Quantification and three-dimensional imaging of the insulitis-induced destruction of beta-cells in murine type 1 diabetes.
OBJECTIVE
The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the nonobese diabetic (NOD) mouse model of the disease.


METHODS
Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the three-dimensional spatial development and progression of insulitis and beta-cell destruction in pancreata 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 beta-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 provide 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.
Alanentalo
Tomas
T
Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
Hörnblad
Andreas
A
Mayans
Sofia
S
Karin Nilsson
Anna
A
Sharpe
James
J
Larefalk
Asa
A
Ahlgren
Ulf
U
Holmberg
Dan
D
D000818:Animals; D048429:Cell Size; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology*; D018450:Disease Progression; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D009929:Organ Size / Q000276:immunology; D010179:Pancreas / Q000276:immunology / Q000473:pathology*; D018709:Statistics, Nonparametric
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