title: Role of the transcription factor sox4 in insulin secretion and impaired glucose tolerance.
abstract: OBJECTIVE
  To identify, map, clone, and functionally validate a novel mouse model for impaired glucose tolerance and insulin secretion.
  
  
  METHODS
  Haploinsufficiency of the insulin receptor and associated mild insulin resistance has been used to sensitize an N-ethyl-N-nitrosourea (ENU) screen to identify novel mutations resulting in impaired glucose tolerance and diabetes. The new impaired glucose tolerance 4 (IGT4) model was selected using an intraperitoneal glucose tolerance test and inheritance of the phenotype confirmed by generation of backcross progeny. Segregation of the phenotype was correlated with genotype information to map the location of the gene and candidates sequenced for mutations. The function of the SRY-related high mobility group (HMG)-box 4 (Sox4) gene in insulin secretion was tested using another ENU allele and by small interfering RNA silencing in insulinoma cells.
  
  
  RESULTS
  We describe two allelic autosomal dominant mutations in the highly conserved HMG box of the transcription factor Sox4. Previously associated with pancreas development, Sox4 mutations in the adult mouse result in an insulin secretory defect, which exhibits impaired glucose tolerance in association with insulin receptor(+/-)-induced insulin resistance. Elimination of the Sox4 transcript in INS1 and Min6 cells resulted in the abolition of glucose-stimulated insulin release similar to that observed for silencing of the key metabolic enzyme glucokinase. Intracellular calcium measurements in treated cells indicate that this defect lies downstream of the ATP-sensitive K(+) channel (K(ATP) channel) and calcium influx.
  
  
  CONCLUSIONS
  IGT4 represents a novel digenic model of insulin resistance coupled with an insulin secretory defect. The Sox4 gene has a role in insulin secretion in the adult beta-cell downstream of the K(ATP) channel.
authors.affiliation: Medical Research Council, Mammalian Genetics Unit, Harwell, Oxfordshire, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Goldsworthy
authors.forename: Alison
authors.initials: A
authors.lastname: Hugill
authors.forename: Helen
authors.initials: H
authors.lastname: Freeman
authors.forename: Emma
authors.initials: E
authors.lastname: Horner
authors.forename: Kenju
authors.initials: K
authors.lastname: Shimomura
authors.forename: Debora
authors.initials: D
authors.lastname: Bogani
authors.forename: Guido
authors.initials: G
authors.lastname: Pieles
authors.forename: Vesna
authors.initials: V
authors.lastname: Mijat
authors.forename: Ruth
authors.initials: R
authors.lastname: Arkell
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cox
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005816:Genetic Complementation Test; D005838:Genotype; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D006609:High Mobility Group Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055751:SOXC Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
chemical_list: D006609:High Mobility Group Proteins; D007328:Insulin; D034741:RNA, Small Interfering; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse; D015534:Trans-Activators; D011972:Receptor, Insulin; D005947:Glucose; D002118:Calcium