Glucagon Acting at the GLP-1 Receptor Contributes to β-Cell Regeneration Induced by Glucagon Receptor Antagonism in Diabetic Mice
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Abstract
Dysfunction of glucagon-secreting α-cells participates in the progression of diabetes, and glucagon receptor (GCGR) antagonism is regarded as a novel strategy for diabetes therapy. GCGR antagonism upregulates glucagon and glucagon-like peptide 1 (GLP-1) secretion and, notably, promotes β-cell regeneration in diabetic mice. Here, we aimed to clarify the role of GLP-1 receptor (GLP-1R) activated by glucagon and/or GLP-1 in the GCGR antagonism–induced β-cell regeneration. We showed that in db/db mice and type 1 diabetic wild-type or Flox/cre mice, GCGR monoclonal antibody (mAb) improved glucose control, upregulated plasma insulin level, and increased β-cell area. Notably, blockage of systemic or pancreatic GLP-1R signaling by exendin 9-39 (Ex9) or Glp1r knockout diminished the above effects of GCGR mAb. Furthermore, glucagon-neutralizing antibody (nAb), which prevents activation of GLP-1R by glucagon, also attenuated the GCGR mAb–induced insulinotropic effect and β-cell regeneration. In cultured primary mouse islets isolated from normal mice and db/db mice, GCGR mAb action to increase insulin release and to upregulate β-cell–specific marker expression was reduced by a glucagon nAb, by the GLP-1R antagonist Ex9, or by a pancreas-specific Glp1r knockout. These findings suggest that activation of GLP-1R by glucagon participates in β-cell regeneration induced by GCGR antagonism in diabetic mice. Article Highlights: Glucagon receptor (GCGR) antagonism promotes β-cell regeneration in type 1 and type 2 diabetic mice and in euglycemic nonhuman primates. Glucagon and glucagon-like peptide 1 (GLP-1) can activate the GLP-1 receptor (GLP-1R), and their levels are upregulated following GCGR antagonism. We investigated whether GLP-1R activated by glucagon and/or GLP-1 contributed to β-cell regeneration induced by GCGR antagonism. We found that blockage of glucagon–GLP-1R signaling attenuated the GCGR monoclonal antibody–induced insulinotropic effect and β-cell regeneration in diabetic mice. Our study reveals a novel mechanism of β-cell regeneration and uncovers the communication between α-cells and β-cells in regulating β-cell mass.
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GLP-1 inhibits glucagon release from α-cells, which is beneficial for reducing blood glucose levels since glucagon promotes hepatic gluconeogenesis.
“GLP-1 also inhibits glucagon release from α-cells, which is beneficial for reducing blood glucose levels since glucagon promotes hepatic gluconeogenesis.131,225”
From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [225]
The Introduction (page unavailable) describes glucagon as counterregulatory to insulin, identifies the liver as its main target, and says glucagon-receptor antagonism improves glucose control. But the paper does not say that GLP-1 inhibits glucagon release from α-cells or specify hepatic gluconeogenesis as the mechanism. Its Results instead examine GLP-1 receptor signaling in insulin secretion and glucose lowering. (LLM, conf=0.82)
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Cites
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890 · see citing works
Glucagon-like peptide 1 (GLP-1)
Müller, T. D., Finan, B., Bloom, S. R., D'Alessio, D., Drucker, D. J., Flatt, P. R., Fritsche, A., Gribble, F., Grill, H. J., Habener, J. F., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.09.010 · Cited by 1,868 · see citing works
Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure
Eizirik, D. L., Pasquali, L., & Cnop, M. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0355-7 · Cited by 854 · see citing works
Mechanisms controlling pancreatic islet cell function in insulin secretion
