Hippocampal volumes in youth with type 1 diabetes

Abstract

Objective: Hippocampal neurons in adult animals and humans are vulnerable to severe hypoglycemia and hyperglycemia. Effects are hypothesized to be exacerbated during development, but existing studies on developing human brains are limited. We examined whether hypoglycemia or hyperglycemia experienced during brain development in humans affects hippocampal volumes.

Research design and methods: We analyzed T1-weighted magnetic resonance images in 95 youth with type 1 diabetes and 49 sibling control subjects aged 7-17 years. Youth with diabetes were categorized as having 0 (n = 37), 1-2 (n = 41), or 3 or more (3+; n = 17) prior severe hypoglycemic episodes. Hyperglycemia exposure was estimated from median lifetime A1C, weighted for duration of diabetes. Stereologic measurements of hippocampal volumes were performed in atlas-registered space to correct for whole brain volume.

Results: Greater exposure to severe hypoglycemia was associated with larger hippocampal volumes (F [3,138] = 3.6, P = 0.016; 3+ larger than all other groups, P < 0.05). Hyperglycemia exposure was not associated with hippocampal volumes (R(2) change = 0.003, F [1,89] = 0.31, P = 0.58, semipartial r = 0.06; one outlier removed for high median A1C), and the 3+ severe hypoglycemia group still had larger hippocampal volumes after controlling for age of onset and hyperglycemia exposure (main effect of hypoglycemia category, F [2,88] = 6.4, P = 0.002; 3+ larger than all other groups, P < 0.01).

Conclusions: Enlargement of the hippocampus may reflect a pathological reaction to hypoglycemia during brain development, such as gliosis, reactive neurogenesis, or disruption of normal developmental pruning.

FIG. 1.

Example of the stereologic method for measuring hippocampal volumes. Selected points (black) were determined to be within the left hippocampal gray matter on a coronal view (shown), while simultaneously viewed in the sagittal and transverse perspectives.

FIG. 2.

A: Effects of repeated severe hypoglycemia on mean ± SEM total relative hippocampal volumes (corrected for age and sex). The 3+ group had larger hippocampal volume than all other groups (P < 0.05). B: Hyperglycemia exposure did not correlate with hippocampal volumes across the entire type 1 diabetes group after controlling for age, sex, and age of onset (P = 0.58). T1DM, type 1 diabetes.