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

• Autor(a) principal: Carlessi, Rodrigo Maron
• Data de Publicação: 2016
• Outros Autores: Chen, Younan, Rowlands, Jordan, Cruzat, Vinicius Fernandes, Keane, Kevin Noel, Egan, Lauren, Mamotte, Cyril, Stokes, Rebecca, Gunton, Jenny E., Bittencourt Junior, Paulo Ivo Homem de, Newsholme, Philip
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/225545
• topic: Peptídeo 1 semelhante ao glucagón; Receptor do peptídeo semelhante ao glucagon 1; Diabetes mellitus tipo 2; Hormone receptors; Type 2 diabetes

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 (50nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18hours 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 HypoxiaInducible 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.