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Diabetes Pathophysiology Hippocampal Volume in Type 1 Diabetes Michael Murray, 1 Molly Stanley, 2 Heather M Lugar, MA 3 and Tamara Hershey, PhD 4 1. Undergraduate Researcher, Department of Psychiatry; 2. PhD Candidate, Department of Neurology; 3. Image Analyst, Department of Psychiatry; 4. Professor, Departments of Psychiatry, Neurology and Radiology, Washington University School of Medicine, St Louis, Missouri, US Abstract The hippocampus plays an important role in human memory and is known to be vulnerable to extreme hyperglycemia and hypoglycemia in animal models of type 1 diabetes. Within humans with type 1 diabetes, exposure to glycemic extremes has been associated with alterations in hippocampal structure and in memory function, but results are inconsistent. It has been hypothesized that the effects of hypoglycemia and hyperglycemia on the hippocampus may depend on when during neurodevelopment these extremes occur, possibly explaining some of these inconsistencies. However, data addressing this concept are limited. We review here the existing literature on this complex topic and suggest future avenues of required research. Keywords Hippocampus, diabetes, hypoglycemia, hyperglycemia, development, brain Disclosure: The authors have no conflicts of interest to declare. Acknowledgments: The authors gratefully acknowledge the following support from the National Institutes of Health (NIH) DK064832 (Hershey) and from the National Science Foundation (NSF) DGE-1143954 (Stanley). Received: September 5, 2013 Accepted: November 12, 2013 Citation: US Endocrinology, 2013;9(2):91–4 Correspondence: Tamara Hershey, PhD, Washington University School of Medicine, Campus Box 8225, 660 South Euclid Avenue, St Louis, MO 63110, US. E: The hippocampus plays an important role in human learning and memory and is known to be vulnerable to the effects of stress and disease. 1 Within animal models of type 1 diabetes, 2 significant hyperglycemia and hypoglycemia exposure has been shown to cause complex molecular and structural changes in the hippocampus. 2,3 Within humans with type 1 diabetes, exposure to both extremes of the glycemic spectrum have been inconsistently associated with alterations in hippocampal structure 4–9 and worse memory function, 8–11 but it is unclear whether these two findings relate to each other. Given that the diagnosis of type 1 diabetes and exposure to glycemic extremes often occur at a time of dynamic neurodevelopment, it has been hypothesized that exposure at early ages may have different effects on the brain than exposure in adulthood, which could explain some of these inconsistent findings. However, data addressing this concept are limited. In this article, we review the existing literature on the effects of hyperglycemia and hypoglycemia in type 1 diabetes, with focus on the structure and function of the hippocampus during both development and adulthood. Hippocampal Structure, Volume, and Function The hippocampus is a subcortical, primarily gray matter structure residing bilaterally within the medial temporal lobes. It consists of several regions, including the cornu ammonis (CA) and its subregions (CA1–CA4), the dentate gyrus (DG), and the subiculum, which connects the hippocampus to the parahippocampal gyrus. 1 These regions contain intra- and interhippocampal connections through multiple synaptic pathways 12 and have been ascribed specialized roles in the processing of © TO U CH MEDICAL MED IA 2013 information. 13–16 Overall, the hippocampus appears to play an important role in laying down and consciously retrieving explicitly learned, novel information. 17 Within this complex process, the CA1 has been selectively associated with long-term and autobiographical memory, 15,18 the CA2 and CA3 with encoding processes, and the DG with early retrieval and episodic memory formation. 15,19 The hippocampus develops heterogeneously and nonlinearly up to age 25 20,21 and is a site of sustained neurogenesis throughout the lifespan. 20–22 Hippocampal volume is developmentally dynamic, with the posterior and anterior portions increasing and decreasing respectively with age. 20 The total volume steeply increases until approximately age 4, followed by a gradual increase and reaching a peak in volume around age 10. 21 Hippocampal volume remains fairly stable until age 50 in healthy adults, followed by a variable level of decline and a significant decrease in volume by age 80. 23 The relationship between developmental changes in hippocampal volume and memory function is complex and still unclear. A meta-analysis of the literature examining hippocampal volume and memory performance in healthy children, adolescents, and young adults revealed that smaller hippocampal volume was associated with better memory performance and that this effect could reflect sufficient developmental pruning leading to overall lower volume. 24 In healthy adults, the associations are less clear as both larger 25–28 and smaller 29,30 volumes have been associated with better explicit memory performance. The dynamic development of the hippocampus could lead to age-selective vulnerability and differential outcomes in patient populations. In adult 91