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The brain is an expensive organ to run: Most studies suggest that it requires up to 20 percent of the body’s total energy resources despite only taking up approximately 2 percent of its overall weight. Maintaining appropriate glucose levels—the proper amounts of the simple sugar that acts as the body’s main energy source—is key to keeping the brain running at its best. This can be difficult for people—especially children—who have type 1 diabetes mellitus (T1D), an auto-immune disorder that stops the body from producing insulin, the hormone that helps to break down what we eat into that vital glucose fuel. New research reported through a national consortium called the Diabetes Research in Children Network suggest that this can affect brain development in myriad ways, some of which could offer new insights into our understanding of how the brain compensates, over time, for chronic or degenerative disease.
The Effects of Hyper- and Hypoglycemia
Last year, my daughter, Ella, was diagnosed with Type 1 diabetes at age 10. As we learned more about the disease, we were cautioned to look out for both hyperglycemia, or high blood glucose levels, as well as hypoglycemia, low blood glucose levels. High blood sugars result in symptoms like increased thirst, frequent urination, headache, and fatigue. If high glucose levels continue for a long time, there could be long-term damage to the kidneys, eyes, and nerves. Low blood sugars, on the other hand, can lead to shakiness, anxiety, confusion, dizziness, and muscle weakness—and if not treated immediately, seizures or unconsciousness. While there’s no “perfect” number for glucose levels, it is recommended that most children stay between 70 and 180 mg/dL, checking their blood sugar 4-6 times per day with a glucometer, which can measure blood glucose level from a small drop of blood, says Parul Patel Brown, a pediatric endocrinologist.
“It can be a hard thing for children to control because glucose is a bit of a moving target. Sometimes, you are going to go high and sometimes you are going to go low,” she says. “I usually recommend to my patients that they try to stay in range at least 80 percent of the time. And we are definitely seeing that good control of your glucose levels is important to staying healthy overall.”
Despite recommendations for complete control, to date, most pediatric endocrinologists will tell you it’s better to have more highs than lows: The brain needs glucose to function, and too many lows risk seizures or unconsciousness that could lead to brain damage. Some case studies have shown that prolonged hypoglycemia can lead to memory and other severe cognitive deficits.
But Tamara Hershey, a neuropsychologist at the Washington University School of Medicine, says that an open question had been whether prolonged hyperglycemia may be detrimental to the brain as well. “We know that hyperglycemia causes an impact on the peripheral nervous system, neuropathy in the toes and fingers and problems in the eyes,” she says. “But we didn’t know if it had a negative impact on the central nervous system as well. It was something that it seemed like we should study.”
Hershey started working with endocrinologists and neuroscientists across the country to study children with T1D over time, to see how blood sugar may influence the structure and function of the brain.
Mapping the T1D Brain
Using neuroimaging techniques, Hershey and colleagues discovered some fascinating differences between children with T1D and those without the disorder. The T1D children showed structural changes in the brain’s white matter, as well as variations in brain volume and growth in the cortex and cerebellum. The researchers also discovered that T1Ds tended to fare worse than controls on cognitive tests, particularly on measures of executive function, when their glucose levels were consistently on the high side.
“The studies are pretty consistent, and they show a difference,” says Allan Reiss, a member of DirecNet and the Dana Alliance for Brain Initiatives (DABI). “Historically, it was thought that mild hyperglycemia, over time, might not be so bad. But our work suggests that the hyperglycemia may be causing chronic stress to the brain, which looks to have implications for the brain and cognitive abilities.”
Hershey cautions that the cognitive effects are subtle, but do come up as consistently lower than controls, even when children with T1D test against their own siblings. What’s more, Hershey says, you can often see these changes in as little as two years after diagnosis in T1D children, sometimes in as little as three months after diagnosis. This raises a lot of questions.
“It leads you to ask, when and where are these changes happening?” she says. “What is really driving this difference that we’ve found? Is it about the age of diagnosis? How high of a glucose level you had at diagnosis? We just don’t know yet.”
In DirecNet’s most recent study, published in Diabetes in March 2017, the group had T1D children and age-matched non-diabetic children relax in an fMRI scanner to measure resting-state connectivity patterns. They found a pattern of increased connectivity in children with T1D; for them, more connections correlated with better cognitive functioning. This, Reiss suggests, that the brain is trying to compensate for the inconsistent glucose levels by setting itself at a hyperconnected state.
“The human brain is designed with redundant systems to help you maintain homeostasis, so you have good cognitive function and can interact with your environment in an adaptive fashion,” says Reiss. “The brain adapts to stress, and it tries to compensate to make up for it. You certainly see compensatory systems at work in many adult neurological diseases. These systems allow people to function pretty well at the behavioral cognitive level. And it seems like, with T1D, there are some compensatory systems hard at work trying to rebalance brain function with this hyperconnectivity.”
More than Informing Treatment
Currently, the American Diabetes Association estimates that 1.25 million people in the US have T1D; approximately 40,000 people will be newly diagnosed each year. Reiss hopes that their work will one day help better inform practice guidelines for T1D and provide the right guidance for how glucose levels should be best managed at every age.
“Luckily, there have been advances in treatment that mean that children are having hypoglycemic episodes much less frequently. And those tools could help with hyperglycemia, too,” he says. “But there are still a lot of kids who aren’t being monitored, and that needs to change.”
He also thinks that this work has implications for our understanding of the brain’s innate compensatory systems and how the brain deals with insult and injury. Hershey agrees. Twenty years ago, when she started this work, people were surprised that anyone would consider the brain as a potential target of T1D, she says. Now, with rising rates of type 2 diabetes in children, it is becoming more of a concern.
“The story there may be even more profound. We know that type 2 diabetes is a huge risk factor for Alzheimer’s disease. And how it shapes brain development may help shed more light on why that’s so,” she says. “We are learning so much more about the interface between glucose, the body’s fuel, and the brain—and we know that there is interplay between general metabolism and brain function. We just have to continue this work to better understand how it may all fit together.”