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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

Department of Paediatrics, Glostrup University Hospital, Ndr. Ringvej 57, DK-2600 Glostrup, Denmark, ¹ Department of Neurology, Glostrup University Hospital, Glostrup, Denmark, ² Leicester Royal Infirmary Children’s Hospital, Leicester, UK, ³ Department of Medical Anatomy, The Panum Institute, Copenhagen, Denmark, ⁴ Paediatric University Clinic, Chieti, Italy, ⁵ Department of Medical Physiology, The Panum Institute, Copenhagen, Denmark, ⁶ Department of Statistics, University of Southern Denmark, Odense, Denmark, ⁷ The University of Ulm, Ulm, Germany, ⁸ Paediatric Clinic, Luxemburg, Luxemburg, ⁹ Department of Clinical Biochemistry, Glostrup University Hospital, Glostrup, Denmark, ¹⁰ OCDEM, University of Oxford, Oxford OX3 7LJ, UK and ¹¹ Development projects, Novo Nordisk A/S, Bagsværd, Denmark

(Correspondence should be addressed to L B Nielsen; Email: lotbrn01{at}glo.regionh.dk)

Objective: The ATP-dependent K⁺-channel (K_ATP) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine - and ß-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 HbA_1C at bdiagnosis (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 HbA_1C for the given dose of exogenous insulin, the dose-adjusted HbA_1C 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.

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