KIR6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic p-cell ATP-Sensitive K+ channels

E23K, a common single nucleotide polymorphism in K(IR)6.2, the pore-forming subunit of pancreatic P-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 allelle 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.