Early Onset Type 1 Diabetes May Affect Brain Development in Kids

Miriam E. Tucker

June 24, 2019

SAN FRANCISCO — Significant slowing of brain development, apparently linked to hyperglycemia, has been seen in children diagnosed with type 1 diabetes at a young age compared to those without the condition, new research finds.

The data, from the Diabetes Research in Children Network (DirecNet) were presented June 9 at the American Diabetes Association (ADA) 2019 Scientific Sessions during an ADA Presidents' Select oral session by Nelly Mauras, MD, chief, Division of Endocrinology, Diabetes, & Metabolism, Nemours Children's Health System, Jacksonville, Florida.

"Maintenance of near-normoglycemia in young children with diabetes is often limited by parental fears of the risks of hypoglycemia and impaired cognitive development," Mauras said during a press briefing.

However, "data suggest that both hyper- and hypoglycemia, depending on age and severity, can lead to altered brain structure and cognitive function, particularly in the young developing brain."   

Slower total brain and regional gray and white matter growth at about 4.5 years were seen among 138 children with type 1 diabetes compared with 67 age-matched controls, and these changes were correlated to hyperglycemia (all P < .05). The affected brain regions are involved in sensory processing and cognition. The data extend similar DirecNet findings at earlier timepoints (Diabetes. 2016;65:476-485).

The children were aged 4-7 years at the beginning of the study and had a mean diabetes duration of 2.4 years. At the time of the current neuroanatomical evaluation (using voxel-based morphometry) they were a mean age of 11 years, had a mean diabetes duration of 6.5 years, and mean HbA1c of 8.0%.

Mauras and colleagues also presented related DirecNet findings in two posters. One showed persistent decrements in full-scale and verbal IQ over time in children with type 1 diabetes compared with controls, which also correlated with hyperglycemia. The other study, more optimistically, suggested that the children's brains were able to compensate for the decrements so that their cognitive function may be preserved, at least in the short-term.

"I Actually Find It Quite Scary"

The findings challenge some prevalent beliefs about children with diabetes, Mauras noted during the press briefing.

For one, "The striking thing to us is that the greatest association we saw...was with high blood sugars. The notion that parents have that they'd rather keep them high than low...for us, it's been very consistent regardless of how we measure glycemia…At all time points, we see the association with structural changes, and now cognition. It gives one more reason to control them better."

And, she noted, the data also call into question whether ADA guidelines for the management of type 1 diabetes in children are too lenient regarding the general HbA1c target of < 7.5%.

"Are A1cs in the 7s enough to prevent these changes? Can we make an impact with near-normalization of the blood sugars with technology?" asked Mauras.

Moreover, she noted, "We have always had the notion that it takes years to see diabetes complications in children. At baseline, the average diabetes duration in this study was 2.4 years and we already see differences in brain volumes and gray and white matter...We have continued to follow this cohort longitudinally. The differences stick and are readily apparent almost 5 years later."

Briefing moderator Desmond A. Schatz, MD, medical director of the Diabetes Institute and associate director of the General Clinical Research Center, University of Florida, Gainesville, called the data "very provocative."

"As a fellow pediatric endocrinologist and diabetologist, I actually find it quite scary, the fact that brain growth is slowed in young people. There's this controversy about when does the clock for complications really begin?" he noted.

But Schatz also cautioned, "We don't really know what it means."

Regarding the current ADA recommendation of HbA1c < 7.5% for kids, he said, "Now, with continuous glucose monitoring, which we advise at the time of diagnosis, we will in fact be able to get better control."

IQ Differences Seen, But Also Brain Compensation

In a larger DirecNet cohort of 181 children with type 1 diabetes and 90 age-matched controls, as reported in a poster at the meeting, significantly lower full scale IQ (P = .024), verbal IQ (P = .009), and vocabulary (P = .002) scores were seen at 4.5 years among the diabetes group compared with controls. However, processing speed, memory, and learning scores didn't differ between groups.

Among the children with type 1 diabetes, there was a significant inverse relationship between HbA1c at last follow-up and vocabulary (P = .001), and between HbA1c and verbal IQ after controlling for parental IQ (P = .037).

But in slightly more promising news, in the third study from the same cohort, presented as another poster at ADA, among 93 children with type 1 diabetes and 57 controls, the two groups performed similarly on an executive function test. And during the task, the children with type 1 diabetes exhibited greater activation in executive control regions of the brain (P = .010).

"These findings suggest that compensatory recruitment of executive control areas may act to offset type 1 diabetes-related impairments in the [brain's] default mode network and, at least transiently, allow behavioral performance...to be equivalent to that of nondiabetic controls," Mauras and colleagues indicate.

Indeed, Mauras clarified during the briefing, "We are not suggesting that these youngsters aren't performing academically. So far, these differences have not translated into functional outcomes in performance, at least not yet."

"But the concerning thing is that these differences are real. Now, 74 months from baseline, we continue to see changes in structure and cognition. Whether or not, in time, we will see functional changes remains to be seen. That's why we continue to follow these patients."

Mauras has reported receiving research grants from Medtronic and Novo Nordisk and having device/research supply agreements with Medtronic, LifeScan, and Johnson & Johnson. Schatz has reported no relevant financial relationships.

ADA 2019 Scientific Sessions. Presented June 9, 2019. Abstracts 209-OR, 1346-P, 1382-P

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