The Impact of Hypo- and Hyperglycemia on Cognition and Brain Development in Young Children with Type 1 Diabetes
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Mini Review Article
Horm Res Paediatr Received: March 16, 2021
Accepted: May 21, 2021
DOI: 10.1159/000517352 Published online: July 9, 2021
The Impact of Hypo- and Hyperglycemia
on Cognition and Brain Development in
Young Children with Type 1 Diabetes
Michal Nevo-Shenker a Shlomit Shalitin a, b
aJesse Z. and Lea Shafer Institute of Endocrinology and Diabetes, Schneider Children’s Medical Center of
Israel, Petach Tikva, Israel; bSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Keywords deficits manifest across multiple cognitive domains. More-
Type 1 diabetes · Hypoglycemia · Hyperglycemia · Brain over, impaired executive function and mental health can af-
function · Diabetes technology fect patients’ adherence to treatment. This review summa-
rizes the current data on the impact of glycemic extremes
on brain structure and cognitive function in youth with T1D
Abstract and the use of new diabetes technologies that may reduce
Human and experimental animal data suggest both hyper- these complications. © 2021 S. Karger AG, Basel
glycemia and hypoglycemia can lead to altered brain struc-
ture and neurocognitive function in type 1 diabetes (T1D).
Young children with T1D are prone to extreme fluctuations
in glucose levels. The overlap of these potential dysglyce- Introduction
mic insults to the brain during the time of most active brain
and cognitive development may cause cellular and struc- Type 1 diabetes (T1D) is among the most prevalent
tural injuries that appear to persist into adult life. Brain struc- chronic illnesses diagnosed in childhood. Diabetes man-
ture and cognition in persons with T1D are influenced by agement in young children is quite challenging, as they
age of onset, exposure to glycemic extremes such as severe are more prone to experience extreme fluctuations in glu-
hypoglycemic episodes, history of diabetic ketoacidosis, cose levels at a time when their developing brain is under-
persistent hyperglycemia, and glucose variability. Studies going wide-ranging maturational changes [1]. The unique
using brain imaging techniques have shown brain changes properties of major neurodevelopmental changes during
that appear to be influenced by metabolic abnormalities early childhood have led to the hypotheses that the devel-
characteristic of diabetes, changes apparent at diagnosis oping brain may be especially vulnerable to glycemic ex-
and persistent throughout adulthood. Some evidence sug- tremes, with lasting effects on its development and associ-
gests that brain injury might also directly contribute to psy- ated cognition. The implementation of new diabetes
chological and mental health outcomes. Neurocognitive technologies may reduce these complications.
karger@karger.com © 2021 S. Karger AG, Basel Correspondence to:
www.karger.com/hrp Shlomit Shalitin, shalitin @ netvision.net.ilInfluence of T1D on Cerebral Structure and Cognitive Therefore, it may be implied that neurodevelopment may
Function be adversely affected by early-onset diabetes.
Toprak et al. [9] also evaluated brain structure and
Brain synaptic development and metabolic demands neurocognitive functions in children with T1D as com-
vary throughout childhood and continue into young pared to age-matched healthy controls. Fractional anisot-
adulthood. Synaptic density increases rapidly during ear- ropy (FA) and apparent diffusion coefficient (ADC) val-
ly postnatal cortical development, followed by a discrete ues were calculated for both groups. Associations be-
period of synaptic pruning that typically occurs during tween FA and ADC values and neurocognitive function
adolescence [2]. Total brain volume increases between tests were investigated. Subjects with diabetes demon-
the ages of 1 and 6 years and by the age of 6 years reaches strated significant changes in FA and ADC values in
approximately 90% of the adult brain volume [1, 3]. Total widespread brain regions. Such changes could be early
gray matter (GM) volume, cortical volume, and average features of injury to myelinated fibers or axonal degen-
cortical thickness all increase up to ages 9–11 years and eration. Several studies assessing cognition in youth with
then begin to decrease during subsequent childhood and early-onset diabetes have shown worse outcomes across
adolescence years as synaptic pruning occurs. In contrast, a variety of cognitive domains – executive functions,
myelination of white matter (WM), as reflected in WM learning, memory, and processing speed [10, 11].
volume, increases gradually throughout childhood, ado- In a cohort of young children with T1D, with a median
lescence, and even early adulthood [3]. Simultaneously, diabetes duration of approximately 4 years, Cato et al.
