title: A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults.
abstract: OBJECTIVE
  ATP-sensitive K(+) channels (K(ATP) channels) link glucose metabolism to the electrical activity of the pancreatic beta-cell to regulate insulin secretion. Mutations in either the Kir6.2 or sulfonylurea receptor (SUR) 1 subunit of the channel have previously been shown to cause neonatal diabetes. We describe here an activating mutation in the ABCC8 gene, encoding SUR1, that is associated with the development of type 2 diabetes only in adults.
  
  
  METHODS
  Recombinant K(ATP) channel subunits were expressed using pIRES2-based vectors in human embryonic kidney (HEK) 293 or INS1(832/13) cells and the subcellular distribution of c-myc-tagged SUR1 channels analyzed by confocal microscopy. K(ATP) channel activity was measured in inside-out patches and plasma membrane potential in perforated whole-cell patches. Cytoplasmic [Ca(2+)] was imaged using Fura-Red.
  
  
  RESULTS
  A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning alpha-helix, was observed in a patient diagnosed with hyperglycemia at age 39 years and in two adult offspring with impaired insulin secretion. Single K(ATP) channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP (IC(50) = 24 and 95 micromol/l for wild-type and mutant channels, respectively). Similar effects were observed in the absence of Mg(2+), suggesting an allosteric effect via associated Kir6.2 subunits. Overexpression of SUR1-Y356C in INS1(832/13) cells impaired glucose-induced cell depolarization and increased in intracellular free Ca(2+) concentration, albeit more weakly than neonatal diabetes-associated SUR1 mutants.
  
  
  CONCLUSIONS
  An ABCC8/SUR1 mutation with relatively minor effects on K(ATP) channel activity and beta-cell glucose sensing causes diabetes in adulthood. These data suggest a close correlation between altered SUR1 properties and clinical phenotype.
authors.affiliation: Section of Cell Biology, Division of Medicine, Imperial College London, London, UK.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Tarasov
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Nicolson
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Riveline
authors.forename: Tarvinder K
authors.initials: TK
authors.lastname: Taneja
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Baldwin
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Baldwin
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D003593:Cytoplasm / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D004594:Electrophysiology; D005091:Exons; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000502:physiology*; D054086:KATP Channels / Q000502:physiology*; D007668:Kidney / Q000196:embryology; D008564:Membrane Potentials; D009154:Mutation; D018408:Patch-Clamp Techniques; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D002118:Calcium