Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis
Objective: Type 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with β-cell selective loss of the glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor (GCGR) signalling on pan-islet [Ca2+]I activity and ins...
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| Médium: | Journal Article |
| Jazyk: | English |
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2024
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| On-line přístup: | https://hdl.handle.net/10356/179717 |
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| author | Suba, K. Patel, Y. Martin-Alonso, A. Hansen, B. Xu, X. Roberts, A. Norton, M. Chung, P. Shrewsbury, J. Kwok, R. Kalogianni, V. Chen, S. Liu, X. Kalyviotis, K. Rutter, Guy A. Jones, B. Minnion, J. Owen, B. M. Pantazis, P. Distaso, W. Drucker, D. J. Tan, T. M. Bloom, S. R. Murphy, K. G. Salem, V. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Suba, K. Patel, Y. Martin-Alonso, A. Hansen, B. Xu, X. Roberts, A. Norton, M. Chung, P. Shrewsbury, J. Kwok, R. Kalogianni, V. Chen, S. Liu, X. Kalyviotis, K. Rutter, Guy A. Jones, B. Minnion, J. Owen, B. M. Pantazis, P. Distaso, W. Drucker, D. J. Tan, T. M. Bloom, S. R. Murphy, K. G. Salem, V. |
| author_sort | Suba, K. |
| collection | NTU |
| description | Objective: Type 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with β-cell selective loss of the glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor (GCGR) signalling on pan-islet [Ca2+]I activity and insulin secretion. Methods: Metabolic profiling was conducted on Gcgrβ-cell−/− and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. Results: Gcgrβ-cell−/− mice exhibited higher glucose levels following intraperitoneal glucose challenge (control 12.7 mmol/L ± 0.6 vs. Gcgrβ-cell−/− 15.4 mmol/L ± 0.0 at 15 min, p = 0.002); fasting glycaemia was not different to controls. In vitro, Gcgrβ-cell−/− islets showed profound loss of pan-islet [Ca2+]I waves in response to glucose which was only partially rescued in vivo. Diet induced obesity and hyperglycaemia also resulted in a loss of co-ordinated [Ca2+]I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n = 8). Conclusion: These data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised [Ca2+]I waves and support a possible therapeutic role for glucagonergic agents to restore the insulin secretory capacity lost in T2D. |
| first_indexed | 2024-10-01T03:05:42Z |
| format | Journal Article |
| id | ntu-10356/179717 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:05:42Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1797172024-08-25T15:38:23Z Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis Suba, K. Patel, Y. Martin-Alonso, A. Hansen, B. Xu, X. Roberts, A. Norton, M. Chung, P. Shrewsbury, J. Kwok, R. Kalogianni, V. Chen, S. Liu, X. Kalyviotis, K. Rutter, Guy A. Jones, B. Minnion, J. Owen, B. M. Pantazis, P. Distaso, W. Drucker, D. J. Tan, T. M. Bloom, S. R. Murphy, K. G. Salem, V. Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences Calcium waves Glucagon Objective: Type 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with β-cell selective loss of the glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor (GCGR) signalling on pan-islet [Ca2+]I activity and insulin secretion. Methods: Metabolic profiling was conducted on Gcgrβ-cell−/− and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. Results: Gcgrβ-cell−/− mice exhibited higher glucose levels following intraperitoneal glucose challenge (control 12.7 mmol/L ± 0.6 vs. Gcgrβ-cell−/− 15.4 mmol/L ± 0.0 at 15 min, p = 0.002); fasting glycaemia was not different to controls. In vitro, Gcgrβ-cell−/− islets showed profound loss of pan-islet [Ca2+]I waves in response to glucose which was only partially rescued in vivo. Diet induced obesity and hyperglycaemia also resulted in a loss of co-ordinated [Ca2+]I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n = 8). Conclusion: These data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised [Ca2+]I waves and support a possible therapeutic role for glucagonergic agents to restore the insulin secretory capacity lost in T2D. Published version VS is supported by a Diabetes UK Harry Keen Clinician Scientist Fellowship (15/0005317). We thank the Imperial College London and Leica Microsystems Imaging Hub for infrastructure and expertise. G.A.R. was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grant (MR/R022259/1) a start-up grant from the CHUM Research Center at the University of Montreal and a Canadian Foundation for Innovation John R. Evans infrastructure grant. DJD was supported by CIHR grant 154321, a Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology, and the Sinai Health Novo Nordisk Foundation fund in regulatory peptides. 2024-08-19T07:22:32Z 2024-08-19T07:22:32Z 2024 Journal Article Suba, K., Patel, Y., Martin-Alonso, A., Hansen, B., Xu, X., Roberts, A., Norton, M., Chung, P., Shrewsbury, J., Kwok, R., Kalogianni, V., Chen, S., Liu, X., Kalyviotis, K., Rutter, G. A., Jones, B., Minnion, J., Owen, B. M., Pantazis, P., ...Salem, V. (2024). Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis. Molecular Metabolism, 85, 101947-. https://dx.doi.org/10.1016/j.molmet.2024.101947 2212-8778 https://hdl.handle.net/10356/179717 10.1016/j.molmet.2024.101947 38677509 2-s2.0-85194430559 85 101947 en Molecular Metabolism © 2024 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Calcium waves Glucagon Suba, K. Patel, Y. Martin-Alonso, A. Hansen, B. Xu, X. Roberts, A. Norton, M. Chung, P. Shrewsbury, J. Kwok, R. Kalogianni, V. Chen, S. Liu, X. Kalyviotis, K. Rutter, Guy A. Jones, B. Minnion, J. Owen, B. M. Pantazis, P. Distaso, W. Drucker, D. J. Tan, T. M. Bloom, S. R. Murphy, K. G. Salem, V. Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis |
| title | Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis |
| title_full | Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis |
| title_fullStr | Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis |
| title_full_unstemmed | Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis |
| title_short | Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis |
| title_sort | intra islet glucagon signalling regulates beta cell connectivity first phase insulin secretion and glucose homoeostasis |
| topic | Medicine, Health and Life Sciences Calcium waves Glucagon |
| url | https://hdl.handle.net/10356/179717 |
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