Glutamate Is a Positive Autocrine Signal for Glucagon Release
Open accessAbstract
An important feature of glucose homeostasis is the effective release of glucagon from the pancreatic alpha cell. The molecular mechanisms regulating glucagon secretion are still poorly understood. We now demonstrate that human alpha cells express ionotropic glutamate receptors (iGluRs) that are essential for glucagon release. A lowering in glucose concentration results in the release of glutamate from the alpha cell. Glutamate then acts on iGluRs of the AMPA/kainate type, resulting in membrane depolarization, opening of voltage-gated Ca(2+) channels, increase in cytoplasmic free Ca(2+) concentration, and enhanced glucagon release. In vivo blockade of iGluRs reduces glucagon secretion and exacerbates insulin-induced hypoglycemia in mice. Hence, the glutamate autocrine feedback loop endows the alpha cell with the ability to effectively potentiate its own secretory activity. This is a prerequisite to guarantee adequate glucagon release despite relatively modest changes in blood glucose concentration under physiological conditions.
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Glutamate is stored together with glucagon in secretory granules of α-cells and coreleased with glucagon.
“It is stored together with glucagon in the secretory granules of α-cells and coreleased with glucagon (103, 462).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [103]
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“When there is a lowering in blood glucose concentration, the negative paracrine influence of b cells on a cells decreases (the ‘‘switch-off’’ hypothesis; Cryer et al., 2003; Hope et al., 2004; Zhou et al., 2004).”
BackgroundRole of Glucagon, Catecholamines, and Growth Hormone in Human Glucose Counterregulation
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Research works printed but not linked: 11
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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
Physiology of Proglucagon Peptides: Role of Glucagon and GLP-1 in Health and Disease
Sandoval, D. A., & D'Alessio, D. A. (2015) · Physiological Reviews · doi:10.1152/physrev.00013.2014 · Cited by 498 · see citing works
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Gáliková, M., Diesner, M., Klepsatel, P., Hehlert, P., Xu, Y., Bickmeyer, I., Predel, R., & Kühnlein, R. P. (2015) · Genetics · doi:10.1534/genetics.115.178897 · Cited by 206 · see citing works
Wewer Albrechtsen, N. J., Færch, K., Jensen, T. M., Witte, D. R., Pedersen, J., Mahendran, Y., Jonsson, A. E., Galsgaard, K. D., Winther-Sørensen, M., Torekov, S. S., et al. (2018) · Diabetologia · doi:10.1007/s00125-017-4535-5 · Cited by 119 · see citing works
- Authors
- Cabrera, O., Jacques-Silva, M. C., Speier, S., Yang, S.-N., Köhler, M., Fachado, A., Vieira, E., Zierath, J. R., Kibbey, R., Berman, D. M., Kenyon, N. S., Ricordi, C., Caicedo, A., & Berggren, P.-O.
- Affiliations
- University of Miami (US)
- Karolinska Institutet (SE)
- Yale University (US)
- Corresponding author
- Caicedo, Alejandro
- Berggren, Per-Olof
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 7
- Issue
- 6
- Pages
- 545-554
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4396785
- OpenAlex
- W2046064425
- Cited by
- 217
- References
- 2
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 12 · 2023: 14 · 2022: 12 · 2021: 25 · 2020: 17 · 2019: 17 · 2018: 8 · 2017: 9 · 2016: 9 · 2015: 15 · 2014: 15 · 2013: 7 · 2012: 10
- FWCI
- 13.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Familjen Erling-Perssons Stiftelse
- Vetenskapsrådet
- National Institute of Diabetes and Digestive and Kidney Diseases (1R03DK075487, U24 DK59635)
- Novo Nordisk Fonden
- NIH Clinical Center (1R01-DK55347-IU42RR016603, MO1RR16587)
- Juvenile Diabetes Research Foundation International (3-2006-853, 3-2007-73, 4-2004-361)
- Diabetes Research Institute Foundation
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- glutamate, glucagon secretion, alpha cells, ionotropic glutamate receptors, non-NMDA receptors, autocrine signaling, glucose homeostasis, voltage-gated calcium channels, intracellular calcium, insulin-induced hypoglycemia, pancreatic islets
- MeSH terms
- Animals, Haplorhini, Blood Glucose, Cells, Cultured, Glucagon, Homeostasis, Humans, Receptors, AMPA, Receptors, Kainic Acid, Kainic Acid Receptors, Receptors, Metabotropic Glutamate, Glutamic Acid, Autocrine Communication, Glucagon-Secreting Cells, Mice
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