth defects linked to coal and pesticides

July 20, 2011
(Medical Xpress) -- According to a new study published in the Proceedings of the National Academy of Sciences, pregnant mothers who are exposed to pesticides and smoke are as much as four times more likely to give birth to ...

Recommended for you

More surprises about blood development—and a possible lead for making lymphocytes

January 22, 2018
Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we are born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists ...

How metal scaffolds enhance the bone healing process

January 22, 2018
A new study shows how mechanically optimized constructs known as titanium-mesh scaffolds can optimize bone regeneration. The induction of bone regeneration is of importance when treating large bone defects. As demonstrated ...

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.