Abstract

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.

Links

Publisher Full Text

Authors

Lang VY, Fatehi M, Light PE

Institution

Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.

Source

Pharmacogenetics and genomics 22:3 2012 Mar pg 206-14

MeSH

ATP-Binding Cassette Transporters
Chlorpropamide
Cyclohexanes
Diabetes Mellitus, Type 2
Gene Expression Regulation
Gliclazide
Glyburide
Haplotypes
Homozygote
Humans
Isoindoles
Patch-Clamp Techniques
Phenylalanine
Polymorphism, Single Nucleotide
Potassium Channels, Inwardly Rectifying
Receptors, Drug
Structure-Activity Relationship
Sulfonylurea Compounds
Tolbutamide

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22209866