Campbell, J. E., & Newgard, C. B. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00317-7 · Cited by 631 · see citing works
The essential role of glucagon in the pathogenesis of diabetes mellitus
Unger, R., & Orci, L. (1975) · The Lancet · doi:10.1016/s0140-6736(75)92375-2 · Cited by 599 · see citing works
Hansen, L., Deacon, C. F., Ørskov, C., & Holst, J. J. (1999) · Endocrinology · doi:10.1210/endo.140.11.7143 · Cited by 595 · see citing works
Gelling, R. W., Du, X. Q., Dichmann, D. S., Rømer, J., Huang, H., Cui, L., Obici, S., Tang, B., Holst, J. J., Fledelius, C., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237106100 · Cited by 563 · see citing works
Insulin Secretion Depends on Intra-islet Glucagon Signaling
Svendsen, B., Larsen, O., Gabe, M. B. N., Christiansen, C. B., ROSENKILDE, M. M., Drucker, D. J., & Holst, J. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.018 · Cited by 356 · see citing works
Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells
Lee, Y.-S., & Jun, H.-S. (2014) · Metabolism · doi:10.1016/j.metabol.2013.09.010 · Cited by 315 · see citing works
β Cell tone is defined by proglucagon peptides through cAMP signaling
Capozzi, M. E., Svendsen, B., Encisco, S. E., Lewandowski, S. L., Martin, M. D., Lin, H., Jaffe, J. L., Coch, R. W., Haldeman, J. M., MacDonald, P. E., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.126742 · Cited by 248 · see citing works
The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice
Chambers, A. P., Sorrell, J. E., Haller, A. M., Roelofs, K. J., Hutch, C. R., Kim, K., Gutiérrez‐Aguilar, R., Li, B., Drucker, D. J., D’Alessio, D. A., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.02.008 · Cited by 242 · see citing works
Glucagon receptors on human islet cells contribute to glucose competence of insulin release
Huypens, P., Ling, Z., Pipeleers, D., & Schuit, F. (2000) · Diabetologia · doi:10.1007/s001250051484 · Cited by 226 · see citing works
Glucagon lowers glycemia when β cells are active
Capozzi, M. E., Wait, J. B., Koech, J., Gordon, A. N., Coch, R. W., Svendsen, B., Finan, B., D’Alessio, D. A., & Campbell, J. E. (2019) · JCI Insight · doi:10.1172/jci.insight.129954 · Cited by 168 · see citing works
Intraislet glucagon signaling is critical for maintaining glucose homeostasis
Zhu, L., Dattaroy, D., Pham, J., Wang, L., Barella, L. F., Cui, Y., Wilkins, K. J., Roth, B. L., Hochgeschwender, U., Matschinsky, F. M., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.127994 · Cited by 158 · see citing works
Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes
Lee, H., Lee, Y.-S., Harenda, Q., Pietrzak, S., Oktay, H. Z., Schreiber, S., Liao, Y., Sonthalia, S., Ciecko, A. E., Chen, Y.-G., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.03.002 · Cited by 152 · see citing works
glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis
Ye, L., Robertson, M. A., Hesselson, D., Stainier, D. Y. R., & Anderson, R. M. (2015) · Development · doi:10.1242/dev.117911 · Cited by 139 · see citing works
Kilimnik, G., Kim, A., Steiner, D. F., Friedman, T. C., & Hara, M. (2010) · Islets · doi:10.4161/isl.2.3.11396 · Cited by 137 · see citing works
Yan, H., Gu, W., Yang, J., Bi, V., Shen, Y., Lee, E. K., Winters, K. A., Komorowski, R., Zhang, C., Patel, J., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.147009 · Cited by 134 · see citing works
Self-citationA Method for Murine Islet Isolation and Subcapsular Kidney Transplantation
Zmuda, E. J., Powell, C. A., & Hai, T. (2011) · Journal of Visualized Experiments · doi:10.3791/2096 · Cited by 132 · see citing works
Repositioning Glucagon Action in the Physiology and Pharmacology of Diabetes
Finan, B., Capozzi, M. E., & Campbell, J. E. (2019) · Diabetes · doi:10.2337/dbi19-0004 · Cited by 117 · see citing works
Traub, S., Meier, D. T., Schulze, F., Dror, E., Nordmann, T. M., Goetz, N., Koch, N., Dalmas, É., Stawiski, M., Makshana, V., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.03.005 · Cited by 116 · see citing works
Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis
Ali, S., Lamont, B. J., Charron, M. J., & Drucker, D. J. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43615 · Cited by 109 · see citing works
Dual Glucagon Recognition by Pancreatic β-Cells via Glucagon and Glucagon-Like Peptide 1 Receptors
Moens, K., Flamez, D., Schravendijk, C. V., Ling, Z., PIPELEERS, D. G., & Schuit, F. C. (1998) · Diabetes · doi:10.2337/diab.47.1.66 · Cited by 97 · see citing works
Campbell, S. A., Golec, D. P., Hubert, M., Johnson, J., Salamon, N., Barr, A., MacDonald, P. E., Philippaert, K., & Light, P. E. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101014 · Cited by 83 · see citing works
Sørensen, H., Brand, C. L., Neschen, S., Holst, J. J., Fosgerau, K., Nishimura, E., & Shulman, G. I. (2006) · Diabetes · doi:10.2337/db06-0222 · Cited by 80 · see citing works
Role of glucagon in maintenance of euglycemia in fed and fasted rats
Brand, C. L., Jørgensen, P. N., Knigge, U., Warberg, J., Svendsen, I., Kristensen, J. S., & Holst, J. J. (1995) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1995.269.3.e469 · Cited by 77 · see citing works
Jun, L. S., Millican, R. L., Hawkins, E. D., Konkol, D. L., Showalter, A. D., Christe, M. E., Michael, M. D., & Sloop, K. W. (2015) · Diabetes · doi:10.2337/db14-1052 · Cited by 60 · see citing works
GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells
Saikia, M., Holter, M. M., Donahue, L. R., Lee, I. S., Zheng, Q. C., Wise, J. L., Todero, J. E., Phuong, D. J., Garibay, D., Coch, R. W., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.141851 · Cited by 57 · see citing works
Pettus, J., BOEDER, S. C., Christiansen, M. P., Denham, D. S., Bailey, T. S., Aktürk, H. K., Klaff, L. J., Rosenstock, J., Cheng, M., Bode, B. W., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-02011-x · Cited by 55 · see citing works
Gu, 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
Morgan, E. S., Tai, L.-J., Pham, N. C., Overman, J. K., Watts, L. M., Smith, A. V., Jung, S. W., Gajdošík, M., Krššák, M., Krebs, M., et al. (2019) · Diabetes Care · doi:10.2337/dc18-1343 · Cited by 50 · see citing works
Wang, M.-Y., Dean, E. D., Quittner-Strom, E. B., Zhu, Y., Chowdhury, K. H., Zhang, Z., Zhao, S., Li, N., Ye, R., Lee, Y., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2022142118 · Cited by 47 · see citing works
Glucagon 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
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 · see citing works
Cabrera, O., FICORILLI, J. V., Shaw, J., Echeverri, F., Schwede, F., Chepurny, O. G., Leech, C. A., & Holz, G. G. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101484 · Cited by 40 · see citing works
Cui, X., Feng, J. B., Wei, T., Zhang, L., Lang, S., Yang, K., Yang, J., Liu, J., Sterr, M., Lickert, H., et al. (2022) · Diabetologia · doi:10.1007/s00125-022-05822-2 · Cited by 38 · see citing works
Self-citationKostić, A., King, T. A., Yang, F., Chan, K., Yancopoulos, G. D., Gromada, J., & Harp, J. B. (2017) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13075 · Cited by 36 · see citing works
Lang, S., Yang, J., Yang, K., Gu, L., Cui, X., Wei, T., Liu, J., Le, Y., Wang, H., Wei, R., et al. (2020) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2019-001025 · Cited by 36 · see citing works
Self-citationWei, R., Gu, L., Yang, J., Yang, K., Liu, J., Le, Y.-Y., Lang, S., Wang, H.-N., Thai, D., Yan, H., et al. (2019) · iScience · doi:10.1016/j.isci.2019.05.030 · Cited by 35 · see citing works
Self-citationRegulation of Mouse Intestinal L Cell Progenitors Proliferation by the Glucagon Family of Peptides
Grigoryan, M., Kedees, M. H., Charron, M. J., Guz, Y., & Teitelman, G. (2012) · Endocrinology · doi:10.1210/en.2012-1120 · Cited by 34 · see citing works
