K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels.
E23K, a common single nucleotide polymorphism in K(IR)6.2, the pore-forming subunit of pancreatic beta-cell ATP-sensitive K(+) channels, significantly enhanced open probability of these channels, thus reducing their sensitivity toward inhibitory ATP(4-) 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 K(IR)6.2 in one allele and K in the other) and homozygous (K/K; with K in position 23 of K(IR)6.2 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.
Schwanstecher
Christina
C
Institute of Pharmacology and Toxicology, University of Braunschweig, Braunschweig, Germany.
Meyer
Ulrike
U
Schwanstecher
Mathias
M
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000483:Alleles; D000818:Animals; D019556:COS Cells; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007515:Islets of Langerhans / Q000503:physiopathology*; D051379:Mice; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D014162:Transfection
D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000255:Adenosine Triphosphate