GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation
Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic ß-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabo...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/20.500.11937/54805 |
| _version_ | 1848759465579380736 |
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| author | Carlessi, Rodrigo Chen, Y. Rowlands, J. Cruzat, Vinicius Keane, Kevin Egan, L. Mamotte, Cyril Stokes, R. Gunton, J. Bittencourt, P. Newsholme, Philip |
| author_facet | Carlessi, Rodrigo Chen, Y. Rowlands, J. Cruzat, Vinicius Keane, Kevin Egan, L. Mamotte, Cyril Stokes, R. Gunton, J. Bittencourt, P. Newsholme, Philip |
| author_sort | Carlessi, Rodrigo |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic ß-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in ß-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 ß-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of ß-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1a) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in ß-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated ß-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression. |
| first_indexed | 2025-11-14T10:00:19Z |
| format | Journal Article |
| id | curtin-20.500.11937-54805 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:00:19Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-548052017-09-29T00:10:38Z GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation Carlessi, Rodrigo Chen, Y. Rowlands, J. Cruzat, Vinicius Keane, Kevin Egan, L. Mamotte, Cyril Stokes, R. Gunton, J. Bittencourt, P. Newsholme, Philip Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic ß-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in ß-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 ß-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of ß-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1a) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in ß-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated ß-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression. 2017 Journal Article http://hdl.handle.net/20.500.11937/54805 10.1038/s41598-017-02838-2 http://creativecommons.org/licenses/by/4.0/ Nature Publishing Group fulltext |
| spellingShingle | Carlessi, Rodrigo Chen, Y. Rowlands, J. Cruzat, Vinicius Keane, Kevin Egan, L. Mamotte, Cyril Stokes, R. Gunton, J. Bittencourt, P. Newsholme, Philip GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation |
| title | GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation |
| title_full | GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation |
| title_fullStr | GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation |
| title_full_unstemmed | GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation |
| title_short | GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation |
| title_sort | glp-1 receptor signalling promotes β-cell glucose metabolism via mtor-dependent hif-1α activation |
| url | http://hdl.handle.net/20.500.11937/54805 |