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CLINICAL STUDY |
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 (KATP) 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 KATP 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 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 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 KATP channel subunit Kir6.2 may cause defective glucose sensing in several tissues and impaired glycaemic control in children with type 1 diabetes.
This article has been cited by other articles:
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  G. Tolhurst, F. Reimann, and F. M. Gribble Nutritional regulation of glucagon-like peptide-1 secretion J. Physiol., January 1, 2009; 587(1): 27 - 32. [Abstract] [Full Text] [PDF]
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 X. Fan, Y. Ding, H. Cheng, D. X. Gram, R. S. Sherwin, and R. J. McCrimmon Amplified Hormonal Counterregulatory Responses to Hypoglycemia in Rats After Systemic Delivery of a SUR-1-Selective K+ Channel Opener? Diabetes, December 1, 2008; 57(12): 3327 - 3334. [Abstract] [Full Text] [PDF]
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