Based on past findings in humans ( 18) and animals ( 2), we hypothesized that there would be significant reduction of AD in children with type 1 diabetes compared with nondiabetic control subjects and that hyperglycemia severity, early age of diabetes onset, and longer duration of type 1 diabetes would be associated with increased RD. We used continuous glucose monitors (CGMs) to obtain a more detailed measure of short-term glucose levels and variability than is provided by HbA 1c data ( 20). We also sought to identify potential links between WM microstructure, blood glycemic indices, and standardized measures of cognition. In the current study, we investigated WM structure in a much larger sample of young children with type 1 diabetes using DTI compared with sex- and age-matched control subjects. In that small study, significant differences in AD values were observed in children with type 1 diabetes compared with control subjects, and higher lifetime HbA 1c values were positively associated with RD values, suggesting possible brain insult to myelin induced by hyperglycemia in children with type 1 diabetes. However, only one study ( 18) used DTI to investigate WM structure in an exclusively pediatric type 1 diabetes cohort. To date, four studies have used DTI to investigate WM structure in type 1 diabetes ( 16– 19). Definitive conclusions about histology of WM can only be derived from direct microscopic examination of biological tissue. Rather, these scalars can show between-group differences and relationships between WM structure and clinical variables and are suggestive of underlying histology. Often, however, a combination of these WM characteristics results in opposing contributions to the final observed FA/AD/RD value, and thus DTI scalars should not be interpreted globally as “good” or “bad” ( 15). RD, the mean of the diffusivities perpendicular to the vector with the largest eigenvalue, is thought to represent degree of myelination ( 13, 14) (more myelin would decrease RD values) and axonal “leakiness” (which would increase RD). AD, a measure of water diffusivity along the main axis of diffusion within a voxel, is thought to reflect fiber coherence and structure of axonal membranes (increases in which would increase AD), as well as microtubules, neurofilaments, and axonal branching (increases in which would decrease AD) ( 11, 12). FA reflects the degree of diffusion anisotropy of water (how diffusion varies along the three axes) within a voxel (three-dimensional pixel) and is determined by fiber diameter and density, myelination, and intravoxel fiber-tract coherence (increases in which would increase FA), as well as extracellular diffusion and interaxonal spacing (increases in which would decrease FA) ( 10). Results are commonly reported in terms of mathematical scalars (representing vectors in vector space) such as fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD). WM structure can be measured with diffusion tensor imaging (DTI), a method based on magnetic resonance imaging (MRI) that uses the movement of water molecules to characterize WM brain structure ( 8, 9).

Hence, study of the developing brain is particularly important in type 1 diabetes. Early childhood is a period of rapid myelination and brain development ( 6) and of increased sensitivity to insults affecting the brain ( 6, 7).

Specifically, animal studies have shown that hyperglycemia but not hypoglycemia affects brain structure and cognition ( 5). Research in animal models has shown that white matter (WM) may be especially sensitive to dysglycemia-associated insult in diabetes ( 2– 4). Brain cells may be especially sensitive to aberrant blood glucose levels, as glucose is the brain’s principal substrate for its energy needs. However, even with optimal treatment many children with type 1 diabetes have blood glucose levels in the hyperglycemic range for more than half the day and in the hypoglycemic range for an hour or more each day ( 1).

Careful regulation of insulin dosing, dietary intake, and activity levels are essential for optimal glycemic control in individuals with type 1 diabetes.

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