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

• Published in: Scientific reports Vol. 7; no. 1; pp. 2661 - 13
• Main Authors: Carlessi, Rodrigo, Chen, Younan, Rowlands, Jordan, Cruzat, Vinicius F., Keane, Kevin N., Egan, Lauren, Mamotte, Cyril, Stokes, Rebecca, Gunton, Jenny E., Bittencourt, Paulo Ivo Homem de, Newsholme, Philip
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/80/86/2363; 692/163/2743/137/773; 82; 82/80; 96; 96/1; 96/106; 96/109; 96/31; Animals; Cell Line; Gene expression; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose; Glucose - metabolism; Glycolysis; Humanities and Social Sciences; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Insulin; Insulin secretion; Insulin-Secreting Cells - metabolism; Kinases; Male; Metabolism; Mice, Inbred C57BL; Mitochondria - metabolism; multidisciplinary; Pancreas; Phosphorylation; Rats; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Secretion; Signal Transduction; Stimulus-secretion coupling; TOR protein; TOR Serine-Threonine Kinases - metabolism; Up-Regulation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02838-2

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.