4.7 Article

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

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DIABETES
卷 64, 期 11, 页码 3818-3828

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AMER DIABETES ASSOC
DOI: 10.2337/db15-0280

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资金

  1. National Institutes of Health (NIH) [DK-20593]
  2. Vanderbilt Molecular Endocrinology Training Program [5T32-DK-07563]
  3. NIH [DK-20593, DK-059637, DK-081666, DK-097392]
  4. Pilot and Feasibility grant through the Vanderbilt University Diabetes Research Training Center [P60-DK-20593]

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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.

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