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Interplay of Nutrients and Hormones in the Regulation of Glucagon Release*
Abstract
The role of nutrients and hormones in the regulation of glucagon release is investigated in pancreatic A cells purified by autofluorescence-activated cell sorting. Purified A cells lack secretory activity in 1-h incubation at 1.4 mM glucose. Their release mechanism can be activated by arginine, alanine, and glutamine, alone or in combination. Glucose inhibits amino acid-induced glucagon release through a direct insulin-independent action upon pancreatic A cells. Nutrient-induced glucagon release is suppressed by somatostatin and amplified by (Bu)2cAMP or epinephrine. The epinephrine stimulus is inhibited by 10(-11) M somatostatin and abolished by 10(-10) M of this peptide. The effects of somatostatin and epinephrine are associated with parallel changes in cellular cAMP levels, which is not the case for the variations induced by amino acids or glucose. It is confirmed that calcium is an essential requirement for glucagon release. In contrast to its exquisite sensitivity for somatostatin, the glucagon release process is relatively insensitive to insulin during a 1-h exposure. The hormone affects solely epinephrine-induced glucagon release and its inhibitory action is partial and only observed at 10(-7) M. This suppressive effect of insulin is not attributable to variations in glucose handling but appears associated with the stimulatory effect of epinephrine. It is concluded that a nutrient-induced signal interacts with a hormone-inducible cAMP signal to activate the secretory process in pancreatic A cells.
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“and studies of pancreatic islets and cells have provided additional evidence that glucose regulates glucagon release by a direct effect on the alpha cell [5,[8][9][10][12][13][14][15][16][17].”
From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [8]
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Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells
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Self-citationDifferences in Adrenergic Recognition by Pancreatic A and B Cells
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Ma, X., Zhang, Y., Gromada, J., Sewing, S., Berggren, P., Buschard, K., Salehi, A. A., Vikman, J., Rorsman, P., & Eliasson, L. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0059 · Cited by 130
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“9) incubated with amino acids showed increased proliferation and glucagon secretion, supporting a role for amino acids as growth factors for the alpha-cells (32, 41) and as stimulators of glucagon secretion as previously suggested (3, 26, 36, 38, 41, 45).”
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“Thus, at marked hyperglycemia an insulin-independent process could be responsible for some glucagon suppression as suggested by previous work with isolated A cells (5).”
BackgroundResultKATP-channels and glucose-regulated glucagon secretion
Rorsman, P., Salehi, A. A., Abdulkader, F., Braun, M., & MacDonald, P. E. (2008) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2008.07.003 · Cited by 102
Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line.
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Self-citationMetabolic Pathways That Mediate Inhibition of Hypothalamic Neurons by Glucose
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“However, much less is known about how glucose inhibits, for example, glucagon-producing -cells, and inhibition of glucagon secretion by glucose seems to be complex and may involve indirect mechanisms (9,10).”
BackgroundHamilton, A., Zhang, Q., Salehi, A. A., Willems, M., Knudsen, J. G., Ringgaard, A. K., Chapman, C., González, A., Surdo, N. C., Zaccolo, M., et al. (2018) · Diabetes · doi:10.2337/db17-1102 · Cited by 100
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Tolbutamide Controls Glucagon Release From Mouse Islets Differently Than Glucose
Cheng, R., Gómez-Ruiz, A., Antoine, N., Noël, L. A., Chae, H., Ravier, M. A., Chimienti, F., Schuit, F. C., & Gilon, P. (2013) · Diabetes · doi:10.2337/db12-0347 · Cited by 89
“A direct effect of glucose on a-cells was first proposed as a result of studies on purified rat a-cells (3), but the underlying mechanisms are still disputed.”
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“Thus, the effect of palmitate is unlikely to be mediated by an increase in intracellular cAMP with resultant stimulation of glucagon secretion (18,19).”
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InfluentialGlucagon secretion and signaling in the development of diabetes
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“Based solely on studies of dispersed or purified α-cells (Pipeleers et al., 1985; Ishihara et al., 2003; Olsen et al., 2005; Le Marchand and Piston, 2010), the answer would seem to be no, since under these conditions glucose stimulates glucagon secretion.”
BackgroundEvidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion
Burcelin, R., & Thorens, B. (2001) · Diabetes · doi:10.2337/diabetes.50.6.1282 · Cited by 74
“First, direct glucose sensing by a-cells may account for the glucagon secretory activity detected, for instance, in perfused pancreas experiments (5) or with isolated islets of Langerhans (6).”
BackgroundMechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells
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“Secretion of glucagon is stimulated by low blood glucose (Gorus et al. 1984), amino acids (Pipeleers et al. 1985), and a variety of hormones and neurotransmitters, such as adrenaline, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (Ding et al. 1997; Gromada et al.…”
BackgroundHemodynamic Effects of Glucagon: A Literature Review
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Pancreatic α-cell dysfunction in diabetes
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Zinc transporters and their role in the pancreatic β‐cell
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Self-citationGlucose homeostasis in the newborn
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“However, such a mechanism could not be verified in a study of purified a-cells (17).”
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“Glucagon secretion from α cells is affected by paracrine modulators such as intra-islet insulin (12), zinc (13), somatostatin secreted from δ cells (14), cAMP (15) and cAMP-activated ion channels (16), Ca2+ (17), cytokine effects (18), gap junctions (19), direct effects of glucose BACKGROUND.”
BackgroundLoss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
Bozadjieva-Kramer, N., Blandino-Rosano, M., Chase, J., Dai, X., Cummings, K., Gimeno, J., Dean, E. D., Powers, A. C., Gittes, G. K., Rüegg, M. A., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90004 · Cited by 60
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BackgroundMethodInfluentialRole of the Decrement in Intraislet Insulin for the Glucagon Response to Hypoglycemia in Humans
Gosmanov, N. R., Szoke, E., Israelian, Z., Smith, T., Cryer, P. E., Gerich, J. E., & Meyer, C. (2005) · Diabetes Care · doi:10.2337/diacare.28.5.1124 · Cited by 60
Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis
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“Therefore, this system is regulated by glucose and has positive feedback on insulin secretion [71] but negative feedback on glucagon secretion [73].”
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Localized glucoprivation of hindbrain sites elicits corticosterone and glucagon secretion
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“2b) may be mediated by a paracrine signaling mechanism similar to that of glycine (31) and/or arginine (60).”
BackgroundSuppression of Ca2+ oscillations in glucagon-producing α2-cells by insulin/glucose and amino acids
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“3) (Gerber and Hare 1980; Pipeleers et al. 1985).”
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“These results are consistent with previous reports on the effect of arginine or epinephrine on glucagon secretion in glucagon-secreting cell lines or isolated pancreatic alpha cells [9, 23, 24].”
ResultSoy protein, casein, and zein regulate histidase gene expression by modulating serum glucagon
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Regulation of corticotropin-releasing factor secretion in vitro by glucose
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“secretory responses to other stimuli remaining largely intact), develops concomitantly with progressive loss of beta-cell function (21), is not affected by pharmacological blockade of classical autonomic mediators (27;53), and that isolated alpha-cells do not appear able to respond to hypoglycemia per se (40), suggest…”
BackgroundModeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion
Watts, M., & Sherman, A. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2013.11.4504 · Cited by 45
Is GLUT2 required for glucose sensing?
Schuit, F. C. (1997) · Diabetologia · doi:10.1007/s001250050651 · Cited by 43
Self-citationLai, B. K., Chae, H., Gómez-Ruiz, A., Cheng, P., Gallo, P., Antoine, N., Beauloye, C., Jonas, J., Seghers, V. J., Seino, S., et al. (2018) · Diabetes · doi:10.2337/db17-0880 · Cited by 40
“It has been shown that glucose inhibits (9) or, conversely, stimulates (10,11) glucagon release of isolated a-cells.”
BackgroundHomotypic cell contact enhances insulin but not glucagon secretion
Brereton, H., Carvell, M. J., Asare‐Anane, H., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.03.214 · Cited by 41
Moens, K., Berger, V., Ahn, J., Schravendijk, C. V., Hruby, V. J., PIPELEERS, D. G., & Schuit, F. C. (2002) · Diabetes · doi:10.2337/diabetes.51.3.669 · Cited by 41
“We previously reported that 1 mol/l exendin-(9-39)-NH2 had no effect on glucagoninduced cAMP production by rat hepatocytes (8).”
BackgroundMethodInfluentialSelf-citationGrapengiesser, E., Salehi, A. A., Qader, S. S., & Hellman, B. (2006) · Endocrinology · doi:10.1210/en.2005-1431 · Cited by 40
Jackson, L., Williams, F. L. R., Burchell, A., Coughtrie, M. W. H., & Hume, R. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0550 · Cited by 36
“Glucagon release by pancreatic -cells is stimulated directly by low blood glucose levels (44) or indirectly by autonomic inputs from sympathetic (NE) and parasympathetic (acetylcholine) innervations as well as adrenal medulla (EPI) (45).”
BackgroundGlucose and amino acid metabolism in mice depend mutually on glucagon and insulin receptor signaling
Galsgaard, K. D., Winther‐Sørensen, M., Pedersen, J., Kjeldsen, S. A. S., ROSENKILDE, M. M., Albrechtsen, N. J. W., & Holst, J. J. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00410.2018 · Cited by 36
“To determine the inhibitory potency of GRA (25-2648), we tested its ability to inhibit glucagon-induced cAMP production using COS-7 cells transiently transfected with the mouse glucagon receptor or the mouse glucagon-like peptide 1 (GLP-1) receptor.”
