Publication
Title
In vitro recovery of ATP-sensitive potassium channels in -cells from patients with congenital hyperinsulinism of infancy
Author
Abstract
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.
Language
English
Source (journal)
Diabetes / American Diabetes Association. - New York, N.Y., - 2006
Publication
New York, N.Y. : 2011
ISSN
0012-1797
Volume/pages
60:4(2011), p. 1223-1228
ISI
000289496100017
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 26.05.2011
Last edited 21.09.2017
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