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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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A computational systems analysis of factors regulating α cell glucagon secretion
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“Glucose inhibited glucagon secretion in isolated mouse and rat islets.(3,27,39,76) However, we were able to find only one article where AP firing was measured directly in α-cells inside rodent islets.”
BackgroundInfluentialResearch progress of GLP-1RAs in the treatment of type 2 diabetes mellitus
He, X., Zhao, W., Li, P., Zhang, Y., Li, G., Su, H., Lu, B., & Pang, Z. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1483792 · Cited by 17
Aumueller, E., Remely, M., Baeck, H., Hippe, B., Brath, H., & Haslberger, A. G. (2015) · Lifestyle Genomics · doi:10.1159/000381714 · Cited by 13
Regulation of α‐cell glucagon secretion: The role of second messengers
Acreman, S., & Zhang, Q. (2021) · Chronic Diseases and Translational Medicine · doi:10.1016/j.cdtm.2021.06.001 · Cited by 12
“Similarly, Nav channels may be phosphorylated by PKA.129 This acts to reduce the peak Na+ current through the channel.130,131”
BackgroundResultInfluentialSelf-citationKozawa, J., Okita, K., Iwahashi, H., Yamagata, K., Imagawa, A., & Shimomura, I. (2013) · Endocrine Journal · doi:10.1507/endocrj.ej13-0018 · Cited by 12
On depolarization-evoked exocytosis as a function of calcium entry: possibilities and pitfalls.
Pedersen, M. G. (2011) · Biophysical Journal · doi:10.1016/j.bpj.2011.06.061 · Cited by 12
“Endocrine cells express several types of Ca2+-channels (14, 34, 36, 37).”
BackgroundOgawa, S., Nako, K., Okamura, M., Sakamoto, T., & Ito, S. (2014) · Journal of Diabetes Investigation · doi:10.1111/jdi.12314 · Cited by 12
Riz, M., & Pedersen, M. G. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004600 · Cited by 11
“for pancreatic ↵-cells [32, 41].”
Viloria, K., Hewison, M., & Hodson, D. J. (2021) · The Journal of Physiology · doi:10.1113/jp280890 · Cited by 13
Huang, W. Q., Guo, J. H., Yuan, C., Cui, Y. G., Diao, F., Yu, M., Liu, J. Y., Ruan, Y. C., & Chan, H. C. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00835 · Cited by 11
“Taken together, these results suggest that CFTR is a suppressor of glucagon production intrinsic to α cells since the use of an α cell line in the present study excludes the involvement of paracrine factors, such as GLP-1 (De Marinis et al., 2010), insulin (Llu et al., 1991), somatostatin (Strowski et al., 2000) or GA…”
BackgroundLi, D., Shang, Y., Shen, C., Li, L., Zhao, D., Ma, L., & Yu, Y. (2018) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000002066 · Cited by 11
GLP-1R in diabetes mellitus: from basic discovery to therapeutics development
Li, S., Huang, N., Wang, M., Huang, W., Luo, Y., & Huang, J. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1610512 · Cited by 12
Shinjo, T., Nakatsu, Y., Iwashita, M., Sano, T., Sakoda, H., Ishihara, H., Kushiyama, A., Fujishiro, M., Nishimura, F., & Asano, T. (2015) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-015-0047-y · Cited by 10
Willekens, S. M. A., Joosten, L., Boerman, O. C., Brom, M., & Gotthardt, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-21259-3 · Cited by 10
Guida, C., MIRANDA, C. A., Asterholm, I. W., Basco, D., Benrick, A., Chanclón, B., Chibalina, M. V., Harris, M., Kellard, J. A., McCulloch, L. J., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/785667 · Cited by 13
“Similar dual and dose-dependent effects on glucagon secretion are produced by the adenylate cyclase activator forskolin(De 10 Marinis et al., 2010).”
BackgroundResultInfluentialSelf-citationThe relationship between glucose and the liver-alpha cell axis – A systematic review
Pixner, T., Stummer, N., Schneider, A.-M., Lukas, A., Gramlinger, K., Julian, V., Thivel, D., Mörwald, K., Mangge, H., Dalus, C., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1061682 · Cited by 9
Tian, H., Chang, M., Lyu, Y., Dong, N., Yu, N., Yin, T., Zhang, Y. X., He, H., Gou, J., & Tang, X. (2024) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2024.2305110 · Cited by 9
The effect of oral essential amino acids on incretin hormone production in youth and ageing
Abdulla, H., Bass, J. J., Stokes, T., Gorissen, S. H. M., McGlory, C., Phillips, B. E., Phillips, S. M., Smith, K., IDRIS, I. R., & Atherton, P. J. (2019) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.85 · Cited by 8
In vitro assessment of pancreatic hormone secretion from isolated porcine islets
Mourad, N. I., Xhema, D., & Gianello, P. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.935060 · Cited by 10
“This observation is similar to what has been previously reported in mouse and human islets (27, 28) but differs from other experiments using human islets where GLP-1 and forskolin both induced a 2-3-fold inhibition of glucagon secretion in the presence of 1 mM glucose (29).”
