title: Deletion of ARNT/HIF1β in pancreatic beta cells does not impair glucose homeostasis in mice, but is associated with defective glucose sensing ex vivo.
abstract: OBJECTIVE
  It has been suggested that the transcription factor ARNT/HIF1β is critical for maintaining in vivo glucose homeostasis and pancreatic beta cell glucose-stimulated insulin secretion (GSIS). Our goal was to gain more insights into the metabolic defects seen after the loss of ARNT/HIF1β in beta cells.
  
  
  METHODS
  The in vivo and in vitro consequences of the loss of ARNT/HIF1β were investigated in beta cell specific Arnt/Hif1β knockout mice (β-Arnt (fl/fl/Cre) mice).
  
  
  RESULTS
  The only in vivo defects found in β-Arnt (fl/fl/Cre) mice were significant increases in the respiratory exchange ratio and in vivo carbohydrate oxidation, and a decrease in lipid oxidation. The mitochondrial oxygen consumption rate was unaltered in mouse β-Arnt (fl/fl/Cre) islets upon glucose stimulation. β-Arnt (fl/fl/Cre) islets had an impairment in the glucose-stimulated increase in Ca(2+) signalling and a reduced insulin secretory response to glucose in the presence of KCl and diazoxide. The glucose-stimulated increase in the NADPH/NADP(+) ratio was reduced in β-Arnt (fl/fl/Cre) islets. The reduced GSIS and NADPH/NADP(+) levels in β-Arnt (fl/fl/Cre) islets could be rescued by treatment with membrane-permeable tricarboxylic acid intermediates. Small interfering (si)RNA mediated knockdown of ARNT/HIF1β in human islets also inhibited GSIS. These results suggest that the regulation of GSIS by the KATP channel-dependent and -independent pathways is affected by the loss of ARNT/HIF1β in islets.
  
  
  CONCLUSIONS
  This study provides three new insights into the role of ARNT/HIF1β in beta cells: (1) ARNT/HIF1β deletion in mice impairs GSIS ex vivo; (2) β-Arnt (fl/fl/Cre) mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1β is required for GSIS in human islets.
authors.affiliation: School of Pharmacy, University of Waterloo, Health Science Campus building A, room 4008, 10A Victoria Street South, Kitchener, ON, Canada, N2G 1C5.
authors.forename: Renjitha
authors.initials: R
authors.lastname: Pillai
authors.affiliation: School of Pharmacy, University of Waterloo, Health Science Campus building A, room 4008, 10A Victoria Street South, Kitchener, ON, Canada, N2G 1C5.
authors.forename: Sabina
authors.initials: S
authors.lastname: Paglialunga
authors.affiliation: School of Pharmacy, University of Waterloo, Health Science Campus building A, room 4008, 10A Victoria Street South, Kitchener, ON, Canada, N2G 1C5.
authors.forename: Monica
authors.initials: M
authors.lastname: Hoang
authors.affiliation: School of Pharmacy, University of Waterloo, Health Science Campus building A, room 4008, 10A Victoria Street South, Kitchener, ON, Canada, N2G 1C5.
authors.forename: Katelyn
authors.initials: K
authors.lastname: Cousteils
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Kacey J
authors.initials: KJ
authors.lastname: Prentice
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bombardier
authors.affiliation: School of Pharmacy, University of Waterloo, Health Science Campus building A, room 4008, 10A Victoria Street South, Kitchener, ON, Canada, N2G 1C5.
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada.
authors.forename: A Russell
authors.initials: AR
authors.lastname: Tupling
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
authors.affiliation: School of Pharmacy, University of Waterloo, Health Science Campus building A, room 4008, 10A Victoria Street South, Kitchener, ON, Canada, N2G 1C5. j3joseph@uwaterloo.ca.
authors.forename: Jamie W
authors.initials: JW
authors.lastname: Joseph
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000172:deficiency / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000235:genetics*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption; D011659:Pulmonary Gas Exchange
chemical_list: C497397:Arnt protein, mouse; D007328:Insulin; D019382:Human Growth Hormone; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D009249:NADP; D005947:Glucose
keywords: ARNT/HIF1β; Insulin release; Metabolism; Pancreatic beta cell