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K_IR6.2 Polymorphism Predisposes to Type 2 Diabetes by Inducing Overactivity of Pancreatic ß-Cell ATP-Sensitive K⁺ Channels

From the Institute of Pharmacology and Toxicology, University of Braunschweig, Braunschweig, Germany.

E23K, a common single nucleotide polymorphism in K_IR6.2, the pore-forming subunit of pancreatic ß-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_IR6.2 in one allele and K in the other) and homozygous (K/K; with K in position 23 of K_IR6.2 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.

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