دورية أكاديمية
GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation
| العنوان: | GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation |
|---|---|
| المؤلفون: | Carlessi, R, Chen, Y, Rowlands, J, Cruzat, VF, Keane, KN, Egan, L, Mamotte, C, Stokes, R, Gunton, JE, Bittencourt, PIHD, Newsholme, P |
| المصدر: | urn:ISSN:2045-2322 ; Scientific Reports, 7, 1, 2661 |
| بيانات النشر: | Springer Nature |
| سنة النشر: | 2017 |
| المجموعة: | UNSW Sydney (The University of New South Wales): UNSWorks |
| مصطلحات موضوعية: | Diabetes, 1 Underpinning research, 5 Development of treatments and therapeutic interventions, 1.1 Normal biological development and functioning, 5.1 Pharmaceuticals, Metabolic and endocrine, Animals, Cell Line, Glucagon-Like Peptide-1 Receptor, Glucose, Glycolysis, Hypoxia-Inducible Factor 1, alpha Subunit, Insulin-Secreting Cells, Male, Mice, Inbred C57BL, Mitochondria, RNA, Messenger, Rats, Signal Transduction, TOR Serine-Threonine Kinases, Up-Regulation |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| العلاقة: | http://hdl.handle.net/1959.4/unsworks_53845Test; https://doi.org/10.1038/s41598-017-02838-2Test |
| DOI: | 10.1038/s41598-017-02838-2 |
| الإتاحة: | https://doi.org/10.1038/s41598-017-02838-2Test http://hdl.handle.net/1959.4/unsworks_53845Test |
| حقوق: | open access ; https://purl.org/coar/access_right/c_abf2Test ; CC-BY-NC-ND ; https://creativecommons.org/licenses/by-nc-nd/4.0Test/ ; CC BY ; https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.6C82FB1 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41598-017-02838-2 |
|---|