Pettus, J., D’Alessio, D. A., Frías, J. P., Vajda, E. G., Pipkin, J. D., Rosenstock, J., Williamson, G., Zangmeister, M. A., Zhi, L., & Marschke, K. B. (2019) · Diabetes Care · doi:10.2337/dc19-1328 · Cited by 32 · see citing works
Metabolic regulation of GLP-1 and PC1/3 in pancreatic α-cell line
Sancho, V., Daniele, G., Lucchesi, D., Lupi, R., Ciccarone, A., Penno, G., Bianchi, C., Dardano, A., Miccoli, R., & Prato, S. D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0187836 · Cited by 30 · see citing works
Neutralization of Glucagon by Antiserum as a Tool in Glucagon Physiology
Holst, J. J., Galbo, H., & Richter, E. A. (1978) · Journal of Clinical Investigation · doi:10.1172/jci109104 · Cited by 25 · see citing works
In vivo studies of glucagon secretion by human islets transplanted in mice
Tellez, K., Hang, Y., Gu, X.-Y., Chang, C. A., Stein, R., & Kim, S. K. (2019) · Nature Metabolism · doi:10.1038/s42255-020-0213-x · Cited by 23 · see citing works
Cui, X., Feng, J. B., Wei, T., Gu, L., Wang, D., Lang, S., Yang, K., Yang, J., Yan, H., Wei, R., et al. (2022) · iScience · doi:10.1016/j.isci.2022.104567 · Cited by 22 · see citing works
Self-citationGlucagon-receptor-antagonism-mediated β-cell regeneration as an effective anti-diabetic therapy
Xi, Y., Song, B., Ngan, I., Solloway, M. J., Humphrey, M., Wang, Y., Mondal, K., Wu, H., Liu, W., Lindhout, D. A., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110872 · Cited by 21 · see citing works
Lang, S., Wei, R., Wei, T., Gu, L., Feng, J. B., Yan, H., Yang, J., & Hong, T. (2020) · Peptides · doi:10.1016/j.peptides.2020.170349 · Cited by 19 · see citing works
Self-citationGlucagon receptor blockage inhibits β-cell dedifferentiation through FoxO1
Wang, K., Cui, X., Li, F., Li, X., Wei, T., Liu, J., Fu, W., Yang, J., Hong, T., & Wei, R. (2022) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00101.2022 · Cited by 11 · see citing works
Self-citationGreen, A. D., Vasu, S., Moffett, R. C., & Flatt, P. R. (2016) · Biochimie · doi:10.1016/j.biochi.2016.03.007 · Cited by 10 · see citing works
Gu, L., Wang, D., Cui, X., Wei, T., Yang, K., Yang, J., Wei, R., & Hong, T. (2021) · Journal of Diabetes Research · doi:10.1155/2021/7765623 · Cited by 8 · see citing works
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Glucagon-like peptide-1 receptor: mechanisms and advances in therapy
Zheng, Z., Zong, Y., Ma, Y., Tian, Y., Pang, Y., Zhang, C., & Gao, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01931-z · Cited by 1,036 · see citing works
“131,225 GLP-1 ’ s action on α -cells regulates glucagon release.”
Background
- Authors
- Wei, T., Cui, X., Jiang, Y., Wang, K., Wang, D., Li, F., Lin, X., Gu, L., Yang, K., Yang, J., Hong, T., & Wei, R.
- Affiliations
- Peking University Third Hospital (CN)
- Corresponding author
- Hong, Tianpei
- Wei, Rui
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2023-02-24
- Volume
- 72
- Issue
- 5
- Pages
- 599-610
- ISSN
- 0012-1797 (ISSN-L)
- PMC
- PMC10130488
- OpenAlex
- W4321748203
- Cited by
- 50
- References
- 50
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 17 · 2023: 2
- FWCI
- 13.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation
- National Natural Science Foundation of China (81830022, 81970671, 82170875, 82270843, 82271611)
- Talent Project of Clinical Key Project of Peking University Third Hospital
- 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 › Genetics › Diabetes and associated disorders
- Keywords
- GLP-1 receptor, beta cell regeneration, glucagon, glucagon-like peptide-1, alpha cells, pancreatic beta cells, type 1 diabetes, type 2 diabetes, db/db mice, exendin-9-39
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Animals, Antibodies, Monoclonal, Diabetes Mellitus, Experimental, Glucagon, Insulin, Regeneration, Receptors, Glucagon, Glucagon-Secreting Cells, Mice, Glucagon-Like Peptide 1
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