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Ca2+, NAD(P)H and membrane potential changes in pancreatic beta-cells by methyl succinate: comparison with glucose

Ca2+, NAD(P)H and membrane potential changes in pancreatic beta-cells by methyl succinate: comparison with glucose
Ca2+, NAD(P)H and membrane potential changes in pancreatic beta-cells by methyl succinate: comparison with glucose
The present study was undertaken to determine the main metabolic secretory signals generated by the mitochondrial substrate MeS (methyl succinate) compared with glucose in mouse and rat islets and to understand the differences. Glycolysis and mitochondrial metabolism both have key roles in the stimulation of insulin secretion by glucose. Both fuels elicited comparable oscillatory patterns of Ca2+ and changes in plasma and mitochondrial membrane potential in rat islet cells and clonal pancreatic beta-cells (INS-1). Saturation of the Ca2+ signal occurred between 5 and 6 mM MeS, while secretion reached its maximum at 15 mM, suggesting operation of a K(ATP)-channel-independent pathway. Additional responses to MeS and glucose included elevated NAD(P)H autofluorescence in INS-1 cells and islets and increases in assayed NADH and NADPH and the ATP/ADP ratio. Increased NADPH and ATP/ADP ratios occurred more rapidly with MeS, although similar levels were reached after 5 min of exposure to each fuel, whereas NADH increased more with MeS than with glucose. Reversal of MeS-induced cell depolarization by Methylene Blue completely inhibited MeS-stimulated secretion, whereas basal secretion and KCl-induced changes in these parameters were not affected. MeS had no effect on secretion or signals in the mouse islets, in contrast with glucose, possibly due to a lack of malic enzyme. The data are consistent with the common intermediates being pyruvate, cytosolic NADPH or both, and suggest that cytosolic NADPH production could account for the more rapid onset of MeS-induced secretion compared with glucose stimulation
1470-8728
197-205
Heart, Emma
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Yaney, Gordon C.
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Corkey, Richard F.
491e731c-fc76-43c8-ae2b-5d179295dbe6
Schultz, Vera
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Luc, Esthere
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Liu, Lihan
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Deeney, Jude T.
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Shirihai, Orian
48936be0-53bd-4426-9c18-a41acd02287d
Tornheim, Keith
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Smith, Peter J.S.
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Corkey, Barbara E.
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Heart, Emma
f8b99fd2-026e-43cd-9db6-67edd6d18c98
Yaney, Gordon C.
cce59419-aef9-448c-a6e4-343525366c74
Corkey, Richard F.
491e731c-fc76-43c8-ae2b-5d179295dbe6
Schultz, Vera
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Luc, Esthere
549686e5-1d70-486f-8756-12e000994743
Liu, Lihan
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Deeney, Jude T.
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Shirihai, Orian
48936be0-53bd-4426-9c18-a41acd02287d
Tornheim, Keith
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Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Corkey, Barbara E.
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Heart, Emma, Yaney, Gordon C., Corkey, Richard F., Schultz, Vera, Luc, Esthere, Liu, Lihan, Deeney, Jude T., Shirihai, Orian, Tornheim, Keith, Smith, Peter J.S. and Corkey, Barbara E. (2007) Ca2+, NAD(P)H and membrane potential changes in pancreatic beta-cells by methyl succinate: comparison with glucose. Biochemical Journal, 403 (1), 197-205. (doi:10.1042/BJ20061209). (PMID:17181533)

Record type: Article

Abstract

The present study was undertaken to determine the main metabolic secretory signals generated by the mitochondrial substrate MeS (methyl succinate) compared with glucose in mouse and rat islets and to understand the differences. Glycolysis and mitochondrial metabolism both have key roles in the stimulation of insulin secretion by glucose. Both fuels elicited comparable oscillatory patterns of Ca2+ and changes in plasma and mitochondrial membrane potential in rat islet cells and clonal pancreatic beta-cells (INS-1). Saturation of the Ca2+ signal occurred between 5 and 6 mM MeS, while secretion reached its maximum at 15 mM, suggesting operation of a K(ATP)-channel-independent pathway. Additional responses to MeS and glucose included elevated NAD(P)H autofluorescence in INS-1 cells and islets and increases in assayed NADH and NADPH and the ATP/ADP ratio. Increased NADPH and ATP/ADP ratios occurred more rapidly with MeS, although similar levels were reached after 5 min of exposure to each fuel, whereas NADH increased more with MeS than with glucose. Reversal of MeS-induced cell depolarization by Methylene Blue completely inhibited MeS-stimulated secretion, whereas basal secretion and KCl-induced changes in these parameters were not affected. MeS had no effect on secretion or signals in the mouse islets, in contrast with glucose, possibly due to a lack of malic enzyme. The data are consistent with the common intermediates being pyruvate, cytosolic NADPH or both, and suggest that cytosolic NADPH production could account for the more rapid onset of MeS-induced secretion compared with glucose stimulation

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Published date: 1 April 2007
Organisations: University of Southampton

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Local EPrints ID: 190281
URI: http://eprints.soton.ac.uk/id/eprint/190281
ISSN: 1470-8728
PURE UUID: 95312d4b-3598-4f9d-9780-769da7a947ba
ORCID for Peter J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

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Date deposited: 16 Jun 2011 10:14
Last modified: 31 Jul 2019 00:36

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Contributors

Author: Emma Heart
Author: Gordon C. Yaney
Author: Richard F. Corkey
Author: Vera Schultz
Author: Esthere Luc
Author: Lihan Liu
Author: Jude T. Deeney
Author: Orian Shirihai
Author: Keith Tornheim
Author: Barbara E. Corkey

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