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.
“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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Cites
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“[32] suggested that the expression level of the GLP-1 receptor is just right for causing inhibition of glucagon secretion, Ding et al.”
BackgroundAst, J., Arvaniti, A., Fine, N. H. F., Nasteska, D., Ashford, F. B., Stamataki, Z., Kőszegi, Z., Bacon, A., Jones, B. J., Lucey, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14309-w · Cited by 135 · see citing works
Self-citationMinireview: Glucagon in Stress and Energy Homeostasis
Jones, B. J., Tan, T., & Bloom, S. R. (2012) · Endocrinology · doi:10.1210/en.2011-1979 · Cited by 140 · see citing works
“In isolated rat islets, a paradoxical inhibitory effect of epinephrine at concentrations found in the systemic circulation was noted on glucagon release, whereas at higher concentrations akin to those produced locally by direct neurotransmitter release, glucagon secretion was enhanced (27).”
BackgroundEdlund, A., Esguerra, J. L. S., Wendt, A., Flodström‐Tullberg, M., & Eliasson, L. (2014) · BMC Medicine · doi:10.1186/1741-7015-12-87 · Cited by 138 · see citing works
“Localization of CFTR was analyzed as described elsewhere [22].”
MethodSelf-citationRamracheya, R., Chapman, C., Chibalina, M., Dou, H., Miranda, C., González, A., Moritoh, Y., Shigeto, M., Zhang, Q., Braun, M., et al. (2018) · Physiological Reports · doi:10.14814/phy2.13852 · Cited by 128 · see citing works
“We used GLP-1 at a concentration of 10 nM, in keeping with other islet cell studies (Bode et al. 1999; Tsuboi et al. 2003; de Heer et al. 2008; De Marinis et al. 2010; Shigeto et al. 2015; Traub et al. 2017). x-Agatoxin was purchased from the Peptide Institute (Minoh-shi Osaka, Japan),…”
BackgroundMethodResultInfluentialSelf-citationGlucose- and Hormone-Induced cAMP Oscillations in α- and β-Cells Within Intact Pancreatic Islets
Tian, G., Sandler, S., Gylfe, E., & Tengholm, A. (2011) · Diabetes · doi:10.2337/db10-1087 · Cited by 128 · see citing works
Elliott, A. D., Ustione, A., & Piston, D. W. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00344.2014 · Cited by 118 · see citing works
DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets
Hall, E., Dayeh, T., Kirkpatrick, C. L., Wollheim, C. B., Nitert, M. D., & Ling, C. (2013) · BMC Medical Genetics · doi:10.1186/1471-2350-14-76 · Cited by 113 · see citing works
“Furthermore, while several studies have shown that GLP1R is expressed in pancreatic β cells, its expression is low or absent in pancreatic α cells [5,6].”
Glucagon secretion from pancreatic α-cells
Briant, L., Salehi, A., Vergari, E., Zhang, Q., & Rorsman, P. (2016) · Upsala Journal of Medical Sciences · doi:10.3109/03009734.2016.1156789 · Cited by 109 · see citing works
“The L-type Ca2þ channel, although contributing the majority of Ca2þ currents (>50%), plays a minor role in the glucagon secretion under these conditions (50,51).”
BackgroundSelf-citationParacrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes
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 · see citing works
Zhang, Y., Parajuli, K. R., Fava, G. E., Gupta, R., Xu, W., Nguyen, L. U., Zakaria, A. F., Fonseca, V. A., Wang, H., Mauvais-Jarvis, F., et al. (2019) · Diabetes · doi:10.2337/db18-0317 · Cited by 104 · see citing works
“Some studies show no GLP-1R protein or mRNA expression in a-cells of normal mice (7), some show GLP-1R is expressed in a small portion of a-cells in adult mice (8,9), and others show clear GLP-1R expression in a-cells, especially during early development and throughout life in mice with a-cell hyperplasia (10,11).”
BackgroundToki, S., Goleniewska, K., Reiss, S., Zhang, J., Bloodworth, M. H., Stier, M. T., Zhou, W., Newcomb, D. C., Ware, L. B., Stanwood, G. D., et al. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.11.043 · Cited by 106 · see citing works
“GLP-1 has a role in glycemic control by inducing glucose-dependent insulin secretion from b cells and inhibiting glucagon release from a cells in the pancreas.(11,12) GLP-1 also induces weight loss by promoting satiety.”
The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice
Orgaard, A., & Holst, J. (2017) · Diabetologia · doi:10.1007/s00125-017-4315-2 · Cited by 102 · see citing works
Glucose regulation of glucagon secretion
Gylfe, E., & Gilon, P. (2013) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2013.11.019 · Cited by 98 · see citing works
“of adrenaline, which depolarizes the α-cells and mobilizes Ca 2+ from the ER [45, 46] entry of extracellular Ca 2+ through the L-type channels will be the most impor tant trigger of secretion [43, 47].”
BackgroundThe role of glucagon on type 2 diabetes at a glance
Godoy‐Matos, A. F. (2014) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-6-91 · Cited by 97 · see citing works
“2% of that in beta-cells and that GLP-1-induced suppression of glucagon release is dependent of PKA and independent of glucose or paracrine effects mediated by insulin or somatostatin [18].”
BackgroundSuga, T., Kikuchi, O., Kobayashi, M., Matsui, S., Yokota‐Hashimoto, H., Wada, E., Kohno, D., Sasaki, T., Takeuchi, K., Kakizaki, S., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.10.009 · Cited by 98 · see citing works
Briant, L. J. B., Dodd, M. S., Chibalina, M. V., Rorsman, N. J. G., Johnson, P., Carmeliet, P., Rorsman, P., & Knudsen, J. G. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.035 · Cited by 97 · see citing works
Self-citationDiabetes resolution and hyperinsulinaemia after metabolic Roux‐en‐Y gastric bypass
Ashrafian, H., Athanasiou, T., Li, J. V., Bueter, M., Ahmed, K., Nagpal, K., Holmes, E. C., Darzi, A. W., & Bloom, S. R. (2010) · Obesity Reviews · doi:10.1111/j.1467-789x.2010.00802.x · Cited by 95 · see citing works
“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).”
