title: A mutation in KCNJ11 causing human hyperinsulinism (Y12X) results in a glucose-intolerant phenotype in the mouse.
abstract: OBJECTIVE
  We identified a mouse with a point mutation (Y12STOP) in the Kcnj11 subunit of the K(ATP) channel. This point mutation is identical to that found in a patient with congenital hyperinsulinism of infancy (HI). We aimed to characterise the phenotype arising from this loss-of-function mutation and to compare it with that of other mouse models and patients with HI.
  
  
  METHODS
  We phenotyped an N-ethyl-N-nitrosourea-induced mutation on a C3H/HeH background (Kcnj11 ( Y12STOP )) using intraperitoneal glucose tolerance testing to measure glucose and insulin plasma concentrations. Insulin secretion and response to incretins were measured on isolated islets.
  
  
  RESULTS
  Homozygous male and female adult Kcnj11 ( Y12STOP ) mice exhibited impaired glucose tolerance and a defect in insulin secretion as measured in vivo and in vitro. Islets had an impaired incretin response and reduced insulin content.
  
  
  CONCLUSIONS
  The phenotype of homozygous Kcnj11 ( Y12STOP ) mice is consistent with that of other Kcnj11-knockout mouse models. In contrast to the patient carrying this mutation homozygously, the mice studied did not have hyperinsulinaemia or hypoglycaemia. It has been reported that HI patients may develop diabetes and our mouse model may reflect this clinical feature. The Kcnj11 ( Y12STOP ) model may thus be useful in further studies of K(ATP) channel function in various cell types and in investigation of the development of hyperglycaemia in HI patients.
authors.affiliation: Metabolism and Inflammation, MRC Harwell Mammalian Genetics Unit, Harwell Science and Innovation Campus, Harwell, OX11 0RD, UK.
authors.forename: A
authors.initials: A
authors.lastname: Hugill
authors.forename: K
authors.initials: K
authors.lastname: Shimomura
authors.forename: F M
authors.initials: FM
authors.lastname: Ashcroft
authors.forename: R D
authors.initials: RD
authors.lastname: Cox
mesh_terms: D000818:Animals; D005260:Female; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics*; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099161:Kcnj11 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel