Incretin-modulated beta cell energetics in intact islets of Langerhans

David J Hodson, Andrei I Tarasov, Silvia Gimeno Brias, Ryan K Mitchell, Natalie R Johnston, Shahab Haghollahi, Matthew C Cane, Marco Bugliani, Piero Marchetti, Domenico Bosco, Paul R Johnson, Stephen J Hughes, Guy A Rutter

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)
99 Downloads (Pure)

Abstract

Incretins such as glucagon-like peptide 1 (GLP-1) are released from the gut and potentiate insulin release in a glucose-dependent manner. Although this action is generally believed to hinge on cAMP and protein kinase A signaling, up-regulated beta cell intermediary metabolism may also play a role in incretin-stimulated insulin secretion. By employing recombinant probes to image ATP dynamically in situ within intact mouse and human islets, we sought to clarify the role of GLP-1-modulated energetics in beta cell function. Using these techniques, we show that GLP-1 engages a metabolically coupled subnetwork of beta cells to increase cytosolic ATP levels, an action independent of prevailing energy status. We further demonstrate that the effects of GLP-1 are accompanied by alterations in the mitochondrial inner membrane potential and, at elevated glucose concentration, depend upon GLP-1 receptor-directed calcium influx through voltage-dependent calcium channels. Lastly, and highlighting critical species differences, beta cells within mouse but not human islets respond coordinately to incretin stimulation. Together, these findings suggest that GLP-1 alters beta cell intermediary metabolism to influence ATP dynamics in a species-specific manner, and this may contribute to divergent regulation of the incretin-axis in rodents and man.

Original languageEnglish
Pages (from-to)860-71
Number of pages12
JournalMolecular Endocrinology
Volume28
Issue number6
Early online date25 Apr 2014
DOIs
Publication statusPublished - Jun 2014

Keywords

  • Adenosine Triphosphate
  • Adult
  • Animals
  • Calcium Signaling
  • Energy Metabolism
  • Glucagon-Like Peptide 1
  • Glucose
  • Humans
  • Incretins
  • Insulin-Secreting Cells
  • Membrane Potential, Mitochondrial
  • Mice
  • Middle Aged
  • Receptors, Glucagon
  • Species Specificity
  • Tissue Culture Techniques

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