Referenced in: none

Automatically associated channels: TALK1

Title: Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates β-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis.

Authors: Nicholas C Vierra, Prasanna K Dadi, Imju Jeong, Matthew Dickerson, David R Powell, David A Jacobson

Journal, date & volume: Diabetes, 2015 Nov , 64, 3818-28

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26239056

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.