title: Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes.
abstract: OBJECTIVE
  The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the K(ATP) channel subunits, Kir6.2 and SUR1, in human L- and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu23Lys, exerts a functional impact on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes.
  
  
  METHODS
  Western blot and immunohistochemical analyses were performed for expression and co-localisation studies. Meal-stimulated C-peptide test was carried out in 257 children at 1, 6 and 12 months after diagnosis. Genotyping for the Glu23Lys variant was by PCR-restriction fragment length polymorphism.
  
  
  RESULTS
  Kir6.2 and SUR1 co-localise with GLP-1 in L-cells and with GIP in K-cells in human ileum tissue. Children with type 1 diabetes carrying the hyperactive Glu23Lys variant had higher HbA1C at diagnosis (coefficient = 0.61%, P = 0.02) and 1 month after initial insulin therapy (coefficient = 0.30%, P = 0.05), but later disappeared. However, when adjusting HbA1C for the given dose of exogenous insulin, the dose-adjusted HbA1C remained higher throughout the 12 month study period (coefficient = 0.42%, P = 0.03).
  
  
  CONCLUSIONS
  Kir6.2 and SUR1 co-localise in the gastrointestinal endocrine L- and K-cells. The hyperactive Glu23Lys variant of the K(ATP) channel subunit Kir6.2 may cause defective glucose sensing in several tissues and impaired glycaemic control in children with type 1 diabetes.
authors.affiliation: Department of Paediatrics, Glostrup University Hospital, Ndr. Ringvej 57, DK-2600 Glostrup, Denmark. lotbrn01@glo.regionh.dk
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Nielsen
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Ploug
authors.forename: Peter
authors.initials: P
authors.lastname: Swift
authors.forename: Cathrine
authors.initials: C
authors.lastname: Ørskov
authors.forename: Inger
authors.initials: I
authors.lastname: Jansen-Olesen
authors.forename: Francesco
authors.initials: F
authors.lastname: Chiarelli
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Philip
authors.initials: P
authors.lastname: Hougaard
authors.forename: Sven
authors.initials: S
authors.lastname: Pörksen
authors.forename: Reinhard
authors.initials: R
authors.lastname: Holl
authors.forename: Carine
authors.initials: C
authors.lastname: de Beaufort
authors.forename: Steen
authors.initials: S
authors.lastname: Gammeltoft
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Henrik B
authors.initials: HB
authors.lastname: Mortensen
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000293:Adolescent; D015153:Blotting, Western; D002096:C-Peptide / Q000378:metabolism; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D004435:Eating / Q000502:physiology; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D005838:Genotype; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007082:Ileum / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D012150:Polymorphism, Restriction Fragment Length; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D002096:C-Peptide; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human