pp 1–10 | Cite as

Persistence of abnormalities in white matter in children with type 1 diabetes

  • Larry A. Fox
  • Tamara Hershey
  • Nelly Mauras
  • Ana Maria Arbeláez
  • William V. Tamborlane
  • Bruce Buckingham
  • Eva Tsalikian
  • Kim Englert
  • Mira Raman
  • Booil Jo
  • Hanyang Shen
  • Allan Reiss
  • Paul Mazaika
  • for the Diabetes Research in Children Network (DirecNet)



Prior studies suggest white matter growth is reduced and white matter microstructure is altered in the brains of young children with type 1 diabetes when compared with brains of non-diabetic children, due in part to adverse effects of hyperglycaemia. This longitudinal observational study examines whether dysglycaemia alters the developmental trajectory of white matter microstructure over time in young children with type 1 diabetes.


One hundred and eighteen children, aged 4 to <10 years old with type 1 diabetes and 58 age-matched, non-diabetic children were studied at baseline and 18 months, at five Diabetes Research in Children Network clinical centres. We analysed longitudinal trajectories of white matter using diffusion tensor imaging. Continuous glucose monitoring profiles and HbA1c levels were obtained every 3 months.


Axial diffusivity was lower in children with diabetes at baseline (p = 0.022) and at 18 months (p = 0.015), indicating that differences in white matter microstructure persist over time in children with diabetes. Within the diabetes group, lower exposure to hyperglycaemia, averaged over the time since diagnosis, was associated with higher fractional anisotropy (p = 0.037). Fractional anisotropy was positively correlated with performance (p < 0.002) and full-scale IQ (p < 0.02).


These results suggest that hyperglycaemia is associated with altered white matter development, which may contribute to the mild cognitive deficits in this population.


Brain development Paediatric diabetes White matter 



Continuous glucose monitor


Diabetes Research in Children Network


Diabetic ketoacidosis


Diffusion tensor imaging



The authors thank the participants and their families, as well as the clinical and imaging staff at all investigator sites. They also thank the external collaborators at the University of California at San Francisco (San Francisco, CA, USA), El Camino Hospital (Mountain View, CA, USA) and University of Florida/Shands-Jacksonville Medical Center (Jacksonville, FL, USA) for the use of their imaging facilities. The authors also thank K. Winer, at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, for advice and support.

Contribution statement

Each listed author has participated in the work represented by the article. Participation has included: (1) substantial contributions to the conception and design of the work or the acquisition, analysis or interpretation of data and (2) drafting the article or revising it critically for important intellectual content. All authors have given final approval of the version to be published. LAF and PM are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Duality of interest

LAF reports a research device agreement with Johnson & Johnson (Animas, Inc.); NM reports a research device supply agreement with her institution from Medtronic and Lifescan, research grant support from Medtronic and consultancy from PicoLife Technologies; BB is a consultant for Dexcom and has received research support from and conducted research studies for Dexcom and Medtronic. WVT, AMA and KE report consultancy from PicoLife Technologies. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Larry A. Fox
    • 1
  • Tamara Hershey
    • 2
  • Nelly Mauras
    • 1
  • Ana Maria Arbeláez
    • 2
  • William V. Tamborlane
    • 3
  • Bruce Buckingham
    • 4
  • Eva Tsalikian
    • 5
  • Kim Englert
    • 1
  • Mira Raman
    • 6
  • Booil Jo
    • 6
  • Hanyang Shen
    • 6
  • Allan Reiss
    • 4
    • 6
    • 7
  • Paul Mazaika
    • 6
  • for the Diabetes Research in Children Network (DirecNet)
  1. 1.Pediatric EndocrinologyNemours Children’s Health SystemJacksonvilleUSA
  2. 2.Department of Psychiatry and RadiologyWashington University in St Louis and the St Louis Children’s HospitalSt LouisUSA
  3. 3.Pediatric EndocrinologyYale UniversityNew HavenUSA
  4. 4.Department of PediatricsStanford University School of MedicineStanfordUSA
  5. 5.Department of Pediatric EndocrinologyThe University of IowaIowa CityUSA
  6. 6.Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral SciencesStanford UniversityStanfordUSA
  7. 7.Department of RadiologyStanford University School of MedicineStanfordUSA

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