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 language | English |
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Pages (from-to) | 860-71 |
Number of pages | 12 |
Journal | Molecular Endocrinology |
Volume | 28 |
Issue number | 6 |
Early online date | 25 Apr 2014 |
DOIs | |
Publication status | Published - 1 Jun 2014 |
Keywords
- Adenosine Triphosphate/metabolism
- Adult
- Animals
- Calcium Signaling
- Energy Metabolism
- Glucagon-Like Peptide 1/physiology
- Glucagon-Like Peptide-1 Receptor
- Glucose/metabolism
- Humans
- Incretins/physiology
- Insulin-Secreting Cells/metabolism
- Membrane Potential, Mitochondrial
- Mice
- Middle Aged
- Receptors, Glucagon/metabolism
- Species Specificity
- Tissue Culture Techniques