A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K + channel activity and β-cell glucose sensing is associated with type 2 diabetes in adults

Andrei I. Tarasov, Tamara J. Nicolson, Jean Pierre Riveline, Tarvinder K. Taneja, Stephen A. Baldwin, Jocelyn M. Baldwin, Guillaume Charpentier, Jean Francois Gautier, Philippe Froguel, Martine Vaxillaire, Guy A. Rutter

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

Abstract

OBJECTIVE-ATP-sensitive K+ channels (KATP channels) link glucose metabolism to the electrical activity of the pancreatic β-cell to regulate insulin secretion. Mutations in either the Kir6.2 or sulfonylurea receptor (SUR) 1 subunit of the channel have previously been shown to cause neonatal diabetes. We describe here an activating mutation in the ABCC8 gene, encoding SUR1, that is associated with the development of type 2 diabetes only in adults. RESEARCH DESIGN AND METHODS-Recombinant KATP channel subunits were expressed using pIRES2-based vectors in human embryonic kidney (HEK) 293 or INS1(832/13) cells and the subcellular distribution of c-myc-tagged SUR1 channels analyzed by confocal microscopy. KATP channel activity was measured in inside-out patches and plasma membrane potential in perforated whole-cell patches. Cytoplasmic [Ca2+] was imaged using Fura-Red. RESULTS-A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning α-helix, was observed in a patient diagnosed with hyperglycemia at age 39 years and in two adult offspring with impaired insulin secretion. Single KATP channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP (IC50 = 24 and 95 μmol/l for wild-type and mutant channels, respectively). Similar effects were observed in the absence of Mg2+, suggesting an allosteric effect via associated Kir6.2 subunits. Overexpression of SUR1-Y356C in INS1(832/13) cells impaired glucose-induced cell depolarization and increased in intracellular free Ca2+ concentration, albeit more weakly than neonatal diabetes-associated SUR1 mutants. CONCLUSIONS-An ABCC8/SUR1 mutation with relatively minor effects on KATP channel activity and β-cell glucose sensing causes diabetes in adulthood. These data suggest a close correlation between altered SUR1 properties and clinical phenotype.

Original languageEnglish
Pages (from-to)1595-1604
Number of pages10
JournalDiabetes
Volume57
Issue number6
DOIs
Publication statusPublished (in print/issue) - 1 Jun 2008

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