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


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.


CONCLUSIONS
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.
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
Veronica Y
VY
Lang
Mohammad
M
Fatehi
Peter E
PE
Light
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics*; D002747:Chlorpropamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003510:Cyclohexanes / Q000008:administration & dosage; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005907:Gliclazide / Q000008:administration & dosage; D005905:Glyburide / Q000008:administration & dosage; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage; D000077715:Nateglinide; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000235:genetics*; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics*; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000008:administration & dosage; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D002747:Chlorpropamide; D003510:Cyclohexanes; D005907:Gliclazide; D005905:Glyburide; D054833:Isoindoles; D000077715:Nateglinide; D010649:Phenylalanine; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D000099161:Kcnj11 Channel; C057619:glimepiride; C087255:mitiglinide