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GLP-1 Inhibits and Adrenaline Stimulates Glucagon Release by Differential Modulation of N- and L-Type Ca2+ Channel-Dependent Exocytosis
Open accessAbstract
Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 muM) concentrations of forskolin, respectively. The expression of GLP-1 receptors in alpha cells is <0.2% of that in beta cells. The GLP-1-induced suppression of glucagon secretion is PKA dependent, is glucose independent, and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on alpha cell electrical activity but selectively inhibits N-type Ca(2+) channels and exocytosis. Adrenaline stimulates alpha cell electrical activity, increases [Ca(2+)](i), enhances L-type Ca(2+) channel activity, and accelerates exocytosis. The stimulatory effect is partially PKA independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca(2+) channels via a small increase in intracellular cAMP ([cAMP](i)). Adrenaline stimulates L-type Ca(2+) channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP](i).
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“GLP-1 can directly bind to the receptors on the surface of α-cells in the pancreas, inhibiting the secretion of glucagon from these cells.234,235”
From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [235]
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Citations
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Glucagon-like peptide 1 (GLP-1)
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Self-citationcAMP signalling in insulin and glucagon secretion
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Self-citationCardiovascular effects of Glucagon-like peptide 1 (GLP-1) receptor agonists
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Glucagon secretion from pancreatic α-cells
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Omar-Hmeadi, M., Lund, P.-E., Gandasi, N. R., Tengholm, A., & Barg, S. (2020) · Nature Communications · doi:10.1038/s41467-020-15717-8 · Cited by 105
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The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice
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Glucose regulation of glucagon secretion
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“Blood hormone assays reveal an early increase in glucagon levels after a test meal (50) despite the finding that the level of incretins such as Glucagon-like peptide-1 (GLP-1) are also elevated after surgery and can inhibit glucagon secretion (70).”
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BackgroundResultInfluentialSelf-citationAlteration of the Glucagon Axis in GPR120 (FFAR4) Knockout Mice
Suckow, A. T., Polidori, D., Yan, W., Chon, S., Jing, Y., Leonard, J. N., & Briscoe, C. P. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.568683 · Cited by 94
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BackgroundInfluentialSelf-citationThe Role of α-Cells in Islet Function and Glucose Homeostasis in Health and Type 2 Diabetes
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Na+ current properties in islet α‐ and β‐cells reflect cell‐specific Scn3a and Scn9a expression
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Glucose controls glucagon secretion by directly modulating cAMP in alpha cells
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“GLP-1R activation increases the somatostatin secretion from d cells and reduces the endogenous production of glucose in the liver as a result of its inhibitory effect on glucagon secretion from a pancreatic cells (31).”
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“Consistent with what was observed in mouse islets (De Marinis et al., 2010), GLP-1 inhibited glucagon secretion at low glucose, and 0.1 M TAK-875 was equally inhibitory.”
BackgroundInfluentialSelf-citationChristensen, M., Calanna, S., Sparre‐Ulrich, A. H., Kristensen, P. L., ROSENKILDE, M. M., Faber, J. O., Purrello, F., van Hall, G., Holst, J. J., Vilsbøll, T., et al. (2014) · Diabetes · doi:10.2337/db14-0440 · Cited by 83
“inhibitory effects of GLP-1 have been attributed to paracrine inhibitory signaling (somatostatin) from neighboring d-cells (16) or—more controversially—direct effects via GLP-1 receptors present on a-cells (1,19).”
BackgroundmiR-204 Controls Glucagon-Like Peptide 1 Receptor Expression and Agonist Function
JO, S., Chen, J., Xu, G., Grayson, T. B., Thielen, L. A., & Shalev, A. (2017) · Diabetes · doi:10.2337/db17-0506 · Cited by 81
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BackgroundThe effects of dual GLP-1/GIP receptor agonism on glucagon secretion-A Review
Mathiesen, D. S., Bagger, J. I., Bergmann, N. C., Lund, A., Christensen, M. B., Vilsbøll, T., & Knop, F. K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174092 · Cited by 80
A comparative analysis of human and mouse islet G-protein coupled receptor expression
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Self-citationGlucagon secretion and signaling in the development of diabetes
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“…involved in α-cell electrical activity that are activated under similar conditions in β-cells (Ramracheya et al., 2010; Spigelman et al., 2010); and hormonal signals, notably GLP-1, activates Ca2+ currents in β-cells (Salapatek et al., 1999) but inhibits these in α-cells (De Marinis et al., 2010).”
BackgroundGlucose control of glucagon secretion—‘There’s a brand-new gimmick every year’
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“In the presence of adrenaline, which depolarizes a-cells, mobilizes Ca2þ from the endoplasmic reticulum (ER) (81,94), and elevates cAMP (33), entry of extracellular Ca2þ through the L-type channels triggers exocytosis of glucagon granules that do not co-localize with these channels (31,95).”
