Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-cells causes islet transplant failure with impaired β-cell function

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Abstract

Background: Replacing β-cells by islet-transplantation can cure type 1 diabetes, but up to 70% of β-cells die within 10 days of transplantation. ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) regulates β-cell function, and potentially survival. Lack of ARNT impairs the ability of β-cells to respond to physiological stress and potentiates the onset of diabetes, but the exact role of ARNT in graft outcome is unknown. Aim: To investigate the effect of β-cell deletion of ARNT on graft outcomes. Methods: Islets were isolated from donor mice which had β-cell specific ARNT-deletion (β-ARNT) or littermate floxed controls. The islets were transplanted into diabetic SCID recipients in ratios of (a) 3 donors: 1 recipient, (b) 1 donor: 1 recipient or (c) 1/2 of the islets from 1 donor: 1 recipient. After 28 days, the kidney containing the graft was removed (nephrectomy) to exclude regeneration of the endogenous pancreas. Results: In the supra-physiological-mass model (3:1), both groups achieved reasonable glycaemia, with slightly higher levels in β-ARNT-recipients. In adequate-mass model (1:1), β-ARNT recipients had poor glucose control versus floxed-control recipients and versus the β-ARNT donors. In the low-β-cell-mass model (1/2:1) β-ARNT transplants completely failed, whereas controls had good outcomes. Unexpectedly, there was no difference in the graft insulin content or β-cell mass between groups indicating that the defect was not due to early altered β-cell survival. Conclusion: Outcomes for islet transplants lacking β-cell ARNT were poor, unless markedly supra-physiological masses of islets were transplanted. In the 1:1 transplant model, there was no difference in β-cell volume. This is surprising because transplants of islets lacking one of the ARNT-partners HIF-1α have increased apoptosis and decreased islet volume. ARNT also partners HIF-2α and AhR (aryl hydrocarbon receptor) to form active transcriptional complexes, and further work to understand the roles of HIF-2α and AhR in transplant outcomes is needed. © 2014 Lalwani et al.

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Lalwani, A., Stokes, R. A., Lau, S. M., & Gunton, J. E. (2014). Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-cells causes islet transplant failure with impaired β-cell function. PLoS ONE, 9(5). https://doi.org/10.1371/journal.pone.0098435

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