Improved blood sugar control helps normalize diabetic teens’ brains, Stanford-led study finds

Tightly controlling blood sugar can reduce brain-structure and function differences in teens with diabetes, according to a pilot study co-led by researchers at the Stanford School of Medicine and Nemours Children’s Health System, in Jacksonville, Florida.

The study published online Aug. 30 in Nature Communications. It is the most detailed study showing that brain structure and function can be improved in teens with diabetes via better control of blood sugar. The finding follows decades of evidence that better blood sugar control prevents long-term diabetes complications in other organs.

In Type 1 diabetes, the body stops making insulin, a hormone that regulates sugar transport from the blood into muscle and other tissues. Children and teens with the disease experience detrimental changes in brain structure and function, including lower IQ, and these differences are related to high blood sugars, prior research has shown.

In the randomized controlled trial, investigators evaluated the use of automated treatment technology against routine care for six months. The technology enabled teenagers with diabetes to tightly manage their blood sugar, increasing the amount of time their sugar levels were in the target range. The teens using the technology showed better results on brain scans and cognitive tests than those using traditional treatment methods.

“It strongly suggests that with significantly improved glucose control, one can attenuate and perhaps even reverse some of the deleterious effects of diabetes on the brain and cognition,” said the study’s lead author, Allan Reiss, MD, the Howard C. Robbins Professor in Psychiatry and the Behavioral Sciences and a professor of radiology at the Stanford School of Medicine.

The fact that both brain structure and cognitive abilities improved after only six months is especially striking, Reiss said.

“I would have been happy if we had just seen brain structure improvements,” he said. “But we saw both improvement in performance and changes in the brain that strongly suggested a trend toward normality.”

The study’s senior author is pediatric endocrinologist Nelly Mauras, MD, of Nemours Children’s Health and the Mayo Clinic College of Medicine and Science. “These results offer hope that some of these diabetes complications may indeed be reversible,” Mauras said. The study was conducted at five sites across the country.

Cognitive, brain-structure improvements

People with Type 1 diabetes must count the carbohydrates they eat, monitor their blood sugar levels and regularly inject themselves with insulin to enable their bodies to handle sugar. Teenagers — who often keep erratic schedules and may dislike that the disease makes them feel different from their friends — frequently struggle to manage the disease.

But recent advances in diabetes technology have made things a little easier. Patients can now wear a continuous glucose monitor, which measures blood sugar every five minutes via a sensor placed under the skin. It’s connected wirelessly to an insulin pump, which adjusts the amount of insulin it supplies based on the monitor’s reading. This system, known as closed-loop monitoring, can increase the time teens spend with their blood sugar in a healthy range, and it is especially good at stabilizing blood sugar during sleep.

The researchers randomly assigned 44 study participants to use closed-loop monitoring or standard diabetes care for six months. All of the participants were 14 to 17 years old and had been diagnosed with diabetes before age 8. They received clinical, cognitive and brain-imaging evaluations at the beginning of the study and again six months later.

After six months, the closed-loop group showed greater improvements than the control group on a standard test of perceptual reasoning, or nonverbal reasoning skills, which assesses the ability to think flexibly.

Prior studies by the same researchers had shown that children and teens with diabetes need to activate more cognitive resources to achieve the same level of brain performance as typically developing kids; in other words, the brain ramps up its activity to compensate for losses linked to the disease. In the new study, functional brain scans of the teens in the closed-loop group showed less compensation — a good sign.

When the researchers looked at brain imaging of the study participants after six months, they found that among the closed-loop group, several aspects of brain structure looked more like typically developing teenagers. They had lower cortical gray matter volume, lower subcortical tissue volume, and lower cortical surface area and thickness than teens using conventional diabetes management techniques.

Gray matter volume normally declines as teens’ maturing brains prune the connections between neurons to those that are most important.

The teens in the closed-loop group also had more white matter, meaning they had better insulation of important long-range connections in the brain that are normally becoming more efficient during adolescence, in line with healthy adolescent brain development.

“The gray-matter and white-matter changes observed with better blood sugar control are consistent with the brain becoming more efficient as it matures,” Reiss said. Gray matter is where information processing and decision making occurs, whereas white matter consists of groups of fibers that connect different brain areas to each other and to the rest of the nervous system. “Overall, the closed-loop group was moving more in the direction of what you see in typical adolescent brain development,” Reiss said.

Because both treatment groups included individuals who managed their blood sugar levels well along with those who struggled, the researchers re-analyzed their data on the basis of success at blood sugar control, without regard to treatment group. They found that individuals with better blood sugar control had more normal brain structure and cognition.

Reiss noted that the prior research on tight blood sugar control has shown that it leads to lower rates of diabetes complications such as blindness, kidney failure and limb amputations.

The Stanford team is planning a follow-up study to confirm their findings in a wider age group and to see if there are additional benefits to newer closed-loop monitoring devices, which are easier to use than the devices that were available when the study was conducted, from 2018 to 2020.

“This study gives hope that, with significantly improved glucose control, perhaps most of the deleterious effects of diabetes can be attenuated or reversed,” Reiss said. “That’s the punchline, and it’s big.”

The study’s authors include members of Stanford Bio-X, the Stanford Wu Tsai Human Performance Alliance, the Stanford Maternal and Child Health Research Institute, and the Stanford Wu Tsai Neurosciences Institute.

Researchers at Washington University in St. Louis (Neil White, MD), the University of Iowa (Eva Tsalikian, MD), Yale University (Stuart Weinzimer, MD) and the Jaeb Center for Health Research (John Lum) also contributed to the project.

The research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant 5R01-HD-078463) and the Juvenile Diabetes Research Foundation.