There is a growing literature documenting central nervous system (CNS) changes in adults with type 1 diabetes, including lower density of cortical gray matter (GM) and white matter (WM) lesions (4). Neuroimaging studies in children with type 1 diabetes have been limited to date, and findings have implicated different brain regions and variable associations with illness-specific risk factors (5). These albeit inconsistent findings do suggest an adverse impact of type 1 diabetes on the developing brain, in line with evidence for neurocognitive deficits in childhood-onset type 1 diabetes (6). The exact nature, explanatory mechanisms, and timing of CNS damage, however, remain to be clarified.

Controlled studies that follow participants across childhood and into adulthood may be particularly informative in documenting the impact of type 1 diabetes on brain development. The Royal Children’s Hospital, Melbourne (RCH) Cohort Study recruited consecutive admissions with newly diagnosed type 1 diabetes between 1990 and 1992, together with a healthy control group, into a longitudinal study. Twelve years after diagnosis, a subset of the cohort underwent neuroimaging with magnetic resonance imaging (MRI) to document structural changes in the CNS. Relative to control participants, a number of brain regions in participants with type 1 diabetes showed decreased GM and WM volumes and alterations in the T2 relaxation time, a fundamental MRI parameter that reflects the chemical environment of the brain and developmental changes such as myelination (7). In addition, we examined age-related volume loss and T2 relaxation time change in two brain regions, the thalamus and lentiform nuclei, that were the areas of most widespread change in the analyses of group (type 1 diabetes vs. control) differences. This report extends the initial analyses by examining the relationship between age with volume and T2 across the whole brain.

Volume loss and T2 reductions are characteristic of normal ageing, thus our findings could be interpreted as accelerated brain ageing. MRI studies of healthy individuals have shown that brain volume increases during childhood, reaching a maximum in adolescence, thereafter declining in a fairly linear fashion, with acceleration in the rate of decline at ~55 years of age (11). T2 relaxation time also changes in an age-related manner across the life span. During early development, T2 relaxation time shortens, mainly reflecting the progression of myelination in WM. In addition, a decrease in T2 relaxation time in extrapyramidal structures such as the putamen and caudate nucleus, clearly evident from ~20 years of age, reflects age-dependent accumulation of iron (12). It is interesting to note that the accelerated T2 reduction observed in the type 1 diabetic participants in this study includes several of these extrapyramidal brain regions, which therefore may indicate a modified rate of iron deposition in these subjects. Indeed, elevated levels of iron have been found in blood plasma in both type 1 and type 2 diabetes (13), which may be due to modified turnover of erythrocytes (14). The phenomenon of accelerated brain ageing in diabetes has previously been described by Biessels et al. (15), but only in older adults, and particularly, but not exclusively, in reference to type 2 diabetes. To our knowledge, this is the first study to raise the possibility of such an effect in a population of youth with type 1 diabetes and a mean age of just 20 years.

Alternatively to a process of premature senescence, our findings might indicate some disruption to the final stages of neurodevelopment, in a process qualitatively different from the neurodegenerative changes postulated by Biessels et al. (15). Type 1 diabetes, or an aspect of the disease, may affect neurodevelopment such that youth with the disease show less normative age-related increase in brain volume. This is consistent with the findings in a recent study in which the expected rate of increase in total WM volume during early development was not observed in a group of younger (3–10 years old) children with type 1 diabetes (16). Diabetes-related effects on GM may occur later in neurodevelopment (i.e., during adolescence). Perantie et al. (5) imaged a sample (mean age of ~12 years) and found no overall differences in GM volume between those with type 1 diabetes and healthy control subjects. In contrast, Musen et al. (17) conducted voxel-based analyses of a sample of young adults with a mean age ~32 years and reported volume loss in frontal and temporal regions and left thalamus, brain regions that overlap considerably with our own findings (7). Taken together, these findings suggest that late adolescence-early adulthood may be a critical period in which the GM volumes of youth with type 1 diabetes diverge from those of their healthy peers. This interpretation is consistent with Ryan’s diathesis hypothesis (18), which posits that early exposure to hyperglycemia increases the vulnerability of the brain to subsequent CNS disruption.

The mechanisms underlying neural changes in our cohort with type 1 diabetes are unclear. Hyperglycemia is linked to excessive activation of the polyol pathway with resulting formation of advanced glycation end products and atrophy, as well as increased oxidative stress associated with cell death (4). Alternatively, as a consequence of elevated blood glucose levels, the cells may become desensitized to glucose due to saturation of their metabolic activity, endoplasmic reticulum stress, or mitochondrial dysfunction. Glucose has been shown to act as a mitogen in some contexts such as human β-cells (19). In a different context, hyperglycemia was shown to lead to myocyte cell death (20) and to reduced cell differentiation in endothelial progenitor cells that is indicative of advanced cell senescence (21). The effects observed in this study may suggest the existence of a cell-survival failsafe mechanism following sustained hyperglycemia in which glucotoxicity and apoptosis are avoided by desensitization to raised glucose levels such that the propensity for cell division is reduced. In addition, the interaction of age with diabetes demonstrated in this study may reflect diabetes-induced modulation of synaptic plasticity. In groups of young and aged rats exposed to streptozotocin-induced diabetes, the impairment in plasticity was shown to be greater in the older group, implying an interaction between ageing and plasticity-related dysfunction in a model of type 1 diabetes (22).

It is important to note that the CNS changes that we demonstrated are subtle and of uncertain functional significance, although we have previously reported lower school completion rates in our cohort (7). Scans were scrutinized by a neuroradiologist (A.M.), and three participants only had abnormalities that required clinical investigation, two of whom were control participants. Although meta-analyses of both children (6) and adults (23) with type 1 diabetes confirm subtle neurocognitive deficits, and there is increasing evidence of structural brain changes [see (24) for review], the literature is difficult to interpret because of inconsistency across individual reports. Different methodologies and samples heterogeneous for age, age of disease onset, illness duration, and metabolic control history almost certainly contribute to inconsistent findings. We have previously reported that neurocognitive deficits were greater in those with early onset (<5 years) diabetes (7,25), yet brain volume and T2 reduction was most evident in our older and later-onset participants. It is difficult to explain the lack of correspondence between structural CNS changes and functional neurocognitive deficits, but this disassociation has been reported before (3,11). Lenroot and Giedd (26) caution that relationships between brain structures and cognition are rarely straightforward even in healthy youth. In our cohort, constant exposure to abnormal glycemic variation may disrupt skill acquisition in the very young child even in the absence of structural CNS change, whereas subtle changes in brain structure may precede global cognitive difficulties in the participants who were older at disease onset.

It is possible that some, or all, of the pathophysiological processes described above have contributed to our findings of age-related brain volume loss and T2 reduction in type 1 diabetic participants. The selectively greater impact on our older participants suggests an interaction between disease effects and neurodevelopmental stage, but serial imaging of a diabetic cohort through childhood to CNS maturity in a controlled design would be necessary to confirm this. Further exploration to clarify age-related changes and the mechanisms underlying brain changes in type 1 diabetes in general are important though, as animal studies have indicated that adjunctive neuroprotective strategies may be possible using either systemic IGF-I (27) or glucocorticoid receptor antagonists such as mifepristone (28). These strategies, though promising, are either untried or nascent in the human context.