title: Deletion of ARNT (Aryl hydrocarbon receptor nuclear translocator) in β-cells causes islet transplant failure with impaired β-cell function.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, Australia; Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, Australia.
authors.forename: Amit
authors.initials: A
authors.lastname: Lalwani
authors.affiliation: Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, Australia.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Stokes
authors.affiliation: Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Sue Mei
authors.initials: SM
authors.lastname: Lau
authors.affiliation: Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, Australia; Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, Australia.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gunton
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics* / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000637:transplantation*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D010179:Pancreas / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D018336:Receptors, Aryl Hydrocarbon; D000099162:Endothelial PAS Domain-Containing Protein 1; C497397:Arnt protein, mouse; C497443:Hif1a protein, mouse