Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic β-cells initiated by yet unknown factors. Although animal models of type 1 diabetes have substantially increased our understanding of disease pathogenesis, heterogeneity seen in human patients cannot be reflected by a single model and calls for additional models covering different aspects of human pathophysiology. IKK/NF-κB signaling is a master regulator of inflammation; however its role in diabetes pathogenesis is controversially discussed by studies using different inhibition approaches. To investigate the potential diabetogenic effects of NF-κB in β-cells, we generated a gain-of-function model allowing conditional IKK2/NF-κB activation in β-cells. IKK2-CAPdx-1 mice spontaneously develop full-blown immune-mediated diabetes with insulitis, hyperglycemia and hypoinsulinemia. Disease development involves gene expression program mimicking virus-induced diabetes and allergic inflammatory responses as well as increased MHCI/II expression by β-cells that could collectively promote diabetes development. Potential novel diabetes candidate genes were also identified. Interestingly, animals successfully recovered from diabetes upon transgene inactivation. Our data gives the first direct evidence that β-cell-specific IKK2/NF-κB activation is a potential trigger of immune-mediated diabetes. Moreover, IKK2-CAPdx-1 mice provide a novel tool for studying critical checkpoints in diabetes pathogenesis and mechanisms governing β-cell degeneration/regeneration.
* LKC School of Medicine, Imperial College London and NTU, Singapore
- Received July 2, 2013.
- Accepted November 25, 2013.
- © 2013 by the American Diabetes Association.
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