GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation

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

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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.

Original languageEnglish
Article number2661
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017
Externally publishedYes

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Carlessi, R., Chen, Y., Rowlands, J., Cruzat, V. F., Keane, K. N., Egan, L., Mamotte, C., Stokes, R., Gunton, J. E., Bittencourt, P. I. H. D., & Newsholme, P. (2017). GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation. Scientific Reports, 7(1), [2661]. https://doi.org/10.1038/s41598-017-02838-2