BackgroundTimper, K., Dalmas, E., Dror, E., Rütti, S., Thienel, C., Sauter, N. S., Bouzakri, K., Bédat, B., Pattou, F., Kerr-Conte, J., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.03.003 · Cited by 67
Regulation of islet glucagon secretion: Beyond calcium
Hughes, J. W., Ustione, A., Lavagnino, Z., & Piston, D. W. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13381 · Cited by 78
Yue, J. T. Y., Burdett, E., Coy, D. H., Giacca, A., Efendic, S., & Vranic, M. (2012) · Diabetes · doi:10.2337/db11-0690 · Cited by 75
“Furthermore, hormones such as glucagonlike peptide 1 can regulate glucagon release independent of glucose levels, insulin, or somatostatin, at least in vitro (41).”
BackgroundProglucagon-Derived Peptides as Therapeutics
Lafferty, R. A., O'Harte, F. P. M., Irwin, N., Gault, V. A., & Flatt, P. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.689678 · Cited by 76
“The mechanisms behind this have been hotly debated, with it claimed to be an indirect effect mediated through increased insulin or somatostatin secretion (98, 99), while some have indicated the effect is more direct (100), especially given the presence, albeit at low expression (~10%), of GLP-1R on alpha-cells (101).”
BackgroundThe Somatostatin Receptor in Human Pancreatic β-Cells
Braun, M. (2014) · Vitamins and hormones · doi:10.1016/b978-0-12-800174-5.00007-7 · Cited by 70
“By contrast, in mouse islets the effect of GLP-1 appears to be independent of SST (De Marinis et al., 2010).”
BackgroundSelf-citationPancreatic α-cells – The unsung heroes in islet function
Wendt, A., & Eliasson, L. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.01.006 · Cited by 75
Self-citationRecent advances in understanding the role of glucagon-like peptide 1
Reed, J., Bain, S., & Kanamarlapudi, V. (2020) · F1000Research · doi:10.12688/f1000research.20602.1 · Cited by 66
CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells
Edlund, A., Pedersen, M. G., Lindqvist, A., Wierup, N., Flodström-Tullberg, M., & Eliasson, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-00098-8 · Cited by 63
Self-citationG protein-coupled receptors as new therapeutic targets for type 2 diabetes
Reimann, F. M., & Gribble, F. M. (2015) · Diabetologia · doi:10.1007/s00125-015-3825-z · Cited by 61
Self-citationAlpha cell dysfunction in type 1 diabetes
Yosten, G. L. C. (2018) · Peptides · doi:10.1016/j.peptides.2017.12.001 · Cited by 62
“Alternatively, decreased expression of GPCRs in alpha cells, such as the glucagon receptor and the neuronostatin receptor, GPR107, could desensitize the alpha cells to these positive secretory signals.”
BackgroundStructure and functional roles of Epac2 (Rapgef4)
Sugawara, K., Shibasaki, T., Takahashi, H., & Seino, S. (2016) · Gene · doi:10.1016/j.gene.2015.09.029 · Cited by 59
“Adrenaline stimulates glucagon secretion by L-type Ca2+ channeldependent exocytosis through activation of Epac2 as well as PKA via a large increase in intracellular cAMP levels by binding to the Gs-coupled β-adrenergic receptors on α-cells (De Marinis et al., 2010).”
BackgroundSelf-citationHamamoto, S., Kanda, Y., Shimoda, M., Tatsumi, F., Kohara, K., Tawaramoto, K., Hashiramoto, M., & Kaku, K. (2012) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12005 · Cited by 61
“GLP-1, but not GIP, inhibits glucagon secretion [9] and reduces the rate of gastric emptying [10].”
BackgroundAragon, F. C., Karaca, M., Novials, A., Maldonado, R. J., Maechler, P., & Rubı́, B. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.11.005 · Cited by 57
Kristinsson, H., Sargsyan, E., Manell, H., Smith, D. M., Göpel, S., & Bergsten, P. (2017) · Scientific Reports · doi:10.1038/s41598-017-04730-5 · Cited by 56
Hemodynamic Effects of Glucagon: A Literature Review
Petersen, K. M., Bøgevig, S., Holst, J. J., Knop, F. K., & Christensen, M. B. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00050 · Cited by 68
Distribution of melatonin receptors in murine pancreatic islets
Nagorny, C. L. F., Sathanoori, R., Voss, U., Mulder, H., & Wierup, N. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00859.x · Cited by 55
“In a-cells, a sensitization of the cAMP pathway through the MT1 receptor and upregulation of GLP-1 receptors would provoke an inhibition of glucagon secretion [28] followed by a decrease in insulin secretion.”
