TY - JOUR

T1 - 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

AU - Nielsen, Lotte B

AU - Ploug, Kenneth B

AU - Swift, Peter

AU - Ørskov, Cathrine

AU - Jansen-Olesen, Inger

AU - Chiarelli, Francesco

AU - Holst, Jens Juul

AU - Hougaard, Philip

AU - Pörksen, Sven

AU - Holl, Reinhard

AU - de Beaufort, Carine

AU - Gammeltoft, Steen

AU - Rorsman, Patrik

AU - Mortensen, Henrik B

AU - Hansen, Lars

PY - 2007/6

Y1 - 2007/6

N2 - 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.DESIGN AND 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.

AB - 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.DESIGN AND 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.

KW - ATP-Binding Cassette Transporters

KW - Adolescent

KW - Blotting, Western

KW - C-Peptide

KW - Child

KW - Diabetes Mellitus, Type 1

KW - Eating

KW - Female

KW - Gastric Inhibitory Polypeptide

KW - Genotype

KW - Glucagon

KW - Glucagon-Like Peptide 1

KW - Hemoglobin A, Glycosylated

KW - Humans

KW - Hyperglycemia

KW - Hypoglycemic Agents

KW - Ileum

KW - Immunohistochemistry

KW - Insulin

KW - Islets of Langerhans

KW - Male

KW - Polymorphism, Restriction Fragment Length

KW - Potassium Channels

KW - Potassium Channels, Inwardly Rectifying

KW - Receptors, Drug

KW - Sulfonylurea Receptors

U2 - 10.1530/EJE-06-0756

DO - 10.1530/EJE-06-0756

M3 - Journal article

C2 - 17535866

VL - 156

SP - 663

EP - 671

JO - Acta Endocrinologica, Supplement

JF - Acta Endocrinologica, Supplement

SN - 0804-4635

IS - 6

ER -