Pharmacogenomics of Sulfonylureas and Glinides on ATP-Sensitive Potassium Channel

• Author / Creator

  Lang, Yiqiao Veronica

• 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.

• Subjects / Keywords

  • ATP-Sensitive Potassium Channel
  • Pharmacogenomics
  • Type 2 Diabetes
  • Sulfonylureas and Glinides

• Graduation date

  Spring 2012

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3B92T

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.