Glucagon-like peptide-1 (GLP-1) is a potent regulator of glucose-stimulated insulin secretion whose mechanisms of action are only partly understood. In the present paper, we show that at low (3mM) glucose concentrations, GLP-1 increases the free intramitochondrial concentrations of both Ca2+ ([Ca2+]m), and ATP ([ATP]m) in clonal MIN6 β-cells. Suggesting that cAMP-mediated release of Ca2+ from intracellular stores is responsible for these effects, increases in [ATP]m that were induced by GLP-1 were completely blocked by the Rp isomer of adenosine-3′,5′-cyclic monophosphothioate (Rp-cAMPS), or by chelation of intracellular Ca2+. Furthermore, inhibition of Ins(1,4,5)P3 (IP3) receptors with xestospongin C, or application of ryanodine, partially inhibited GLP-1-induced [ATP]m increases, and the simultaneous blockade of both IP3 and ryanodine receptors (RyR) completely eliminated the rise in [ATP]m. GLP-1 appeared to prompt Ca2+-induced Ca2+ release through IP3 receptors via a protein kinase A (PKA)-mediated phosphorylation event, since ryanodine-insensitive [ATP]m increases were abrogated with the PKA inhibitor, H89. In contrast, the effects of GLP-1 on RyR-mediated [ATP]m increases were apparently mediated by the cAMP-regulated guanine nucleotide exchange factor cAMP-GEFII, since xestospongin C-insensitive [ATP]m increases were blocked by a dominant-negative form of cAMP-GEFII (G114E,G422D). Taken together, these results demonstrate that GLP-1 potentiates glucose-stimulated insulin release in part via the mobilization of intracellular Ca2+, and the stimulation of mitochondrial ATP synthesis.
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January 2003
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Research Article|
January 15 2003
Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells
Takashi TSUBOI;
Takashi TSUBOI
∗Henry Wellcome Laboratories for Integrated Cell Signalling, Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
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Gabriela da SILVA XAVIER;
Gabriela da SILVA XAVIER
∗Henry Wellcome Laboratories for Integrated Cell Signalling, Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
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George G. HOLZ;
George G. HOLZ
†Department of Physiology and Neuroscience, New York University School of Medicine, 550 First Avenue, New York, NY 10016, U.S.A.,
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Laurence S. JOUAVILLE;
Laurence S. JOUAVILLE
‡Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey (UMDNJ), 185 South Orange Avenue, University Heights, Newark, NJ 07103, U.S.A.
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Andrew P. THOMAS;
Andrew P. THOMAS
‡Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey (UMDNJ), 185 South Orange Avenue, University Heights, Newark, NJ 07103, U.S.A.
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Guy A. RUTTER
Guy A. RUTTER
1
∗Henry Wellcome Laboratories for Integrated Cell Signalling, Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, U.K.
1To whom correspondence should be addressed (e-mail g.a.rutter@bristol.ac.uk).
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Publisher: Portland Press Ltd
Received:
August 14 2002
Revision Received:
September 25 2002
Accepted:
October 31 2002
Accepted Manuscript online:
October 31 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 369 (2): 287–299.
Article history
Received:
August 14 2002
Revision Received:
September 25 2002
Accepted:
October 31 2002
Accepted Manuscript online:
October 31 2002
Citation
Takashi TSUBOI, Gabriela da SILVA XAVIER, George G. HOLZ, Laurence S. JOUAVILLE, Andrew P. THOMAS, Guy A. RUTTER; Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells. Biochem J 15 January 2003; 369 (2): 287–299. doi: https://doi.org/10.1042/bj20021288
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