Eat, Play, Grow

Children face an onslaught of health problems related to nutrition and fitness. Every year, over 15,000 US children are diagnosed with type 1 diabetes—high blood sugar resulting from a lack of insulin production. Type 2 diabetes, which is caused by an inability to metabolize sugar even at normal insulin levels (insulin resistance), has been rising in children and is linked to increasing childhood obesity. Finally, children worldwide are malnourished.

At the Children’s Discovery Institute, investigators from Washington University and its School of Medicine are examining the basic science behind these urgent health issues.

Diabetes and diet

In the US, as type 2 diabetes has increased, so has the total consumption of sugars—including, table sugar, high-fructose corn syrup, and honey. But how does a high-sugar diet trigger diabetes? Two scientists want to answer this question. The Institute has funded the collaboration of Thomas Baranski, MD, PhD, Associate Professor of Medicine and Developmental Biology, and Michael Brent, PhD, Henry Edwin Sever Professor in Computer Science and Genetics.

“When I was a medical student, it was unheard of to see a teenager with type 2 diabetes,” said Dr. Baranski. “Now, I see them all the time.” There is growing evidence that a diet high in simple sugars predisposes people to insulin-resistant diabetes. “We want to understand the molecular mechanisms involved in this.”

To do this, the project will employ powerful genomic techniques to a simple animal model: fruit flies fed a high-sugar diet. Fruit flies mimic several traits of humans with diabetes. “We’ll use this model to detect changes in gene signaling in response to a high-sugar diet,” said Dr. Brent. “We want to see how cells are transformed to an insulin resistant state.”

“Over the long term,” suggested Dr. Baranski, “if our study and others describe the molecular effects of a high-sugar diet in type 2 diabetes, we’ll be in a better position to pinpoint diets, supplements, or even drugs that might reset a diabetic patient’s molecular balance.”

Exercise, diabetes, and low blood sugar

Children with type 1 diabetes take insulin to avoid high blood sugar. But a side effect of insulin is low blood sugar (hypoglycemia). Unfortunately, children with type 1 diabetes don’t always get strong warning signs of hypoglycemia, like shaking and sweating, especially after exercise. Blunted warning signs put these children at risk of repeated low blood sugar and even death, because they don’t realize they have a low blood sugar and need to eat to treat it.  

To study this phenomenon, known as hypoglycemia-associated autonomic failure (HAAF), researcher Ana Maria Arbelaez, MD, Assistant Professor of Pediatrics, collaborates with Philip E. Cryer, MD, Professor of Medicine, and Tamara Hershey, PhD, Associate Professor of Neurology.

According to Dr. Arbelaez, one region of the brain, called the thalamus, “shows increased activity in people with blunted responses to hypoglycemia.”  A goal of Dr. Arbelaez’s research is to learn whether the thalamus is also involved in blunting responses to hypoglycemia after children have exercised. “That’s important,” said Dr. Arbelaez, “because it might provide a target for therapy in HAAF. It can also help us make sure that children with diabetes can safely get the exercise they need.”

Nutrition before a child’s birth

“We know that a mother’s nutrition, lifestyle, and prenatal care make a difference in her baby’s health,” said Robert Heuckeroth, MD, PhD, Professor of Pediatrics and Developmental Biology. “But we need to know more about how particular factors—such as deficiency of one vitamin—may interact with parental genetics and link to specific birth defects.”

Dr. Heuckeroth studies the developmental pathways of the neural crest—a structure within the growing human embryo. With help from the Children’s Discovery Institute, Dr. Heuckeroth and his team have already discovered a connection between vitamin A deficiency and development of the bowel’s enteric nervous system (ENS). His studies are conducted within the Congenital Heart Disease Center, because problems in neural crest development give rise to some congenital heart defects, as well as bowel defects, cleft palate, and other birth defects.

Under his newest grant, Dr. Heuckeroth will examine the effect of the nutrient folate on an ENS birth defect called Hirschsprung disease, which occurs in 1 of 5000 babies. Even after corrective surgery, about 30% of children with Hirschsprung disease develop enterocolitis, a complication that may often be fatal. That’s why new prevention strategies are needed.

“Parents wonder, ‘What did I do to cause this birth defect?’,” said Dr. Heuckeroth. “And they ask how they can prevent it in a future child. I believe that research will one day help us make individualized diet and lifestyle recommendations for each set of parents, to reduce the risk of birth defects that have occurred in their family.”

Malnutrition and microbes

Every hour of every day, 700 children worldwide die of malnutrition. Mark Manary, MD, Helene Roberson Professor of Pediatrics, has pioneered use of a peanut-butter based therapeutic food, which is sustaining malnourished children in Malawi and other countries. Now, one of Dr. Manary’s associates, Michelle Smith, PhD,  has received an Institute fellowship to study  the intriguing link between microbes in the gut and malnutrition.

Using novel methods of microbiology, Dr. Smith will introduce bacteria, taken from stool samples of Malawian children, into bacteria-free “gnotobiotic” mice. By studying the mice, Dr. Smith hopes to learn how gut microbiology and the ability to absorb nutrients are interrelated in a malnourished child.

“Getting maximum nutrition from food depends on having a full, diverse range of gut bacteria,” said Dr. Smith. “Conversely, the quality of a diet might degrade the microbial mix.” The more we know about this process, added Dr. Smith, “the closer we will be to identifying probiotic diets or other interventions that improve gut microbiology and nutrient absorption.” Dr. Manary concurred, noting that “ultimately, the research could be a tool that helps us test the best interventions for malnourished kids.”

Funding makes the difference

All of these projects would not be possible without the Children’s Discovery Institute and its centers devoted to metabolic disease and congenital heart disease. Dr. Heuckeroth summed it up: “To get funding from the NIH—that is, to start translating your research into better care for kids—you need extensive data. The Children’s Discovery Institute provides the funding to amass that data. For that, we’re all very, very grateful.”