Pharmacogenomic analysis of ATP-sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A

Pharmacogenet Genomics. 2012 Mar;22(3):206-14. doi: 10.1097/FPC.0b013e32835001e7.


Objectives: The common ATP-sensitive potassium (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes, respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure-activity relationships in KATP channels containing either the E23/S1369 nonrisk or K23/A1369 risk haplotypes.

Research design and methods: The patch-clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23/S1369 or the K23/A1369 haplotype.

Results: KATP channels containing the K23/A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide, chlorpropamide, and glimepiride (IC50 values for K23/A1369 vs. E23/S1369=1.15 vs. 0.71 μmol/l; 4.19 vs. 3.04 μmol/l; 4.38 vs. 2.41 nmol/l, respectively). In contrast, KATP channels containing the K23/A1369 haplotype were significantly more sensitive to inhibition by mitiglinide (IC50=9.73 vs. 28.19 nmol/l for K23/A1369 vs. E23/S1369) and gliclazide. Nateglinide, glipizide, and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype.

Conclusion: Our results demonstrate that the ring-fused pyrrole moiety in several A-site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the K23/A1369 risk haplotype. It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / genetics*
  • Chlorpropamide / administration & dosage
  • Chlorpropamide / pharmacokinetics*
  • Cyclohexanes / administration & dosage
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Gene Expression Regulation / drug effects*
  • Gliclazide / administration & dosage
  • Glyburide / administration & dosage
  • Haplotypes
  • Homozygote
  • Humans
  • Isoindoles / administration & dosage
  • Nateglinide
  • Patch-Clamp Techniques
  • Phenylalanine / administration & dosage
  • Phenylalanine / analogs & derivatives
  • Polymorphism, Single Nucleotide
  • Potassium Channels, Inwardly Rectifying / antagonists & inhibitors
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Receptors, Drug / antagonists & inhibitors
  • Receptors, Drug / genetics*
  • Structure-Activity Relationship
  • Sulfonylurea Compounds / administration & dosage
  • Sulfonylurea Receptors
  • Tolbutamide / administration & dosage
  • Tolbutamide / pharmacokinetics*


  • ATP-Binding Cassette Transporters
  • Cyclohexanes
  • Isoindoles
  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Compounds
  • Sulfonylurea Receptors
  • Nateglinide
  • Phenylalanine
  • glimepiride
  • Tolbutamide
  • mitiglinide
  • Gliclazide
  • Glyburide
  • Chlorpropamide