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Cited by 71Pancreatic function and diabetesIon channel regulation and functionIon Transport and Channel Regulation

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

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Vierra, Nicholas C., Dadi, Prasanna K., Jeong, Imju, Dickerson, Matthew, Powell, David R., Jacobson, David A.·2015·Diabetes
DOI 10.2337/db15-0280PMC PMC4613978
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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.

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  • The enhanced GIIS in Kcnk16/TALK1-deficient mice correlates with a moderate improvement of glucose tolerance in vivo.

    “This correlates with a moderate improvement of glucose tolerance in vivo (708).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [708]

    The Results section (‘TALK-1 Channels Are Critical for Maintaining Fasting Glycemia’; page not provided) explicitly reports no altered glucose tolerance in chow-fed TALK-1 knockout mice. Although the paper reports increased glucose-stimulated insulin secretion in isolated knockout islets and lower fasting glucose after a high-fat diet, it does not report the claimed improvement in glucose tolerance in vivo. (LLM, conf=0.87)

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  • Kcnk16 (TALK1) gives rise to an outwardly rectifying current that becomes detectable at voltages above -45 mV.

    “Kcnk16 (TALK1) gives rise to an outwardly rectifying current that becomes detectable at voltages above -45 mV (708).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [708]

    The Introduction (page unavailable) describes TALK-1 channels as producing outwardly rectifying K+ currents, and the Results section on functional expression (page unavailable) reports such a current in mouse β-cells that is reduced in TALK-1 knockouts. Neither passage establishes that the current becomes detectable specifically above −45 mV. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • GIIS is enhanced in Kcnk16/TALK1-deficient mice, especially at glucose concentrations that are just above the threshold for stimulation of insulin release.

    “GIIS is enhanced, especially at glucose concentrations that are just above the threshold for stimulation of insulin release.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [708]

    The Results (TALK-1 Regulates β-Cell Electrical Excitability and Ca2+ Entry; page not provided) report increased insulin secretion from TALK-1-deficient islets at 7 and 14 mmol/L glucose, and increased second-phase secretion at 11 mmol/L. The Discussion calls 7 mmol/L a basal glucose level in mice, but the paper does not identify it as just above the threshold for insulin release or establish that the enhancement is especially pronounced there. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In Kcnk16/TALK1-deficient mice, action potential frequency is unaffected, but the average interburst duration is reduced by 60%.

    “Action potential frequency is unaffected, but the average interburst duration is reduced by 60%.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [708]

    The Results section ('TALK-1 Regulates β-Cell Electrical Excitability and Ca2+ Entry'; page not provided) reports that the interburst interval fell from 144.4 s in wild-type islets to 51.4 s in TALK-1 knockout islets, approximately a 64% reduction. It does not report that action-potential firing frequency was unaffected; its Discussion instead describes increased Ca2+ oscillation frequency, which is a different measure. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Despite the high expression of TALK1, the TALK1-dependent current is small and limited to about 1 pA/pF at 0 mV.

    “Despite the high expression, the TALK1-dependent current is small and limited to ~1 pA/pF at 0 mV.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [708]

    The Introduction describes KCNK16 as the most abundant K⁺-channel transcript in mouse and human β-cells, and the Results report TALK-1-dependent currents. Figure 1C quantifies current density at 0 mV, but the text of our copy does not give a value of approximately 1 pA/pF there or characterize that current as small. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Authors
Vierra, N. C., Dadi, P. K., Jeong, I., Dickerson, M., Powell, D. R., & Jacobson, D. A.
Affiliations
  • Vanderbilt University (US)
  • Lexicon Pharmaceuticals (United States) (US)
Corresponding author
Jacobson, David A.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2015-08-03
Volume
64
Issue
11
Pages
3818-3828
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db15-0280
PMC
PMC4613978
OpenAlex
W1988278839
Cited by
71
References
4
Citations by year
2026: 5 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 13 · 2020: 8 · 2019: 8 · 2018: 4 · 2017: 9 · 2016: 3
FWCI
5.38
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/site/license (vor, 272 d)
Locations
  • Diabetes (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (DK-20593, DK-07563, DK-059637, DK-081666, DK-097392)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
type 2 diabetes, pancreatic beta cells, glucose-stimulated insulin secretion, second-phase insulin secretion, high-fat diet, glucose homeostasis, fasting blood glucose
MeSH terms
Insulin Secretion, Animals, Blood Glucose, Diabetes Mellitus, Type 2, Homeostasis, Humans, Insulin, Male, Membrane Potentials, Potassium Channels, Tandem Pore Domain, Insulin-Secreting Cells, Mice

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