ResultPancreatic Islet Cell Hormones: Secretion, Function, and Diabetes Therapy
Ma, J., Mao, L., Yang, L., Xie, Q., Fan, R., Lu, X., Huang, X., Tong, N., & Duan, Z. (2025) · MedComm · doi:10.1002/mco2.70359 · Cited by 11
“P/Q-type Ca v channels predominantly mediate exocytosis, whereas L-type Ca v channels play a key role during adrenergic stimulation [59, 64, 65].”
Adipose Tissue, Hormones, and Treatment of Type 1 Diabetes
Gunawardana, S. C. (2012) · Current Diabetes Reports · doi:10.1007/s11892-012-0300-9 · Cited by 8
Physiological and Pathophysiological Control of Glucagon Secretion by Pancreatic α-Cells
Gilon, P., Cheng, R., Lai, B. K., Chae, H., & Gómez-Ruiz, A. (2014) · Springer eBooks · doi:10.1007/978-94-007-6884-0_37-2 · Cited by 8
Villalpando, S., Cazevieille, C., Fernandez, A., Lamb, N. J. C., & Hani, E.-H. (2016) · Biochimie · doi:10.1016/j.biochi.2016.02.008 · Cited by 8
Henriksen, K., Rufer, C., Title, A. C., Jawurek, S., Hartmann, B., Holst, J. J., Knop, F. K., Yesildag, B., & Størling, J. (2025) · Diabetologia · doi:10.1007/s00125-025-06425-3 · Cited by 7
Verma, M. K., Biswas, S., Chandravanshi, B., Neelima, K., Oommen, A. M., Jagannath, M. R., & Somesh, B. P. (2014) · BMC Research Notes · doi:10.1186/1756-0500-7-595 · Cited by 7
“Interestingly, a similar pattern for GLP1 receptor expression in alpha and beta cells and its ability to increase insulin secretion and decrease glucagon secretion has been reported [10].”
Alpha-cells and therapy of diabetes: Inhibition, antagonism or death?
Klempel, N., Thomas, K. G., Conlon, J. M., Flatt, P. R., & Irwin, N. (2022) · Peptides · doi:10.1016/j.peptides.2022.170877 · Cited by 7
History of key regulatory peptide systems and perspectives for future research
Chen, D., Rehfeld, J. F., Watts, A. G., Rorsman, P., & Gundlach, A. L. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13251 · Cited by 7
“187 For example, the gut peptides, GIP and glucagon-like peptide (GLP)-1, stimulate and inhibit glucagon secretion, 188 respectively.”
BackgroundSelf-citationTajima, K., Shirakawa, J., Togashi, Y., Inoue, H., Sato, K., Orime, K., Ito, Y., Kaji, M., Sakamoto, E., Nakamura, A., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064633 · Cited by 7
Physiology and pharmacology of glucagon-like peptide-1 receptor
Куркин, Д. В., Bakulin, D. A., Morkovin, E. I., Petrov, V. I., Strygin, A. V., Koryanova, K. N., Gorbunova, Y. V., Kolosov, Y. A., Ivanova, O. V., Pavlova, E. V., et al. (2024) · Pharmacy & Pharmacology · doi:10.19163/2307-9266-2023-11-4-347-380 · Cited by 9
Shi, W., Zhang, L., Zhao, Y., & Li, X. (2024) · Insects · doi:10.3390/insects15070503 · Cited by 7
Urocortin 3 contributes to paracrine inhibition of islet alpha cells in mice
Noguchi, G. M., Castillo, V., Donaldson, C. J., Flisher, M. F., Momen, A. T., Saghatelian, A., & Huising, M. O. (2024) · Journal of Endocrinology · doi:10.1530/joe-24-0018 · Cited by 7
Rebelos, E., Anastasiou, I. A., Tentolouris, N., Karagiannis, T., Τσάπας, Α., Ferrannini, E., & Liakos, A. (2025) · HORMONES · doi:10.1007/s42000-025-00704-9 · Cited by 6
“Moreover, GLP-1 suppresses glucagon secretion [9].”
Pancreatic safety of GLP-1-based therapeutic agents: further insights from rodent studies?
Holst, J. J. (2013) · Diabetologia · doi:10.1007/s00125-013-2984-z · Cited by 6
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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