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        Incretin-modulated beta cell energetics in intact islets of Langerhans

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        Author
        Hodson, David J
        Tarasov, Andrei I
        Gimeno Brias, Silvia
        Mitchell, Ryan K
        Johnston, Natalie R
        Haghollahi, Shahab
        Cane, Matthew C
        Bugliani, Marco
        Marchetti, Piero
        Bosco, Domenico
        Johnson, Paul R
        Hughes, Stephen J
        Rutter, Guy A
        Attention
        2299/20515
        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.
        Publication date
        2014-06-01
        Published in
        Molecular endocrinology (Baltimore, Md.)
        Published version
        https://doi.org/10.1210/me.2014-1038
        Other links
        http://hdl.handle.net/2299/20515
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