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

ABSTRACT: Two-pore domain K+ (K2P) channels play an important role in tuning ?-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 ?-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 ?-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.

SUBMITTER: Vierra NC 

PROVIDER: S-EPMC4613978 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature