title: Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates β-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis.
abstract: Two-pore domain K+ (K2P) channels play an important role in tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel TWIK-related alkaline pH-activated K2P (TALK)-1 is linked to type 2 diabetes risk through a coding sequence polymorphism (rs1535500); however, its physiological function has remained elusive. Here, we show that TALK-1 channels are expressed in mouse and human β-cells, where they serve as key regulators of electrical excitability and GSIS. We find that the rs1535500 polymorphism, which results in an alanine-to-glutamate substitution in the C-terminus of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in β-cell membrane potential depolarization, increased islet Ca2+ influx, and enhanced second-phase GSIS. Moreover, mice lacking TALK-1 channels are resistant to high-fat diet-induced elevations in fasting glycemia. These findings reveal TALK-1 channels as important modulators of second-phase insulin secretion and suggest a clinically relevant mechanism for rs1535500, which may increase type 2 diabetes risk by limiting GSIS.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Vierra
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Dadi
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Imju
authors.initials: I
authors.lastname: Jeong
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dickerson
authors.affiliation: Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN david.a.jacobson@vanderbilt.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C477398:KCNK16 protein, human; D024683:Potassium Channels, Tandem Pore Domain