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GLP-1 receptor signalling promotes beta-cell glucose metabolism via mTOR-dependent HIF-1alpha activation


Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic beta-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 beta-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 beta-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 beta-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-1alpha) 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 beta-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated beta-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression.

Type Journal
ISBN 2045-2322 (Electronic) 2045-2322 (Linking)
Authors 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.; Newsholme, P.
Responsible Garvan Author (missing name)
Publisher Name Scientific Reports
Published Date 2017-06-01
Published Volume 7
Published Issue 1
Published Pages 2661
Status Published in-print
DOI 10.1038/s41598-017-02838-2
URL link to publisher's version