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Pharmacogenomics of Sulfonylureas and Glinides on ATP-Sensitive Potassium Channel Open Access


Other title
Type 2 Diabetes
ATP-Sensitive Potassium Channel
Sulfonylureas and Glinides
Type of item
Degree grantor
University of Alberta
Author or creator
Lang, Yiqiao Veronica
Supervisor and department
Light, Peter E. (Pharmacology)
Examining committee member and department
Tse, Amy (Pharmacology)
Chan, Cathy (Agricultural, Food & Nutritional Science)
Simpson, Scot (Pharmacy and Pharmaceutical Sciences)
Department of Pharmacology

Date accepted
Graduation date
Master of Science
Degree level
The common ATP-sensitive (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, I studied the pharmacogenomics of eight more clinically used sulfonylureas and glinides to determine their structure activity relationships in KATP channels containing either the E23/S1369 non-risk or K23/A1369 risk haplotypes by utilizing patch-clamp technique. The 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 therapies or design novel drugs that display increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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