We compared diabetic and control groups and examined the association of hippocampal volumes, measured with validated and unbiased stereologic methods, with previous histories of severe hypoglycemia and chronic hyperglycemia exposure. In this study, we acquired structural magnetic resonance imaging (MRI) and glycemic history from a large sample of youth with type 1 diabetes and nondiabetic siblings who have already been characterized cognitively ( 22). Further understanding of the effects of exposure to glycemic extremes on the hippocampus in development may provide critical information for minimizing risks and maximizing clinical benefits over a patient's childhood. However, previous studies have not been able to disentangle the effects of severe hypoglycemia and chronic hyperglycemia exposure during development on the hippocampus in humans with type 1 diabetes. In fact, studies have found that hyperglycemia is related to decreased hippocampal gray matter in adults with type 2 diabetes ( 19) and possibly decreased hippocampal function in adult animal models ( 20, 21). The possibility of acute severe hypoglycemia occurs within a context of chronic hyperglycemia, which may have its own effects on brain integrity. Interestingly, studies on children with temporal lobe seizures have found that early exposure to seizures can cause greater long-term memory deficits ( 15) and greater hippocampal damage ( 16, – 18) than seizures that occur during adulthood. However, no correction for whole brain volume was performed and no control group was assessed ( 14). In addition, no differences were found in absolute hippocampal volumes across these small groups. One recent study reported an increased incidence of medial temporal sclerosis in diabetic children with early hypoglycemia (before 6 years of age) compared with those with later hypoglycemia (6 years or older), but not compared with those with no hypoglycemia history. Although it is possible to measure the volume of the hippocampus reliably and detect even subtle atrophy in this structure in children with temporal lobe epilepsy, anoxia, and other medial temporal lobe insults ( 13), examinations of the effects of hypoglycemia on the hippocampus using quantitative neuroimaging methods have been limited. Notably, these studies did find significant cell death in cortical regions, which could correspond to the regional cortical volume loss observed in voxel-wise neuroimaging analyses of youth with type 1 diabetes ( 12). However, neither of two relevant studies found increased neuronal death in the hippocampus after moderate hypoglycemia in young rats ( 10, 11). Animal studies of hypoglycemic effects on the developing hippocampus have been limited.
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