the young brain has a rapidly changing metabolic de- [12] observed trends toward cognitive differences relative
mand. Between 2 and 3 months until 4 years of age, brain to controls in areas of intellectual ability and executive
glucose use increases dramatically, reaching double the functions after accounting for parental IQ and level of
rate of the adult brain by the end of the first decade of life, parent-reported depression. However, cognitive domain
followed by a gradual reduction toward adult levels in the scores did not differ between the groups after an 18-month
next decade [4]. testing session and did not change significantly over the
Research on brain structure and neurocognitive con- follow-up period [13]. A recent study conducted in South
sequences of early-onset T1D and related glycemic vari- Australia evaluated educational outcomes in children
ability is emerging. Studies comparing brain structure with T1D while also comparing the effect of times from
and neuropsychological functioning in young children T1D diagnosis (Children and adolescents with T1D are more likely to es. Perantie et al. [19] found significant differences be-
perform worse on tasks that require sustained attention, tween young patients with T1D and healthy control
rapid processing speed, memory, and visuospatial func- groups with regard to GM or WM. However, within the
tioning compared to their nondiabetic peers [11]. A me- diabetic group, a history of severe hypoglycemia was as-
ta-analysis showed that executive functions, including sociated with smaller GM volume in the left superior tem-
processes like working memory, attention, and response poral region. The same group, in a prospective study, re-
inhibition, are particularly affected [16]. Nevertheless, a ported that severe hypoglycemia experienced between
recent study from DirecNet [17] reported that despite brain imaging scans was related to reduced WM volume
equivalent cognitive and behavioral functioning between growth in the parietal occipital cortex over a 2-year time
children with T1D and age-matched nondiabetic con- period [20]. Musen et al. [21] found, in patients with T1D
trols, young children with T1D exhibited increased acti- with early-onset diabetes, lower levels of GM density as-
vation in executive control regions (e.g., dorsal anterior sociated with worse glycemic control and higher frequen-
cingulate cortex, inferior frontal gyri, cerebellum, and su- cy of recurrent severe, hypoglycemic events. However,
pramarginal gyri) during performance of an attention- another retrospective study found no significant effects of
demanding task. The magnitudes of these increases were severe hypoglycemia on WM integrity across the brain in
significantly correlated with deficits in deactivation of the T1D youth [22]. Clearly, there is a lack of consistent find-
posterior node of the default mode network, suggesting a ings of the impact of previous severe hypoglycemia on
putative compensatory role of brain function in T1D, regional or whole brain volumes.
whereby higher activation in task-relevant regions acted Many studies evaluated the magnitude and pattern of
both to offset T1D-related impairments in default mode cognitive dysfunction in children with T1D and possible
network function and to facilitate behavioral perfor- effects associated with severe hypoglycemia and poor
mance levels equivalent to those of their nondiabetic cognitive outcomes [23–26]. A meta-analysis of 10 stud-
peers. Another study by the DirecNet group assessed ies described the impact of severe hypoglycemic episodes
brain activation in children with T1D via functional MRI, on cognitive function [27]. The severe hypoglycemia
while the children performed visuospatial working mem- group included patients who had at least one severe hy-
ory tasks. The study showed that children with T1D per- poglycemic episode, and the nonhypoglycemia group in-
formed the tasks less accurately, yet again functional MRI cluded those with no hypoglycemic episodes. The perfor-
indicated increased activation of relevant brain regions mance of T1D participants with severe hypoglycemia
(frontoparietal cortex, cerebellum, and thalamus), mean- (n = 347) was compared to those without hypoglycemic
ing higher working memory load, presumably indicative episodes (n = 364). Children with severe hypoglycemic
of compensatory mechanisms needed by the T1D group. episodes were somewhat more impaired in overall cogni-
In this study, the end results showed that this compensa- tion than children without hypoglycemia and showed
tion was not sufficiently effective to raise the T1D group’s slightly lower performance in memory. In other cognitive
results to those of the control group. It is noteworthy that domains, the effects were not significant. The results in-
the findings were more prominent in children with dicated that children with severe hypoglycemia showed
younger age at T1D onset [18]. significantly poorer performance in overall cognition.
These findings are consistent with previous reviews and
developmental cognitive studies in children with recur-
The Impact of Hypoglycemia on Cognitive Function rent hypoglycemic episodes [24, 25].
and Brain An additional sub-meta-analysis explored differences
in cognitive domains between children with early-onset
The young age at diagnosis of T1D contributes to sig- (up to 7 years of age) compared with late-onset severe hy-
nificant concerns regarding hypoglycemia. For different poglycemia [27]. Children with early-onset severe hypo-
reasons, including lack of expressive language skills and glycemia performed more poorly than those with late-
cognitive immaturity, young children may be unable to onset severe hypoglycemia in overall cognition. These
reliably detect and/or report early symptoms of hypogly- findings indicate that severe hypoglycemia experienced
cemia. early in development might be more harmful to cognitive
Several studies of patients with childhood-onset T1D performance than severe hypoglycemia later in life. In the
documented associations between severe hypoglycemia latter meta-analysis [27], a subgroup analysis evaluated
(with seizures or loss of consciousness) and brain chang- the cross-sectional and longitudinal studies. Cross-sec-
Cognition and Brain Development in Horm Res Paediatr 3
Young Children with Diabetes DOI: 10.1159/000517352tional studies showed that the effects of severe hypogly- ferences in WM microstructure persisted over time.
cemia on cognitive dysfunction were significant; howev- Within the diabetes group, lower exposure to hyperglyce-
er, longitudinal studies suggested that severe hypoglyce- mia, averaged over time since diagnosis, was associated
mia episodes were not associated with cognitive with higher FA, which in turn was positively correlated
dysfunction. Hence, severe hypoglycemia might be a with performance and full-scale IQ. These studies pro-
plausible cause of cognitive decline in children with T1D. vide strong evidence that the developing brain is a vulner-
Thus, more longitudinal studies are needed to fully ad- able target for hyperglycemia with altered WM develop-
dress the long-term effects of severe hypoglycemia on ment, which may contribute to the mild cognitive deficits
cognitive dysfunction. in this population.
