title: Partial blockade of Kv2.1 channel potentiates GLP-1's insulinotropic effects in islets and reduces its dose required for improving glucose tolerance in type 2 diabetic male mice.
abstract: Glucagon-like peptide-1 (GLP-1)-based medicines have recently been widely used to treat type 2 diabetic patients, whereas adverse effects of nausea and vomiting have been documented. Inhibition of voltage-gated K(+) channel subtype Kv2.1 in pancreatic β-cells has been suggested to contribute to mild depolarization and promotion of insulin release. This study aimed to determine whether the blockade of Kv2.1 channels potentiates the insulinotropic effect of GLP-1 agonists. Kv2.1 channel blocker guangxitoxin-1E (GxTx) and GLP-1 agonist exendin-4 at subthreshold concentrations, when combined, markedly increased the insulin release and cytosolic Ca(2+) concentration ([Ca(2+)]i) in a glucose-dependent manner in mouse islets and β-cells. Exendin-4 at subthreshold concentration alone increased islet insulin release and β-cell [Ca(2+)]i in Kv2.1(+/-) mice. The [Ca(2+)]i response to subthreshold exendin-4 and GxTx in combination was attenuated by pretreatment with protein kinase A inhibitor H-89, indicating the protein kinase A dependency of the cooperative effect. Furthermore, subthreshold doses of GxTx and GLP-1 agonist liraglutide in combination markedly increased plasma insulin and improved glucose tolerance in diabetic db/db mice and NSY mice. These results demonstrate that a modest suppression of Kv2.1 channels dramatically raises insulinotropic potency of GLP-1-based drugs, which opens a new avenue to reduce their doses and associated adverse effects while achieving the same glycemic control in type 2 diabetes.
authors.affiliation: Division of Integrative Physiology (R.S.R., K.D., T.K., T.Y.), Department of Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498, Japan; Department of Internal Medicine (M.K.), Saitama Medical Center, Jichi Medical University School of Medicine, Saitama 337-8503, Japan; and Department of Development Physiology (T.Y.), Division of Adaptation Development, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan.
authors.forename: Rauza
authors.initials: R
authors.lastname: Sukma Rita
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kurashina
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000818:Animals; D060829:Arthropod Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
chemical_list: D060829:Arthropod Proteins; C550903:GxTX-1E, Plesiophrictus guangxiensis; D007328:Insulin; C496990:Kcnb1 protein, mouse; D010455:Peptides; D051669:Shab Potassium Channels; D013111:Spider Venoms; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide