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

Sci Rep. 2017 Jun 1;7(1):2661. doi: 10.1038/s41598-017-02838-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Glucagon-Like Peptide-1 Receptor / metabolism*
  • Glucose / metabolism*
  • Glycolysis
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Up-Regulation

Substances

  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Glucose