- Vierra NC, Dadi PK, Jeong I, Dickerson M, Powell DR, Jacobson DA. The type-2 diabetes-associated K+ channel TALK-1 modulates beta-cell electrical excitability, 2nd-phase insulin secretion, and glucose homeostasis. Diabetes. 2015 Aug 3. PMID: 26239056 [PubMed].
Two-pore domain K(+) (K2P) channels play an important role tuning β-cell glucose-stimulated insulin secretion (GSIS). The K2P channel 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 (Ct) of human TALK-1, increases channel activity. Genetic ablation of TALK-1 results in β-cell membrane potential (Vm) depolarization, increased islet Ca(2+) influx, and enhanced 2(nd) 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 2(nd) phase insulin secretion, and suggest a clinically relevant mechanism for rs1535500, which may increase type-2 diabetes risk by limiting GSIS.