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Cited by 239Pancreatic function and diabetesNeuroscience and Neuropharmacology ResearchReceptor Mechanisms and Signaling

γ-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic β-Cells

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Braun, Matthias, Ramracheya, Reshma, Bengtsson, Martin, Clark, Anne, Walker, Jonathan N., Johnson, Paul R., Rorsman, Patrik·2010·Diabetes
DOI 10.2337/db09-0797PMC PMC2889769
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Abstract

OBJECTIVE: Paracrine signaling via γ-aminobutyric acid (GABA) and GABAA receptors (GABAARs) has been documented in rodent islets. Here we have studied the importance of GABAergic signaling in human pancreatic islets. RESEARCH DESIGN AND METHODS: Expression of GABAARs in islet cells was investigated by quantitative PCR, immunohistochemistry, and patch-clamp experiments. Hormone release was measured from intact islets. GABA release was monitored by whole-cell patch-clamp measurements after adenoviral expression of α1β1 GABAAR subunits. The subcellular localization of GABA was explored by electron microscopy. The effects of GABA on electrical activity were determined by perforated patch whole-cell recordings. RESULTS: PCR analysis detected relatively high levels of the mRNAs encoding GABAAR α2, β3, γ2, and π subunits in human islets. Patch-clamp experiments revealed expression of GABAAR Cl− channels in 52% of β-cells (current density 9 pA/pF), 91% of δ-cells (current density 148 pA/pF), and 6% of α-cells (current density 2 pA/pF). Expression of GABAAR subunits in islet cells was confirmed by immunohistochemistry. β-Cells secreted GABA both by glucose-dependent exocytosis of insulin-containing granules and by a glucose-independent mechanism. The GABAAR antagonist SR95531 inhibited insulin secretion elicited by 6 mmol/l glucose. Application of GABA depolarized β-cells and stimulated action potential firing in β-cells exposed to glucose. CONCLUSIONS: Signaling via GABA and GABAAR constitutes an autocrine positive feedback loop in human β-cells. The presence of GABAAR in non–β-cells suggests that GABA may also be involved in the regulation of somatostatin and glucagon secretion.

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  • In human islets, insulin secretion is triggered at glucose concentrations as low as 3 mM whereas 6 mM is required in mouse islets.

    “In human islets, insulin secretion is triggered at glucose concentrations as low as 3 mM whereas 6 mM is required in mouse islets (89).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [89]

    The Results section (“Effect of GABAAR blockade on insulin secretion”; page not available) reports that 3 mmol/l glucose stimulated insulin secretion in intact human islets compared with 1 mmol/l. Our copy does not establish that mouse islets require 6 mmol/l glucose to trigger insulin secretion, so the mouse comparison is unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The membrane potential during interspike intervals in human β-cells may be as negative as -60 mV at 6 mM glucose, but is between -50 and -40 mV at 10 mM glucose or above.

    “This may be seen from the fact that the membrane potential during the interspike intervals may be as negative as -60 mV at 6 mM glucose, (89), but is between -50 and -40 mV at 10 mM glucose or above (52) (Figure 6 and schematic in Figure 13C-D).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [89]

    The Results section reports that human β-cells at 6 mmol/l glucose had a membrane potential of −64 ± 7 mV before GABA application, supporting the approximate −60 mV value attributed to this source. However, the reported measurement was not identified as an interspike-interval potential; the paper describes the cell in Figure 7A as electrically inactive. The 10 mmol/l-or-above comparison is attached to a different citation in the citing sentence. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In human islets, insulin secretion is detectable at glucose concentrations as low as 3 mM, significantly lower than the secretion threshold in mouse islets (~5 mM).

    “In human islets, insulin secretion is detectable at glucose concentrations as low as 3 mM (89, 150, 266), which is significantly lower than the secretion threshold in mouse islets (~5 mM (257)).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [89]

  • Amino acids, neurotransmitters and hormones can stimulate electrical activity and insulin release in human β-cells only in the presence of a permissive concentration of glucose.

    “Amino acids (arginine and glycine)(744), neurotransmitters (like adenine nucleotides, GABA and acetylcholine) (89, 92, 347, 568) and hormones (618) can also stimulate electrical activity and insulin release but only in the presence of a ‘permissive’ concentration of glucose.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [89]

  • The Cl- equilibrium potential in β-cells is around -35 mV.

    “Because pancreatic β-cells have a high intracellular Cl- concentration (89), an increased Cl- conductance will depolarise the β-cells towards the Cl- equilibrium potential (ECl), which is around -35 mV (89).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [89]

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Authors
Braun, M., Ramracheya, R., Bengtsson, M., Clark, A., Walker, J. N., Johnson, P. R., & Rorsman, P.
Affiliations
  • Churchill Hospital (GB)
  • John Radcliffe Hospital (GB)
Corresponding author
Braun, Matthias
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2010-04-22
Volume
59
Issue
7
Pages
1694-1701
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db09-0797
PMC
PMC2889769
OpenAlex
W2147962660
Cited by
239
References
40
Citations by year
2026: 10 · 2025: 15 · 2024: 11 · 2023: 13 · 2022: 19 · 2021: 20 · 2020: 19 · 2019: 20 · 2018: 12 · 2017: 10 · 2016: 9 · 2015: 17 · 2014: 22 · 2013: 16 · 2012: 14
FWCI
13.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust
  • National Institute for Health and Care Research
  • European Commission (LSHB-CT-2004-005137, 005137)
  • Medical Research Council
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
GABA, GABAA receptor, pancreatic beta cells, autocrine signaling, human pancreatic islets, GABA release, insulin secretion, delta cells, alpha cells, GABAergic neurotransmission, SR95531, beta-cell electrical activity, action potential firing, GABAA receptor subunits
MeSH terms
Insulin Secretion, Action Potentials, Cells, Cultured, gamma-Aminobutyric Acid, Glucose, Humans, Immunohistochemistry, Insulin, Microscopy, Electron, Receptors, GABA-A, RNA, Messenger, Patch-Clamp Techniques, Paracrine Communication, Reverse Transcriptase Polymerase Chain Reaction, Insulin-Secreting Cells

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