Reduction of plasma membrane glutamate transport potentiates insulin but not glucagon secretion in pancreatic islet cells
Open accessAbstract
Glutamate is generated during nutrient stimulation of pancreatic islets and has been proposed to act both as an intra- and extra-cellular messenger molecule. We demonstrate that glutamate is not co-secreted with the hormones from intact islets or purified α- and β-cells. Fractional glutamate release was 5-50 times higher than hormone secretion. Furthermore, various hormone secretagogues did not elicit glutamate efflux. Interestingly, epinephrine even decreased glutamate release while increasing glucagon secretion. Rather than being co-secreted with hormones, we show that glutamate is mainly released via plasma membrane excitatory amino acid transporters (EAAT) by uptake reversal. Transcripts for EAAT1, 2 and 3 were present in both rat α- and β-cells. Inhibition of EAATs by L-trans-pyrrolidine-2,4-dicarboxylate augmented intra-cellular glutamate and α-ketoglutarate contents and potentiated glucose-stimulated insulin secretion from islets and purified β-cells without affecting glucagon secretion from α-cells. In conclusion, intra-cellular glutamate-derived metabolite pools are linked to glucose-stimulated insulin but not glucagon secretion.
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Human β-cells express SLC1A1 (EAAT3), but mouse islets do not contain significant levels of this transporter.
“Human β-cells also express SLC1A1 (encoding EAAT3) (180) but a recent proteome analysis indicates that mouse islets do not contain significant levels of this transporter (767), in agreement with gene expression data (Appendiux Figure 11B).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [180]
Pharmacological inhibition of EAATs results in stimulation of GIIS, demonstrating that glutamate release imposes a tonic inhibition on insulin release.
“This idea is supported by the observation that pharmacological inhibition of EAATs results in stimulation of GIIS (180) and demonstrates that glutamate release imposes a tonic inhibition on insulin release.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [180]
Cites
De Marinis, Y. Z., Salehi, A., Ward, C. E., Zhang, Q., Abdulkader, F., Bengtsson, M., Braha, O., Braun, M., Ramracheya, R., Amisten, S., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.04.007 · Cited by 257 · see citing works
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Mitochondrial signals drive insulin secretion in the pancreatic β-cell
Wiederkehr, A., & Wollheim, C. B. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.07.016 · Cited by 133 · see citing works
Self-citation
- Authors
- Feldmann, N., del Rio, R. M., Gjinovci, A., Tamarit-Rodriguez, J., Wollheim, C. B., & Wiederkehr, A.
- Affiliations
- University of Geneva (CH)
- Corresponding author
- Wollheim, Claes B.
- Wiederkehr, Andreas
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 338
- Issue
- 1-2
- Pages
- 46-57
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W1964027374
- Cited by
- 39
- References
- 1
- Citations by year
- 2024: 1 · 2023: 1 · 2021: 5 · 2020: 1 · 2019: 4 · 2017: 5 · 2016: 1 · 2015: 8 · 2014: 1 · 2013: 7 · 2012: 4
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Academy of Medical Sciences
- Akademie der Naturwissenschaften
- Schweizerische Akademie der Medizinischen Wissenschaften
- Canton de Genève
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- glutamate, glutamate transporters, insulin secretion, glucagon secretion, pancreatic islets, alpha cells, pancreatic beta cells, glucose-stimulated insulin secretion, glutamate release, epinephrine, alpha-ketoglutarate, co-secretion
- MeSH terms
- Insulin Secretion, Alanine, Animals, Aspartic Acid, Cell Membrane, Cells, Cultured, Dicarboxylic Acids, Epinephrine, gamma-Aminobutyric Acid, Glucagon, Glucose, Glutamine, Insulin, Ketoglutaric Acids, Malates, Male, Pyrrolidines, Transcription, Genetic, Rats, Wistar, Glutamic Acid, Glucagon-Secreting Cells, Insulin-Secreting Cells, Glutamate Plasma Membrane Transport Proteins, Rats
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