Incretin-modulated beta cell energetics in intact islets of Langerhans.
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.
Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine (D.J.H, A.I.T., S.G.B., R.K.M., N.R.J., S.H., M.C.C., G.A.R.), Imperial College London, London W12 0NN, United Kingdom; Department of Endocrinology and Metabolism (M.B., P.M.), University of Pisa, 56126 Pisa, Italy; Cell Isolation and Transplantation Center, Department of Surgery (D.B.), Geneva University Hospitals and University of Geneva, 1205 Geneva, Switzerland; Oxford Centre for Diabetes, Endocrinology, & Metabolism (P.R.J., S.J.H.), University of Oxford, Oxford OX3 7LE, United Kingdom; NIHR Oxford Biomedical Research Centre (P.R.J., S.J.H.), Churchill Hospital, Oxford OX3 7LE, United Kingdom; and Nuffield Department of Surgical Sciences (P.R.J., S.J.H.), University of Oxford, Oxford OX3 9DU, United Kingdom.
David J
DJ
Hodson
Andrei I
AI
Tarasov
Silvia
S
Gimeno Brias
Ryan K
RK
Mitchell
Natalie R
NR
Johnston
Shahab
S
Haghollahi
Matthew C
MC
Cane
Marco
M
Bugliani
Piero
P
Marchetti
Domenico
D
Bosco
Paul R
PR
Johnson
Stephen J
SJ
Hughes
Guy A
GA
Rutter
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000818:Animals; D020013:Calcium Signaling; D004734:Energy Metabolism; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006801:Humans; D054795:Incretins / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008875:Middle Aged; D018027:Receptors, Glucagon / Q000378:metabolism; D013045:Species Specificity; D046509:Tissue Culture Techniques
C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; D005947:Glucose