Greater exposure to severe hypoglycemia during childhood was associated with enlargement of hippocampal gray matter volume in youth with type 1 diabetes. This effect was not explained by age, sex, degree of hyperglycemia exposure, age of onset, or duration of disease and was equivalent for both hemispheres. Although the direction of the effect was unexpected, the fact that the subset of youth with three or more severe hypoglycemic episodes in their past was different from all other groups, including sibling control subjects, supports the sensitivity of the hippocampus to effects of repeated hypoglycemic episodes during brain development. These data do not support the idea that chronic hyperglycemia in childhood affects gray matter volume in the hippocampus.
These findings are in contrast to the existing, although limited, data on adults with diabetes. Case studies of adults who suffered profoundly severe hypoglycemia have reported distinct neuronal death in the hippocampus bilaterally (1
). However, one study in adults with type 1 diabetes found that hippocampal volumes were comparable with control subjects (1
= 13). Given the small sample sizes in that study, statistical power likely limited the ability to detect differences in hippocampal volumes. In contrast, a slightly larger study of adults with type 2 diabetes (n
= 23) found reduced hippocampal volume compared with control subjects and a correlation between hyperglycemia exposure and degree of volume loss (40
). Thus, there is no precedent in the adult literature for increased volume of the hippocampus in association with diabetes, hyperglycemia, or hypoglycemia.
The single study using quantified hippocampal volumes in children with type 1 diabetes compared those with versus without hypoglycemia-related seizures and those with early versus late hypoglycemia-related seizures on whole brain gray matter volume and absolute hippocampal volume (14
). No control group was assessed. They found no differences between diabetic groups in absolute hippocampal volumes, but total gray matter volume did tend to be smaller in youth with previous seizures. Thus, if relative hippocampal volumes had been calculated, it is possible that larger relative hippocampal volumes in those with hypoglycemia-related seizures would have been observed. Notably, our study found both enlarged absolute and relative hippocampal volumes in those with multiple severe hypoglycemic episodes. Other differences in the methodology of that study, such as very strict definition of severe hypoglycemia, failure to correct for sex effects, and relatively small sample sizes, make direct comparisons with our findings difficult.
Interestingly, there is a precedent for abnormal enlargement of the hippocampus in other developmental disorders. Hippocampal enlargement has been noted in children with fragile X syndrome (41
), autism, and attention-deficit hyperactivity disorder (ADHD). For example, Plessen et al. (42
) found increased hippocampal volumes in children with combined type ADHD (n
= 51; 6–18 years old) compared with control subjects (n
= 63). However, within the ADHD group, increased symptoms were associated with smaller hippocampi volumes. The authors speculate that the enlargement could thus reflect a compensatory response to ADHD; this is supported by “abundant preclinical evidence for the presence of synaptic remodeling and neurogenesis within the hippocampus … in response to experiential demands.” Enlargement of the hippocampus has also been reported in children (7.5–18.5 years of age) with autism, both with and without mental retardation compared with control subjects but not in adults with autism (43
). The authors suggest that this could be due to “use-dependent expansion of hippocampal connections” or pathological development, perhaps because of reduced programmed cell death (44
Based on these reports and the explanations that are proposed, we speculate that enlargement of the hippocampus in our study could reflect a pathological reaction to repeated severe hypoglycemia during development such as gliosis, disruption of normal developmental pruning or reactive neurogenesis, or a compensatory developmental response to injured neurons. There is little relevant experimental evidence addressing possible mechanisms of altered hippocampal volume in response to hypoglycemia. Estrada et al. (46
) reported increased transient glial reactivity followed by prolonged and enhanced neurogenesis in the hippocampus after hypoglycemia, but these studies were performed in adult rats. In contrast, Yamada et al. (10
) found no change in neurogenesis in the hippocampal dentate granule cell region after moderate hypoglycemia in immature rats, suggesting that this mechanism may not be responsible for our results. Further animal experimentation would be necessary to address other possible mechanisms of hippocampal enlargement in response to hypoglycemia during development.
Our data in a large sample indicate that there is no significant relationship between degree of hyperglycemia exposure and hippocampal volumes. This stands in contrast to some animal work, suggesting that neurons in the hippocampi of immature animals are more affected by hyperglycemia than hypoglycemia (47
). Perhaps greater severity or duration of hyperglycemia exposure is necessary for changes in the hippocampal structure to be detected during development. Importantly, the lack of a relationship between hyperglycemia and volume does not rule out the possibility of functional effects of hyperglycemia within the hippocampus. Studies using functional MRI or other functional imaging measures would be needed to test this possibility.
These findings highlight the possibility that metabolic insults that occur during development can have a qualitatively different impact on brain structure than those occurring in a fully mature system. For example, early damage to the hippocampus and surrounding medial temporal region can produce long-term memory deficits, similar to those found in adults, but can also induce unique social and cognitive deficits (e.g., response inhibition) generally associated with prefrontal dysfunction in adults (48
). Researchers have speculated that these effects could be due to developmental disruption of connections between the hippocampal region and the prefrontal cortex (48
). As noted by Ennis et al. (11
), differential effects of metabolic insults on the brain depending on age could be explained by the developmental stage of the cells affected or changes in the density or function of neurotransmitter receptors.
This highly focused study tested hypotheses about the effects of hypoglycemia and hyperglycemia during development on the gray matter of the hippocampus. Because of this focus, we cannot address possible effects in white matter of the hippocampus or other gray or white matter regions of the brain. In addition, the function of hippocampus could be affected in addition to or in the absence of structural change. Due to limitations in the resolution and methods of MRI, we cannot distinguish among possible mechanisms of structural change. Finally, our cross-sectional study would be complemented by prospective measurement of hippocampal volume and more detailed analyses of hippocampal shape or subfield volume changes over time. Future analyses may also take into account behavioral and cognitive correlates of hippocampal differences. However, our study reports on the largest sample of youth with type 1 diabetes assessed with highly reliable, unbiased, and gold standard measures of hippocampal gray matter volume. Using these powerful techniques, we found an intriguing pattern of results that must be taken into account in neurodevelopmental theories of the brain's response to insults. In addition, our findings support the idea of a special relationship between hypoglycemia and the hippocampus during development.