Review Assesses the Impact of Glycemic Variability on Cognitive Development in Youth With T1D

In a new review, researchers assessed the negative impacts of glycemic variability on cognitive function and brain structure among youth with type 1 diabetes.

Although the impacts of hypoglycemia on brain development and cognitive function among children with type 1 diabetes (T1D) has been investigated, in recent years studies have reported exposure to chronic hyperglycemia and increased glucose variability could affect brain structure and function, according to a review article published in Hormone Research in Pediatrics.

Throughout childhood and early adulthood, brain development and metabolic demands vary, but by the age of 6, children’s brains reach about 90% of the adult brain volume.

“Young children with T1D are prone to extreme fluctuations in glucose levels,” researchers explained. “The overlap of these potential dysglycemic insults to the brain during the time of most active brain and cognitive development may cause cellular and structural injuries that appear to persist into adult life.”

Previous studies have showed age of T1D onset and exposure to glycemic extremes—such as history of diabetic ketoacidosis or severe hypoglycemic episodes—can all influence brain structure and cognition in patients with T1D.

One study revealed “total brain, gray matter (GM), and white matter (WM) volumes and full-scale verbal intelligence quotients were lower in the T1D group at 6, 8, 10, and 12 years of age,” compared with healthy controls. “The brain volumes and cognitive scores had a negative correlation with glycemic control (glycated hemoglobin [A1C] and glucose sensor means),” researchers wrote.

In patients with early-onset T1D, magnetic resonance imaging showed lateral ventricular volumes were 37% greater and ventricular atrophy more prevalent when compared with those with later-onset T1D.

In addition, several studies have detailed associations between severe hypoglycemia and brain changes. However, a lack of consistent findings “of the impact of previous severe hypoglycemia on regional or whole brain volumes,” warrants future research, authors wrote.

An additional analysis sought to assess differences among those with early- or late-onset hypoglycemia and found children with early-onset hypoglycemia “performed more poorly than those with late-onset severe hypoglycemia in overall cognition.” More long-term studies are needed to understand the longitudinal effects of severe hypoglycemia on cognitive capabilities.

When it comes to hyperglycemia, one investigation found that those with a history of significant hyperglycemia had decreased GM volume in brain regions associated with cognitive capacities.

Furthermore, “the association between glycemic variability, particularly hyperglycemia, and cognitive function was more pronounced in young children with earlier onset and longer duration of diabetes, further highlighting the brain’s vulnerability in this age group.”

Some experts believe these brain changes can impact cognition as early as 2 years after T1D onset in youth. Both speed of information processing and executive function seem to be affected by this phenomenon.

Using data from the Diabetes Research in Childhood Network (DirecNet), an additional study “demonstrated that early-onset diabetes significantly affected the development of total and regional GM and WM volumes, with differences between groups enhanced over time,” researchers said.

They continued, “remarkably, in the diabetic group, the slower growth was most strongly associated with hyperglycemia and glycemic variability, as measured by several metrics, including glycated hemoglobin (A1C) and extensive quarterly data from continuous glucose monitoring (CGM).”

Several mechanisms may account for slower total and regional brain growth among children with T1D, but the ultimate mechanism is likely multifactorial.

According to previous studies, blood glucose variability may affect cognitive function via damage to the central nervous system, mitochondrial dysfunction, or neuronal cell damage.

To help prevent these events from taking place in patients with T1D, several technologies have been developed including CGM, sensor-augmented pumps (SAP), predictive low glucose insulin suspension (PLGS), and closed-loop systems that automate insulin delivery in a glucose-responsive manner (artificial pancreas).

These solutions can help “enhance the flexibility of care and optimize glycemic control, while trying to enable a ‘normal’ life with decreased damage to the developing brain and neurocognitive function,” authors concluded.


Nevo-Shenker M, and Shalitin S. The impact of hypo- and hyperglycemia on cognition and brain development in young children with type 1 diabetes. Horm Res Paediatr. Published online July 9, 2021. doi: 10.1159/000517352