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Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-Cells Causes Islet Transplant Failure with Impaired β-Cell Function

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 r...

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Autores principales: Lalwani, Amit, Stokes, Rebecca A., Lau, Sue Mei, Gunton, Jenny E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039512/
https://www.ncbi.nlm.nih.gov/pubmed/24878748
http://dx.doi.org/10.1371/journal.pone.0098435
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author Lalwani, Amit
Stokes, Rebecca A.
Lau, Sue Mei
Gunton, Jenny E.
author_facet Lalwani, Amit
Stokes, Rebecca A.
Lau, Sue Mei
Gunton, Jenny E.
author_sort Lalwani, Amit
collection PubMed
description 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) ½ 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 (½:1) 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.
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spelling pubmed-40395122014-06-02 Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-Cells Causes Islet Transplant Failure with Impaired β-Cell Function Lalwani, Amit Stokes, Rebecca A. Lau, Sue Mei Gunton, Jenny E. PLoS One Research Article 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) ½ 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 (½:1) 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. Public Library of Science 2014-05-30 /pmc/articles/PMC4039512/ /pubmed/24878748 http://dx.doi.org/10.1371/journal.pone.0098435 Text en © 2014 Lalwani et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lalwani, Amit
Stokes, Rebecca A.
Lau, Sue Mei
Gunton, Jenny E.
Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-Cells Causes Islet Transplant Failure with Impaired β-Cell Function
title Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-Cells Causes Islet Transplant Failure with Impaired β-Cell Function
title_full Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-Cells Causes Islet Transplant Failure with Impaired β-Cell Function
title_fullStr Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-Cells Causes Islet Transplant Failure with Impaired β-Cell Function
title_full_unstemmed Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-Cells Causes Islet Transplant Failure with Impaired β-Cell Function
title_short Deletion of ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator) in β-Cells Causes Islet Transplant Failure with Impaired β-Cell Function
title_sort deletion of arnt (aryl hydrocarbon receptor nuclear translocator) in β-cells causes islet transplant failure with impaired β-cell function
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039512/
https://www.ncbi.nlm.nih.gov/pubmed/24878748
http://dx.doi.org/10.1371/journal.pone.0098435
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