Several mechanisms for the observed slower total and
regional brain growth in children with T1D may be opera-
The Impact of Hyperglycemia and Glucose tive. Chronic hyperglycemia can lead to formation of ad-
Variability on the Brain and Cognitive Function vanced glycation end products and their receptors, nucle-
ar factor-κB, greater increased oxidative stress, and even
Chronic hyperglycemia exposure may also affect the neurodegeneration [32–34]. These glycemic correlations
brain, targeting both GM and WM volume in youth with support the notion that increased glucose variability may
T1D. Using structural MRI, Marzelli and colleagues [28] damage developing neurons and myelin in children with
found that young children with T1D with a history of sig- T1D and are congruent with observations from strepto-
nificant hyperglycemia exhibited decreased GM volume zotocin-induced diabetes animal models that show in vivo
in key brain regions associated with cognitive capacities, degenerative changes of neurons and glia, disarrangement
compared to healthy control participants. The associa- of myelin sheaths, and reduced myelin content with hy-
tion between glycemic variability, particularly hypergly- perglycemia [34]. Changes in brain sphingolipid composi-
cemia, and cognitive function was more pronounced in tion (ceramides and sphingomyelin) induced by hypergly-
young children with earlier onset and longer duration of cemia may also provoke membrane rearrangements in
diabetes, further highlighting the brain’s vulnerability in some cell populations, which can disturb cellular signaling
this age group. In this same sample from the DirecNet and cause brain tissue damage [35]. The ultimate mecha-
study, Cato and colleagues [29] reported trending asso- nism of the observed changes is likely multifactorial.
ciations among executive functioning, learning/memory, Central nervous system insult to children with early-
and hyperglycemia, suggesting that the structural brain onset diabetes may have a delayed, progressive, and cu-
changes in youth with diabetes have a subtle yet measur- mulative impact on neuropsychological outcomes and
able impact on cognition as early as 2 years after T1D on- cognition over time. These outcomes might be subtle in
set. These data suggest that glycemic dysregulation or terms of cognition but appear to persist into adult life
variability has significant implications for young children [36]. Concurrent baseline neuroimaging analysis per-
and brain structure and function. formed by DirecNet supports the hypothesis that WM
A large cohort of young children (age 4 toTable 1. The main findings on the effect of hypo- and hyperglycemia on the brain Effect of hypoglycemia on the brain Effect of hyperglycemia on the brain GM GM Lower levels of GM density (in early-onset DM) [21] Less growth of cortical GM [5] Smaller volume in left superior temporal region [19] Decreased volume [7, 28] WM WM Less growth of WM volume in the cortex and cerebellum [5] Lower volume [7] Reduced volume growth in the parietal occipital cortex [20] Decreased WM development [5, 30] No significant effect on WM integrity [22] Altered WM microstructure [31] Cognitive function Cognitive function Poor performance in overall cognition, lower memory Lower cognitive scores [7, 28, 31] performance [24, 25, 27] Lower overall intellectual function [15] Poorer overall performance in early-onset diabetes Impaired executive function [29, 42] (age
siblings without diabetes. Results showed that after con- mate insulin delivery in a glucose-responsive manner (ar- trolling for age, sex, and multiple comparisons, the T1D tificial pancreas). group had lower volume in the left temporal-parietal-oc- CGM use among very young children is feasible and cipital cortex compared with controls. Within the T1D enables reduction of both time spent in hypoglycemia and group, DKA at presentation was associated with lower glucose variability. A recent study by the Strategies to En- radial, axial, and mean diffusivity throughout major WM hance New CGM Use in Early Childhood study group tracts. Higher HbA1c was associated with lower hippo- (SENCE) evaluated the effects of CGM with or without campal, thalamic, and cerebellar WM volumes, lower family behavioral intervention on glycemic outcomes in right posterior parietal cortical thickness, and greater young children (2–8 years). The study showed improve- right occipital cortical thickness. These data suggest that ment in critical glycemic measures in the CGM group severity of clinical presentation is an important factor in (time spent in hypoglycemia, number of severe hypoglyce- predicting brain structural differences in youth with T1D. mic events, and glucose variability), emphasizing the yield Another recent study among young children with T1D of CGM use in this young age group [53]. A Slovenian pop- who participated in the DirecNet study examined wheth- ulation-based cohort assessing the correlation between er a history of DKA was associated with changes in lon- CGM use and glucose variability in young children (age
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