Coexpression of the Type 2 Diabetes Susceptibility Gene Variants KCNJ11 E23K and ABCC8 S1369A Alter the ATP and Sulfonylurea Sensitivities of the ATP-Sensitive K+ Channel

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 10; pp. 2419 - 2424
• Main Authors: Hamming, Kevin S C, Soliman, Daniel, Matemisz, Laura C, Niazi, Omid, Lang, Yiqiao, Gloyn, Anna L, Light, Peter E
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-10-2009
• Subjects: Adenosine Triphosphate - pharmacology; Amino Acid Substitution; ATP-Binding Cassette Transporters - genetics; Cloning; Diabetes; Diabetes Mellitus, Type 2 - genetics; Genes; Genetic Predisposition to Disease - genetics; Genetic Variation; Homozygote; KATP Channels - drug effects; KATP Channels - genetics; KATP Channels - physiology; Mutation; Original; Polymorphism, Single Nucleotide; Potassium Channels, Inwardly Rectifying - genetics; Receptors, Drug - genetics; Research design; Sulfonylurea Compounds - pharmacology; Sulfonylurea Receptors
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-0143

Coexpression of the Type 2 Diabetes Susceptibility Gene Variants KCNJ11 E23K and ABCC8 S1369A Alter the ATP and Sulfonylurea Sensitivities of the ATP-Sensitive K + Channel
Kevin S.C. Hamming 1 ,
Daniel Soliman 1 ,
Laura C. Matemisz 1 ,
Omid Niazi 1 ,
Yiqiao Lang 1 ,
Anna L. Gloyn 2 and
Peter E. Light 1
1 Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada;
2 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
Corresponding author: Peter E. Light, peter.light{at}ualberta.ca .
K.S.C.H. and D.S. contributed equally to this study.
Abstract
OBJECTIVE In the pancreatic β-cell, ATP-sensitive K + (K ATP ) channels couple metabolism with 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, whereas the common variants,
E23K in KCNJ11 and S1369A in ABCC8 , are in strong linkage disequilibrium, constituting a haplotype that predisposes to type 2 diabetes. To date it has not been
possible to establish which of these represents the etiological variant, and functional studies are inconsistent. Furthermore,
there have been no studies of the S1369A variant or the combined effect of the two 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 (half-maximal inhibitory concentration [IC 50 ] = 8.0 vs. 2.5 μmol/l for the E23/S1369 variant), although there was no difference in ADP sensitivity. The K23/A1369 variant
also displayed increased inhibition by gliclazide, an A-site sulfonylurea drug (IC 50 = 52.7 vs. 188.7 nmol/l for the E23/S1369 variant), but not by 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.
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received January 30, 2009.
Accepted June 29, 2009.
© 2009 by the American Diabetes Association.