BackgroundMethodIto, K., Maruyama, H., Hirose, H., Kido, K., Koyama, K., Kataoka, K., & Saruta, T. (1995) · Metabolism · doi:10.1016/0026-0495(95)90166-3 · Cited by 31
Dumonteil, E., Magnan, C., Ritz-Laser, B., Meda, P., Dussoix, P., Gilbert, M., Ktorza, A., & Philippé, J. (1998) · Endocrinology · doi:10.1210/endo.139.11.6294 · Cited by 33
Silvestre, R. A., Rodríguez‐Gallardo, J., Egido, E. M., & Marco, J. (2003) · European Journal of Pharmacology · doi:10.1016/s0014-2999(03)01692-3 · Cited by 31
Characterization of a Novel Protein Kinase C Response Element in the Glucagon Gene
Fürstenau, U., Schwaninger, M., Blume, R., Kennerknecht, I., & Knepel, W. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.4.1805 · Cited by 32
“Whereas the stimulation of b-adrenergic receptors on A cells raises the cellular cyclic AMP (cAMP) levels (59, 67), the islet muscarinic acetylcholine receptors are of the M3 receptor subtype that activates phospholipase C, generating inositol 1,4,5-trisphosphate and diacylglycerol, an activator of protein kinase C is…”
BackgroundPancreatic Response to Mild Non–Insulin-Induced Hypoglycemia Does Not Involve Extrinsic Neural Input
Sherck, S. M., Shiota, M., Saccomando, J., Cardin, S., Allen, E. J., Hastings, J. R., Neal, D. W., Williams, P. E., & Cherrington, A. D. (2001) · Diabetes · doi:10.2337/diabetes.50.11.2487 · Cited by 30
“Changes in blood substrate levels are also unlikely to have caused the rise in plasma glucagon levels, as glucagon secretion is stimulated by amino acids, which fell during the study, and inhibited by NEFA and ketones, which rose during the study (7,38).”
Backgroundα- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog
Flattem, N. L., Igawa, K., Shiota, M., Emshwiller, M., Neal, D. W., & Cherrington, A. D. (2001) · Diabetes · doi:10.2337/diabetes.50.2.367 · Cited by 31
Claessens, M., Calame, W., Siemensma, A. D., Saris, W. H. M., & van Baak, M. A. (2007) · Metabolism · doi:10.1016/j.metabol.2007.04.001 · Cited by 29
Glucagon‐like peptide‐1 drives energy metabolism on the synaptic highway
Liu, J., & Pang, Z. P. (2016) · FEBS Journal · doi:10.1111/febs.13785 · Cited by 27
Dietary carbohydrates and amino acids influence oocyte quality in dairy heifers
Rooke, J. A., Ainslie, A., Watt, R. G., Alink, F. M., McEvoy, T. G., Sinclair, K. D., Garnsworthy, P. C., & WEBB, R. (2009) · Reproduction Fertility and Development · doi:10.1071/rd08193 · Cited by 28
Production et sécrétion de l'insuline par la cellule β pancréatique
Magnan, C., & Ktorza, A. (2005) · EMC - Endocrinologie · doi:10.1016/j.emcend.2005.07.001 · Cited by 55
Pax6 Is a Key Component of Regulated Glucagon Secretion
Gosmain, Y., Cheyssac, C., Masson, M. H., Guérardel, A., Poisson, C., & Philippé, J. (2012) · Endocrinology · doi:10.1210/en.2012-1425 · Cited by 30
Metadata
- Authors
- PIPELEERS, D. G., SCHUIT, F. C., SCHRAVENDIJK, C. F. H. V., & WINKEL, M. V. D.
- Affiliations
- Vrije Universiteit Brussel (BE)
- ORCID
- PIPELEERS, D. G.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1985-09
- Volume
- 117
- Issue
- 3
- Pages
- 817-823
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W4250756743
- Cited by
- 169
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 1 · 2020: 1 · 2019: 7 · 2018: 6 · 2017: 2 · 2016: 5 · 2014: 5 · 2013: 2 · 2012: 5
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- 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, pancreatic A cells, nutrient regulation, amino acids, glucose, somatostatin, epinephrine, cyclic AMP, insulin, calcium, pancreatic islets
- MeSH terms
- Alanine, Amino Acids, Animals, Arginine, Calcium, Bucladesine, Epinephrine, Flow Cytometry, Glucagon, Glucose, Glutamine, Islets of Langerhans, Male, Pancreatic Hormones, Rats, Inbred Strains, Somatostatin, Rats, In Vitro Techniques
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