Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine Type 1 Diabetes

  1. Dan Holmberg (dho{at}life.ku.dk)2,3
  1. 1Umeå Centre for Molecular Medicine, Umeå University, SE-90187, Umeå, Sweden
  2. 2Dept. of Medical Biosciences, Umeå University, SE-901 85, Umeå, Sweden
  3. 3Dept of Disease Biology, Faculty of Life Science, Copenhagen University, DK-1870, Copenhagen, Denmark
  4. 4ICREA and EMBL-CRG Systems Biology Program, Centre for Genomic Regulation, Dr. Aiguader 88, 08003, Barcelona, Spain

Abstract

Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining β-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and β-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

Results: Together with results showing the spatial dynamics of the insulitis process we provide data of β-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin+ islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

Footnotes

    • Received September 21, 2009.
    • Accepted March 26, 2010.

This Article

  1. Diabetes
  1. All Versions of this Article:
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