Abstract

Objectives. In the pancreatic β-cell, ATP-sensitive potassium (K_ATP) channels couple metabolism to excitability and consist of Kir6.2 and SUR1 subunits encoded by KCNJ11 and ABCC8 respectively. Sulfonylureas, which inhibit the K_ATP channel, are used to treat type 2 diabetes. Rare activating mutations cause neonatal diabetes, while the common variants, E23K in KCNJ11 and S1369A in ABCC8, are in strong linkage disequilibrium constituting a haplotype which predisposes to type 2 diabetes. To date it has not been possible to establish which represents the etiological variant and functional studies are inconsistent. Furthermore, there have been no studies of the S1369A variant or their combined effect on K_ATP channel function.

Research Design and Methods. The patch-clamp technique was used to study the nucleotide-sensitivity and sulfonylurea inhibition of recombinant human K_ATP channels containing either the K23/A1369 or E23/S1369 variants.

Results. ATP-sensitivity of the K_ATP channel was decreased in the K23/A1369 variant (IC₅₀=8.0 μmol/l vs 2.5 μmol/l for E23/S1369), although there was no difference in ADP-sensitivity. The K23/A1369 variant also displayed increased inhibition by gliclazide, an A-site sulfonylurea drug (IC₅₀=52.7 nmol/l vs 188.7 nmol/l for E23/S1369), but not with glibenclamide (AB-site) or repaglinide (B-site).

Conclusions. Our findings indicate that the common K23/A1369 variant K_ATP channel displays decreased ATP-inhibition that may contribute to the observed increased risk for type 2 diabetes. Moreover, the increased sensitivity of the K23/A1369 variant to the A-site sulfonylurea drug gliclazide may provide a pharmacogenomic therapeutic approach for patients with type 2 diabetes who are homozygous for both risk alleles.