GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation
Abstract Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-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 gluco...
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Nature Portfolio
2017
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oai:doaj.org-article:caf5cdca187a473db8fc37928e03d4c92021-12-02T11:53:10ZGLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation10.1038/s41598-017-02838-22045-2322https://doaj.org/article/caf5cdca187a473db8fc37928e03d4c92017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02838-2https://doaj.org/toc/2045-2322Abstract Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-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 β-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 β-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 β-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-1α) 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 β-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated β-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression.Rodrigo CarlessiYounan ChenJordan RowlandsVinicius F. CruzatKevin N. KeaneLauren EganCyril MamotteRebecca StokesJenny E. GuntonPaulo Ivo Homem de BittencourtPhilip NewsholmeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017) |
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Medicine R Science Q Rodrigo Carlessi Younan Chen Jordan Rowlands Vinicius F. Cruzat Kevin N. Keane Lauren Egan Cyril Mamotte Rebecca Stokes Jenny E. Gunton Paulo Ivo Homem de Bittencourt Philip Newsholme GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation |
| description |
Abstract Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic β-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 β-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 β-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 β-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-1α) 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 β-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated β-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression. |
| format |
article |
| author |
Rodrigo Carlessi Younan Chen Jordan Rowlands Vinicius F. Cruzat Kevin N. Keane Lauren Egan Cyril Mamotte Rebecca Stokes Jenny E. Gunton Paulo Ivo Homem de Bittencourt Philip Newsholme |
| author_facet |
Rodrigo Carlessi Younan Chen Jordan Rowlands Vinicius F. Cruzat Kevin N. Keane Lauren Egan Cyril Mamotte Rebecca Stokes Jenny E. Gunton Paulo Ivo Homem de Bittencourt Philip Newsholme |
| author_sort |
Rodrigo Carlessi |
| title |
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_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_sort |
glp-1 receptor signalling promotes β-cell glucose metabolism via mtor-dependent hif-1α activation |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/caf5cdca187a473db8fc37928e03d4c9 |
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