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GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation4.80 MB
Published (Version of record)CC BY V4.0, Open Access
Published (Version of record)CC BY V4.0, Open
Journal article
GLP-1 receptor signalling promotes beta-cell glucose metabolism via mTOR-dependent HIF-1 alpha activation
Scientific reports, Vol.7(1), pp.1-13
01/06/2017
PMCID: PMC5454020
PMID: 28572610
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Source: InCites
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.
Details
- Title
- GLP-1 receptor signalling promotes beta-cell glucose metabolism via mTOR-dependent HIF-1 alpha activation
- Creators
- Rodrigo Carlessi - Curtin Hlth Innovat Res Inst, Sch Biomed Sci, Perth, WA, AustraliaYung-Sheng Chen - Curtin Hlth Innovat Res Inst, Sch Biomed Sci, Perth, WA, AustraliaJordan Rowlands - Curtin Hlth Innovat Res Inst, Sch Biomed Sci, Perth, WA, AustraliaVinicius Cruzat - Curtin UniversityKevin Noel Keane - Curtin Hlth Innovat Res Inst, Sch Biomed Sci, Perth, WA, AustraliaLauren Egan - Curtin Hlth Innovat Res Inst, Sch Biomed Sci, Perth, WA, AustraliaCyril Mamotte - Curtin Hlth Innovat Res Inst, Sch Biomed Sci, Perth, WA, AustraliaRebecca Stokes - Univ Sydney, Ctr Diabet Obes & Endocrinol, Westmead Millennium Inst Med Res, Westmead, NSW, AustraliaJenny E. Gunton - Univ Sydney, Ctr Diabet Obes & Endocrinol, Westmead Millennium Inst Med Res, Westmead, NSW, AustraliaPaulo Ivo Homem de Bittencourt - Univ Fed Rio Grande do Sul, Inst Basic Hlth Sci, Dept Physiol, Porto Alegre, RS, BrazilPhilip Newsholme - Curtin Hlth Innovat Res Inst, Sch Biomed Sci, Perth, WA, Australia
- Publication Details
- Scientific reports, Vol.7(1), pp.1-13
- Publisher
- Springer Nature
- Identifiers
- 991013071412502368
- Copyright
- © The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
- Academic Unit
- Faculty of Health
- Language
- English
- Resource Type
- Journal article