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

作者：Andrei I. Tarasov, Tamara Nicolson, Jean-Pierre Riveline, Tarvinder K. Taneja, Stephen A. Baldwin, Jocelyn M. Baldwin, G. Charpentier, Jean–François Gautier, Philippe Froguel, Martine Vaxillaire, Guy A. Rutter · 发表于：Diabetes · 年份：2008 · DOI：10.2337/db07-1547 · 被引用次数：71 · 研究领域：Cardiac Ischemia and Reperfusion、Pancreatic function and diabetes、Mechanical Circulatory Support Devices

OBJECTIVE: ATP-sensitive K(+) channels (K(ATP) channels) link glucose metabolism to the electrical activity of the pancreatic beta-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 K(ATP) 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. K(ATP) channel activity was measured in inside-out patches and plasma membrane potential in perforated whole-cell patches. Cytoplasmic [Ca(2+)] was imaged using Fura-Red. RESULTS: A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning alpha-helix, was observed in a patient diagnosed with hyperglycemia at age 39 years and in two adult offspring with impaired insulin secretion. Single K(ATP) channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP (IC(50) = 24 and 95 micromol/l for wild-type and mutant channels, respectively). Similar effects were observed in the absence of Mg(2+), suggesting an allosteric effect via associated Kir6.2 subunits. Overexpression of SUR1-Y356C in INS1(832/13) cells impaired glucose-induced cell...