BackgroundHamilton, A., Zhang, Q., Salehi, A., Willems, M., Knudsen, J. G., Stephen, S. D., Ringgaard, A. K., Chapman, C. E., Gonzalez-Alvarez, A., Surdo, N. C., et al. (2018) · Diabetes · doi:10.2337/db17-1102 · Cited by 85 · see citing works
“The observation that the adrenaline-induced increase in [Ca]i requires high [cAMP]i (= high forskolin) is consistent with the involvement of EPAC2 (Kd for cAMP 10(25) mol/L (31)) and the previous report that the stimulatory effect of adrenaline on glucagon secretion is dramatically reduced in EPAC2 knockout islets (5).”
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 · see citing works
“GLP-1 is known to have inhibitory effects on glucagon secretion and GPR120 activation is reported to regulate GLP-1 secretion (5, 33).”
BackgroundRorsman, P., Ramracheya, R. D., Rorsman, N. J. G., & Zhang, Q. (2014) · Diabetologia · doi:10.1007/s00125-014-3279-8 · Cited by 89 · see citing works
“channels [21, 65] (Fig.”
BackgroundInfluentialSelf-citationThe Role of α-Cells in Islet Function and Glucose Homeostasis in Health and Type 2 Diabetes
Gilon, P. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.01.004 · Cited by 90 · see citing works
Zhang, Q., Chibalina, M. V., Bengtsson, M., Groschner, L. N., Ramracheya, R., Rorsman, N. J. G., Leiss, V., Nassar, M. A., Welling, A., Gribble, F. M., et al. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.274209 · Cited by 90 · see citing works
“Membrane potential recordings were performed as described previously (De Marinis et al. 2010) using the perforated-patch technique and K2SO4-filled electrodes.”
MethodSelf-citationToki, S., Newcomb, D. C., Printz, R. L., Cahill, K. N., Boyd, K. L., Niswender, K. D., & Peebles, R. S. (2021) · Allergy · doi:10.1111/all.14879 · Cited by 94 · see citing works
Glucose controls glucagon secretion by directly modulating cAMP in alpha cells
Yu, Q., Shuai, H., Ahooghalandari, P., Gylfe, E., & Tengholm, A. (2019) · Diabetologia · doi:10.1007/s00125-019-4857-6 · Cited by 84 · see citing works
Heterogenous impairment of α-cell function in type 2 diabetes is linked to cell maturation state
Dai, X.-Q., Camunas-Soler, J., Briant, L., dos Santos, T., Spigelman, A., Walker, E., Drigo, R. A., Bautista, A., Jones, R. C., Avrahami, D., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2021.12.021 · Cited by 69 · see citing works
Self-citationStepanov, V., Stankov, K., & Mikov, M. (2013) · Journal of Receptors and Signal Transduction · doi:10.3109/10799893.2013.802805 · Cited by 84 · see citing works
“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).”
BackgroundYashiro, H., Tsujihata, Y., Takeuchi, K., Hazama, M., Johnson, P. R. V., & Rorsman, P. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.187708 · Cited by 84 · see citing works
“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 · see citing works
“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 80 · see citing works
“p injections of the GLP1R antagonist, exendin (9-39) (Ex-9) (0.”
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 · see citing works
A comparative analysis of human and mouse islet G-protein coupled receptor expression
Amisten, S., Atanes, P., Hawkes, R. G., Ruz‐Maldonado, I., Liu, B., Parandeh, F., Zhao, M., Huang, G. C., Salehi, A. A., & Persaud, S. J. (2017) · Scientific Reports · doi:10.1038/srep46600 · Cited by 78 · see citing works
Self-citationGlucagon secretion and signaling in the development of diabetes
Gaisano, H. Y., MacDonald, P. E., & Vranić, M. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00349 · Cited by 75 · see citing works
“…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’
Gylfe, E. (2016) · Upsala Journal of Medical Sciences · doi:10.3109/03009734.2016.1154905 · Cited by 71 · see citing works
“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, É., Dror, E., Rütti, S., Thienel, C., Sauter, N. S., Bouzakri, K., Bédat, B., Pattou, F. N., Kerr-Conte, J. A., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.03.003 · Cited by 73 · see citing works
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 75 · see citing works
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 · see citing works
“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 70 · see citing works
“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 60 · see citing works
“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 67 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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. (2015) · Gene · doi:10.1016/j.gene.2015.09.029 · Cited by 63 · see citing works
“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 60 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 55 · see citing works
“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 · see citing works
“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 53 · see citing works
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 50 · see citing works
Kaur, M., & Misra, S. (2024) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-024-03646-0 · Cited by 51 · see citing works
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 49 · see citing works
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 · see citing works
“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 46 · see citing works
“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 · see citing works
“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 45 · see citing works
“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 45 · see citing works
“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 51 · see citing works
Self-citationChen, S., Shimoda, M., Chen, J., Matsumoto, S., & Grayburn, P. A. (2012) · Cell Cycle · doi:10.4161/cc.11.4.19120 · Cited by 44 · see citing works
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 44 · see citing works
“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 44 · see citing works
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 · see citing works
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 43 · see citing works
Peptides in the regulation of glucagon secretion
Andersen, D. B., & Holst, J. J. (2021) · Peptides · doi:10.1016/j.peptides.2021.170683 · Cited by 46 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
Self-citation
- 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 › Surgery › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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