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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

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

Author

  • Peter Spégel
  • Vladimir Sharoyko
  • Isabel Göhring
  • Anders Danielsson
  • Siri Malmgren
  • Cecilia Nagorny
  • Lotta Andersson
  • Thomas Köck
  • Geoffrey W. G. Sharp
  • Susanne G. Straub
  • Claes Wollheim
  • Hindrik Mulder

Summary, in English

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.

Department/s

  • Diabetes - Molecular Metabolism
  • Department of Clinical Sciences, Malmö
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2013

Language

English

Pages

595-605

Publication/Series

Biochemical Journal

Volume

450

Document type

Journal article

Publisher

Portland Press

Topic

  • Biochemistry and Molecular Biology

Keywords

  • glutathione
  • islets
  • mass spectrometry
  • NADPH
  • ribose 5-phosphate
  • Type
  • 2 diabetes

Status

Published

Research group

  • Diabetes - Molecular Metabolism

ISBN/ISSN/Other

  • ISSN: 0264-6021