KIR6.2 Polymorphism Predisposes to Type 2 Diabetes by Inducing Overactivity of Pancreatic β-Cell ATP-Sensitive K+ Channels
- From the Institute of Pharmacology and Toxicology, University of Braunschweig, Braunschweig, Germany.
Abstract
E23K, a common single nucleotide polymorphism in KIR6.2, the pore-forming subunit of pancreatic β-cell ATP-sensitive K+ channels, significantly enhanced open probability of these channels, thus reducing their sensitivity toward inhibitory ATP4− and increasing the threshold concentration for insulin release. Previous association studies and high allelic frequency suggest this effect to critically inhibit secretion and play a major role in pathogenesis of common type 2 diabetes. Based on evidence for functional relevance of E23K in both the heterozygous (E/K; with E in position 23 of KIR6.2 in one allele and K in the other) and homozygous (K/K; with K in position 23 of KIR6.2 in both alleles) genotype, we propose a model in which enhanced susceptibility to type 2 diabetes is associated with evolutionary advantage of the E/K state.
Footnotes
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Address correspondence and reprint requests to Dr. M. Schwanstecher, Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany. E-mail: m.schwanstecher{at}tu-bs.de.
Received for publication 18 December 2000 and accepted in revised form 29 November 2001.
DMEM-HG, Dulbecco’s modified Eagle’s medium–high glucose; ICR2, ATP concentration that suppresses spontaneous open probability to the threshold for insulin secretion (0.02); ΔImax, maximal increment of the spontaneous patch current; KATP, ATP-sensitive K+ channel; KIR6.2E23K, mutant isoform of KIR6.2, with K instead of E in position 23; KIR6.2wt, wild-type isoform of KIR6.2; PO, spontaneous open probability; SNP, single nucleotide polymorphism; SUR1, regulatory sulfonylurea receptor subunit-1.
- DIABETES
