title: Beta-cell ARNT is required for normal glucose tolerance in murine pregnancy.
abstract: OBJECTIVE
  Insulin secretion increases in normal pregnancy to meet increasing demands. Inability to increase beta-cell function results in gestational diabetes mellitus (GDM). We have previously shown that the expression of the transcription factor ARNT (Aryl-hydrocarbon Receptor Nuclear Translocator) is reduced in the islets of humans with type 2 diabetes. Mice with a beta-cell specific deletion of ARNT (β-ARNT mice) have impaired glucose tolerance secondary to defective insulin secretion. We hypothesised that ARNT is required to increase beta-cell function during pregnancy, and that β-ARNT mice would be unable to compensate for the beta-cell stress of pregnancy. The aims of this study were to investigate the mechanisms of ARNT regulation of beta-cell function and glucose tolerance in pregnancy.
  
  
  METHODS
  β-ARNT females were mated with floxed control (FC) males and FC females with β-ARNT males.
  
  
  RESULTS
  During pregnancy, β-ARNT mice had a marked deterioration in glucose tolerance secondary to defective insulin secretion. There was impaired beta-cell proliferation in late pregnancy, associated with decreased protein and mRNA levels of the islet cell-cycle regulator cyclinD2. There was also reduced expression of Irs2 and G6PI. In contrast, in control mice, pregnancy was associated with a 2.1-fold increase in ARNT protein and a 1.6-fold increase in cyclinD2 protein, and with increased beta-cell proliferation.
  
  
  CONCLUSIONS
  Islet ARNT increases in normal murine pregnancy and beta-cell ARNT is required for cyclinD2 induction and increased beta-cell proliferation in pregnancy.
authors.affiliation: Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, Australia ; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Sue Mei
authors.initials: SM
authors.lastname: Lau
authors.forename: Kuan Minn
authors.initials: KM
authors.lastname: Cha
authors.forename: Ayesha
authors.initials: A
authors.lastname: Karunatillake
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Stokes
authors.forename: Kim
authors.initials: K
authors.lastname: Cheng
authors.forename: Mark
authors.initials: M
authors.lastname: McLean
authors.forename: N W
authors.initials: NW
authors.lastname: Cheung
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gunton
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D003433:Crosses, Genetic; D056742:Cyclin D2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy
chemical_list: C497397:Arnt protein, mouse; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D005956:Glucose-6-Phosphate Isomerase; D005947:Glucose