Variations in Brain Volume and Growth in Young Children With Type 1 Diabetes

Paul K. Mazaika; Stuart A. Weinzimer; Nelly Mauras; Bruce Buckingham; Neil H. White; Eva Tsalikian; Tamara Hershey; Allison Cato; Tandy Aye; Larry Fox; Darrell M. Wilson; Michael J. Tansey; William Tamborlane; Daniel Peng; Mira Raman; Matthew Marzelli; Allan L. Reiss


Diabetes. 2016;65(2):476-485. 

In This Article

Abstract and Introduction


Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4–10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (±SD) HbA1c level was 7.9 ± 0.9% (63 ± 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes.


Type 1 diabetes, which is characterized by autoimmune-mediated destruction of the pancreatic β-cells, has been associated with subtle cognitive deficits[1–4] as well as long-term microvascular and macrovascular complications.[5–7] Brain-imaging studies[6–11] have shown that type 1 diabetes is associated with reduced total and regional loss of gray matter volume (GMV) in adolescents and adults. Similarly, in white matter, type 1 diabetes has been associated with total and regional volume losses,[3,5,10] differences in connectivity and microstructure,[12–15] and increased likelihood of white matter hyperintensities in older adults.[16]

While type 1 diabetes usually first appears in childhood or adolescence, an early age of onset, generally defined as earlier than 4–7 years of age by different authors,[2,17–19] is associated with more severe cognitive symptoms than late-onset diabetes; thus, the effects of this disease may be particularly evident in brain development in very young children. In particular, young children are particularly prone to experience extreme swings of hyperglycemia and hypoglycemia; hence, the current treatment guidelines for young children allow some exposure to hyperglycemia in order to reduce the neurological risks of severe hypoglycemia.[20] Previous cross-sectional studies[21–24] of young children with early-onset diabetes have shown differences in regional GMVs and axial diffusivity in white matter. The Diabetes Research in Children Network (DirecNet) Consortium[25] studied a large longitudinal sample of clinically treated young children with type 1 diabetes to investigate the effects of glycemic control on brain development and cognition. Using voxel-based morphometry (VBM), investigators found that children with diabetes had significantly lower growth of GMV over much of the cortical surface,[25] even though the subjects with diabetes were well within the clinical guidelines for diabetes management.[20]

Since many brain differences seen later in life may originate in this crucial early period of brain development,[3,15,16,26] we undertook further studies of this young population. A limitation of VBM is that it cannot discriminate features such as cortical thickness (CT), curvature, or surface area (SA),[27] which may be affected differently and independently in this disease. A surface-based analysis method such as FreeSurfer[28] can measure these surface characteristics, as well as accurately estimate subcortical and white matter volumes (WMVs) in the brain. The growth of WMVs is of particular interest because animal models[29–31] suggest that diabetes may adversely affect myelination early in brain development such that widespread myelination effects may affect white matter growth. Measurements of brain volume also may be confounded in cross-sectional studies because dehydration affects total brain volume,[32,33] and children with diabetes are often mildly dehydrated due to excess blood glucose. However, longitudinal data that include blood glucose measurements provide an opportunity to estimate this potential glycemia-brain volume correlation.

In the current study, we used FreeSurfer-based analyses to investigate the impact of early-onset diabetes on cortical development and regional brain growth in young children. We also sought to explore how age may modify the effects of diabetes on the developing brain and how blood glucose levels at the time of a scan may affect the measurement of brain volume in the population of individuals with diabetes.