In Vitro Recovery of ATP-Sensitive Potassium Channels in β-Cells From Patients With Congenital Hyperinsulinism of Infancy

  1. Karen E. Cosgrove1
  1. 1Faculty of Life Sciences, University of Manchester, Manchester, U.K.
  2. 2Department of Genetics, Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie, Paris, France
  3. 3Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, U.K.
  4. 4Department of Pediatrics, Antwerp University Hospital, Universiteitsplein 1, Wilrijk, Antwerp, Belgium
  5. 5Institute of Child Health, Great Ormond Street Hospital, London, U.K.
  6. 6Department of Endocrinology, Royal Manchester Children's Hospital, Manchester, U.K.
  7. 7Hôpital Necker Enfants Malades, Reference Centre of Metabolic Diseases, Faculté de Médecine, Paris, France
  1. Corresponding author: Karen E. Cosgrove, karen.e.cosgrove{at}


OBJECTIVE Congenital hyperinsulinism in infancy (CHI) is characterized by unregulated insulin secretion from pancreatic β-cells; severe forms are associated with defects in ABCC8 and KCNJ11 genes encoding sulfonylurea receptor 1 (SUR1) and Kir6.2 subunits, which form ATP-sensitive K+ (KATP) channels in β-cells. Diazoxide therapy often fails in the treatment of CHI and may be a result of reduced cell surface expression of KATP channels. We hypothesized that conditions known to facilitate trafficking of cystic fibrosis transmembrane regulator (CFTR) and other proteins in recombinant expression systems might increase surface expression of KATP channels in native CHI β-cells.

RESEARCH DESIGN AND METHODS Tissue was isolated during pancreatectomy from eight patients with CHI and from adult cadaver organ donors. Patients were screened for mutations in ABCC8 and KCNJ11. Isolated β-cells were maintained at 37°C or 25°C and in the presence of 1) phorbol myristic acid, forskolin and 3-isobutyl-1-methylxanthine, 2) BPDZ 154, or 3) 4-phenylbutyrate. Surface expression of functional channels was assessed by patch-clamp electrophysiology.

RESULTS Mutations in ABCC8 were detected for all patients tested (n = 7/8) and included three novel mutations. In five of eight patients, no changes in KATP channel activity were observed under different cell culture conditions. However, in three patients, in vitro recovery of functional KATP channels occurred. Here, we report the first cases of recovery of defective KATP channels in human β-cells using modified cell culture conditions.

CONCLUSIONS Our study establishes the principle that chemical modification of KATP channel subunit trafficking could be of benefit for the future treatment of CHI.

  • Received October 12, 2010.
  • Accepted January 28, 2011.

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  1. Diabetes vol. 60 no. 4 1223-1228
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