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Time-resolved metabolomics analysis of beta-cells implicates the pentose phosphate pathway in the control of insulin release

Spégel, Peter LU ; Sharoyko, Vladimir LU ; Göhring, Isabel LU ; Danielsson, Anders LU ; Malmgren, Siri LU ; Nagorny, Cecilia LU ; Andersson, Lotta LU ; Köck, Thomas LU ; Sharp, Geoffrey W. G. and Straub, Susanne G. , et al. (2013) In Biochemical Journal 450. p.595-605
Abstract
Insulin secretion is coupled with changes in beta-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP(+), NADPH and insulin secretion were measured within 15 mm of stimulation of clonal INS-1 832/13 beta-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 beta-cell metabolic response. This was fulfilled by the NADPH/NADP(+) ratio, which was elevated... (More)
Insulin secretion is coupled with changes in beta-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP(+), NADPH and insulin secretion were measured within 15 mm of stimulation of clonal INS-1 832/13 beta-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 beta-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 beta-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 beta-cell stimulus-secretion coupling. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
glutathione, islets, mass spectrometry, NADPH, ribose 5-phosphate, Type, 2 diabetes
in
Biochemical Journal
volume
450
pages
595 - 605
publisher
Portland Press
external identifiers
  • wos:000315745300015
  • scopus:84874587805
ISSN
0264-6021
DOI
10.1042/BJ20121349
language
English
LU publication?
yes
id
512e5f02-915d-4894-aa1b-8c4ab1fd1d55 (old id 3669913)
date added to LUP
2016-04-01 14:44:35
date last changed
2022-04-22 04:57:18
@article{512e5f02-915d-4894-aa1b-8c4ab1fd1d55,
  abstract     = {{Insulin secretion is coupled with changes in beta-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP(+), NADPH and insulin secretion were measured within 15 mm of stimulation of clonal INS-1 832/13 beta-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 beta-cell metabolic response. This was fulfilled by the NADPH/NADP(+) ratio, which was elevated (8-fold; P &lt; 0.01) at 6 min after glucose stimulation. The NADPH/NADP+ ratio paralleled an increase in ribose 5-phosphate (&gt;2.5-fold; P &lt; 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 beta-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 beta-cell stimulus-secretion coupling.}},
  author       = {{Spégel, Peter and Sharoyko, Vladimir and Göhring, Isabel and Danielsson, Anders and Malmgren, Siri and Nagorny, Cecilia and Andersson, Lotta and Köck, Thomas and Sharp, Geoffrey W. G. and Straub, Susanne G. and Wollheim, Claes and Mulder, Hindrik}},
  issn         = {{0264-6021}},
  keywords     = {{glutathione; islets; mass spectrometry; NADPH; ribose 5-phosphate; Type; 2 diabetes}},
  language     = {{eng}},
  pages        = {{595--605}},
  publisher    = {{Portland Press}},
  series       = {{Biochemical Journal}},
  title        = {{Time-resolved metabolomics analysis of beta-cells implicates the pentose phosphate pathway in the control of insulin release}},
  url          = {{http://dx.doi.org/10.1042/BJ20121349}},
  doi          = {{10.1042/BJ20121349}},
  volume       = {{450}},
  year         = {{2013}},
}