title: Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice.
abstract: Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic β-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive β-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.
authors.affiliation: a Department of Physiology ; Medical College of Southeast University ; Nanjing , China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Liu
authors.forename: Fanfan
authors.initials: F
authors.lastname: Wang
authors.forename: Haiying
authors.initials: H
authors.lastname: Lu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.forename: Jihong
authors.initials: J
authors.lastname: Zou
mesh_terms: D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D007422:Intestines / Q000737:chemistry; D007515:Islets of Langerhans / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D051379:Mice; D010179:Pancreas / Q000737:chemistry; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D002839:Chromans; D007328:Insulin; D051657:KCNQ1 Potassium Channel; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D052216:Glucagon-Like Peptide 1; D005947:Glucose
keywords: AUC, Area under the curve; DMSO, Dimethyl sulfoxide; GLP-1; GLP-1, Glucagon-like peptide-1; GSIS; GSIS, Glucose-stimulated insulin secretion; GTT, Glucose tolerance test; GWAS, Genome wide association studies; IPGTT; ITT; ITT, Insulin tolerance test; IVGTT, Intravenous glucose tolerance tests; KCNQ1; KCNQ1, Potassium voltage-gated channel subfamily KQT member 1; KRBH, Krebs-Ringer bicarbonate HEPES buffer; OCT, Optimal Cutting Temperature Compound; OGTT; OGTT, Oral glucose tolerance tests; SNPs, Single nucleotide polymorphisms; T2D, Type 2 diabetes; chromanol 293B; islets of Langerhans