Insulin secretion is coupled with changes in β-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP+, NADPH and insulin secretion were measured within 15 min of stimulation of clonal INS-1 832/13 β-cells with glucose. Rapid responses in the major metabolic pathways of glucose occurred, involving several previously suggested metabolic coupling factors. The complexity of metabolite changes observed disagreed with the concept of one single metabolite controlling insulin secretion. The complex alterations in metabolite levels suggest that a coupling signal should reflect large parts of the β-cell metabolic response. This was fulfilled by the NADPH/NADP+ ratio, which was elevated (8-fold; P<0.01) at 6 min after glucose stimulation. The NADPH/NADP+ ratio paralleled an increase in ribose 5-phosphate (>2.5-fold; P<0.001). Inhibition of the pentose phosphate pathway by trans-dehydroepiandrosterone (DHEA) suppressed ribose 5-phosphate levels and production of reduced glutathione, as well as insulin secretion in INS-1 832/13 β-cells and rat islets without affecting ATP production. Metabolite profiling of rat islets confirmed the glucose-induced rise in ribose 5-phosphate, which was prevented by DHEA. These findings implicate the pentose phosphate pathway, and support a role for NADPH and glutathione, in β-cell stimulus-secretion coupling.
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Research Article|
February 28 2013
Time-resolved metabolomics analysis of β-cells implicates the pentose phosphate pathway in the control of insulin release
Peter Spégel;
Peter Spégel
1
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
1To whom correspondence should be addressed (email peter.spegel@med.lu.se).
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Vladimir V. Sharoyko;
Vladimir V. Sharoyko
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
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Isabel Goehring;
Isabel Goehring
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
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Anders P. H. Danielsson;
Anders P. H. Danielsson
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
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Siri Malmgren;
Siri Malmgren
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
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Cecilia L. F. Nagorny;
Cecilia L. F. Nagorny
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
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Lotta E. Andersson;
Lotta E. Andersson
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
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Thomas Koeck;
Thomas Koeck
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
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Geoffrey W. G. Sharp;
Geoffrey W. G. Sharp
†Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, U.S.A.
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Susanne G. Straub;
Susanne G. Straub
†Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, U.S.A.
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Claes B. Wollheim;
Claes B. Wollheim
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
‡Department of Cell Physiology and Metabolism, University Medical Center, Rue Michel-Servet 1, Geneva 4, Switzerland
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Hindrik Mulder
Hindrik Mulder
*Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden
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Publisher: Portland Press Ltd
Received:
August 28 2012
Revision Received:
December 14 2012
Accepted:
January 02 2013
Accepted Manuscript online:
January 02 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 450 (3): 595–605.
Article history
Received:
August 28 2012
Revision Received:
December 14 2012
Accepted:
January 02 2013
Accepted Manuscript online:
January 02 2013
Citation
Peter Spégel, Vladimir V. Sharoyko, Isabel Goehring, Anders P. H. Danielsson, Siri Malmgren, Cecilia L. F. Nagorny, Lotta E. Andersson, Thomas Koeck, Geoffrey W. G. Sharp, Susanne G. Straub, Claes B. Wollheim, Hindrik Mulder; Time-resolved metabolomics analysis of β-cells implicates the pentose phosphate pathway in the control of insulin release. Biochem J 15 March 2013; 450 (3): 595–605. doi: https://doi.org/10.1042/BJ20121349
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