| First Author | Vierra NC | Year | 2015 |
| Journal | Diabetes | Volume | 64 |
| Issue | 11 | Pages | 3818-28 |
| PubMed ID | 26239056 | Mgi Jnum | J:252881 |
| Mgi Id | MGI:5924395 | Doi | 10.2337/db15-0280 |
| Citation | Vierra NC, et al. (2015) Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates beta-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis. Diabetes 64(11):3818-28 |
| abstractText | Two-pore domain K+ (K2P) channels play an important role in tuning beta-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 beta-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 beta-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. |