BackgroundChronic Exposure to TNFα Impairs Secretion of Glucagon-Like Peptide-1
Gagnon, J., Sauvé, M., Zhao, W. T., Stacey, H. M., Wiber, S. C., Bolz, S. S., & Brubaker, P. L. (2015) · Endocrinology · doi:10.1210/en.2015-1361 · Cited by 55
Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes
Marroquí, L., Alonso‐Magdalena, P., Merino, B., Fuentes, E., Nadal, Á., & Quesada, I. (2014) · Nutrition Research Reviews · doi:10.1017/s0954422414000031 · Cited by 57
“The effect on glucagon is mediated by the direct action on pancreatic a-cells((70)).”
BackgroundInfluentialGu, W., Winters, K. A., Motani, A. S., Komorowski, R., Zhang, Y., Liu, Q., Wu, X., Rulifson, I. C., Sivits, G. N., Graham, M., et al. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00102.2010 · Cited by 54
“In a wild-type mouse, glucagon secretion would normally be inhibited by 1) GLP-1-potentiated insulin secretion and 2) activation of the -cell GLP-1R (3).”
BackgroundParacrine signaling in islet function and survival
Hartig, S. M., & Cox, A. R. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01887-x · Cited by 65
ZIGIR, a Granule-Specific Zn2+ Indicator, Reveals Human Islet α Cell Heterogeneity
Zadeh, E. H. G., Huang, Z., Xia, J., Li, D., Davidson, H. W., & Li, W.-H. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107904 · Cited by 51
Kaur, M., & Misra, S. (2024) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-024-03646-0 · Cited by 51
Slow potentials encode intercellular coupling and insulin demand in pancreatic beta cells
Lebreton, F., Pirog, A., Belouah, I., Bosco, D., Berney, T., Meda, P., Bornat, Y., Catargi, B., Renaud, S., Raoux, M., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3558-z · Cited by 59
Dou, H., Wang, C., Wu, X., Yao, L., Zhang, X., Teng, S., Xu, H., Liu, B., Wu, Q., Zhang, Q., et al. (2014) · Diabetologia · doi:10.1007/s00125-014-3437-z · Cited by 50
“Similarly, cAMP accumulation activates PKA, leading to phosphorylation of voltage-gated Ca channels (VGCCs) on the plasma membrane [16, 17] and inositol 1,4,5-trisphosphate and ryanodine receptors on the endoplasmic membrane [18, 19].”
BackgroundSelf-citationGLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy
Lafferty, R. A., Flatt, P. R., & Irwin, N. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2192865 · Cited by 50
“mediated indirectly through increased somatostatin secretion from islet delta-cells [26].”
BackgroundGlucose-dependent docking and SNARE protein-mediated exocytosis in mouse pancreatic alpha-cell
Andersson, S. A., Pedersen, M. G., Vikman, J., & Eliasson, L. (2011) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-011-0979-5 · Cited by 46
“How can this be explained? Our measurements where performed in the presence of cAMP where exocytosis is mainly dependent on influx though L-type Ca channels [6, 14].”
Self-citationCroze, M. L., Flisher, M. F., Guillaume, A., Tremblay, C. C., Noguchi, G. M., Granziera, S., Vivot, K., Castillo, V., Campbell, S. A., Ghislain, J. J., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101166 · Cited by 47
“Conversely, GPR120-dependent GLP-1 release in vivo would not be expected to contribute positively to the glucagonotropic effects of Cpd A as GLP-1 has been shown to inhibit glucagon secretion from a cells [40].”
BackgroundGlucagon Potentiates Insulin Secretion Via β-Cell GCGR at Physiological Concentrations of Glucose
Zhang, Y., Han, C., Zhu, W., Yang, G., Peng, X., Mehta, S., Zhang, J., Chen, L., & Liu, Y. (2021) · Cells · doi:10.3390/cells10092495 · Cited by 47
“Additionally, 1 μM MK0893 [23] or 1 μM Exendin 9-39 [18,24,25] was included to block GCGR or GLP-1R that was activated by 100 nM glucagon.”
MethodKim, A., Knudsen, J. G., Madara, J. C., Benrick, A., Hill, T., Kadir, L. A., Kellard, J. A., Mellander, L., Miranda, C., Lin, H., et al. (2021) · eLife · doi:10.7554/elife.72919 · Cited by 52
Self-citationChen, S., Shimoda, M., Chen, J., Matsumoto, S., & Grayburn, P. A. (2012) · Cell Cycle · doi:10.4161/cc.11.4.19120 · Cited by 46
An overview of new GLP-1 receptor agonists for type 2 diabetes
Tomlinson, B., Hu, M., Zhang, Y., Chan, P., & Liu, Z.-M. (2015) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2016.1123249 · Cited by 47
“tors [42] or mediated by local stimulation of insulin and somatostatin.”
BackgroundMetabolic Messengers: glucagon
MacDonald, P. E., & Rorsman, P. (2023) · Nature Metabolism · doi:10.1038/s42255-022-00725-3 · Cited by 47
Self-citationGLP-1 as a target for therapeutic intervention
Rajeev, S. P., & Wilding, J. P. H. (2016) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2016.08.005 · Cited by 43
Metabolic responses and benefits of glucagon‐like peptide‐1 (GLP‐1) receptor ligands
Tanday, N., Flatt, P. R., & Irwin, N. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15485 · Cited by 48
Peptides in the regulation of glucagon secretion
Andersen, D. B., & Holst, J. J. (2021) · Peptides · doi:10.1016/j.peptides.2021.170683 · Cited by 50
“natural α-cell), 20 % of α-cells were reported to express the GLP-1R [177], while in another study it was expressed in only ~1% of a FACS sorted primary α-cell population [178].”
TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion
Dadi, P. K., Luo, B., Vierra, N. C., & Jacobson, D. A. (2015) · Molecular Endocrinology · doi:10.1210/me.2014-1321 · Cited by 40
Amisten, S., Al-Amily, I. M., Soni, A., Hawkes, R. G., Atanes, P., Persaud, S. J., Rorsman, P., & Salehi, A. A. (2017) · Endocrine Journal · doi:10.1507/endocrj.ej16-0338 · Cited by 40
Self-citationNon‐invasive long‐term and real‐time analysis of endocrine cells on micro‐electrode arrays
Raoux, M., Bornat, Y., Quotb, A., Catargi, B., Renaud, S., & Lang, J. (2012) · Journal of Physiology · doi:10.1113/jphysiol.2011.220038 · Cited by 30
“1G), which were differentiated by the effect of adrenalin (Dean & Matthews, 1970; De Marinis et al. 2010).”
BackgroundMethodGLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells
Shilleh, A. H., Viloria, K., Broichhagen, J., Campbell, J. E., & Hodson, D. J. (2024) · Peptides · doi:10.1016/j.peptides.2024.171179 · Cited by 39
“Invoking an important role for cAMP in alpha cell GLP1R signaling, the glucagonostatic effect of GLP1 can largely be prevented by PKA inhibition [81,82], although there is a “ PKA inhibition resistant ” fraction, which depends upon EPAC2 signaling [81].”
Denwood, G., Tarasov, A. I., Salehi, A. A., Vergari, E., Ramracheya, R. D., Takahashi, H., Nikolaev, V. O., Seino, S., Gribble, F. M., Reimann, F. M., et al. (2019) · The Journal of General Physiology · doi:10.1085/jgp.201912351 · Cited by 38
Self-citation
Metadata
- Authors
- De Marinis, Y. Z., Salehi, A., Ward, C. E., Zhang, Q., Abdulkader, F., Bengtsson, M., Braha, O., Braun, M., Ramracheya, R., Amisten, S., Habib, A. M., Moritoh, Y., Zhang, E., Reimann, F., Rosengren, A. H., Shibasaki, T., Gribble, F., Renström, E., Seino, S., Eliasson, L., & Rorsman, P.
- Affiliations
- Lund University (SE)
- Churchill Hospital (GB)
- Universidade de São Paulo (BR)
- University of Cambridge (GB)
- Kobe University (JP)
- Corresponding author
- Eliasson, Lena
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 11
- Issue
- 6
- Pages
- 543-553
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4310935
- OpenAlex
- W2041346929
- Cited by
- 257
- References
- 39
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 16 · 2023: 10 · 2022: 8 · 2021: 16 · 2020: 19 · 2019: 13 · 2018: 26 · 2017: 21 · 2016: 18 · 2015: 20 · 2014: 31 · 2013: 11 · 2012: 12
- FWCI
- 14.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (088357, 084210)
- Novo Nordisk Fonden (NNF10OC1013350)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- glucagon secretion, glucagon-like peptide-1, epinephrine, alpha cells, N-type calcium channels, L-type calcium channels, exocytosis, protein kinase A, Epac2, cAMP signaling, pancreatic islets, GLP-1 receptor
- MeSH terms
- Cyclic AMP, Animals, Carrier Proteins, Cells, Cultured, Epinephrine, Exocytosis, Colforsin, Glucagon, Islets of Langerhans, Membrane Potentials, Mice, Inbred C57BL, Cyclic AMP-Dependent Protein Kinases, Guanine Nucleotide Exchange Factors, Calcium Channels, L-Type, Calcium Channels, N-Type, Mice, Glucagon-Like Peptide 1
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