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

Author:

Spégel Peter1,Sharoyko Vladimir V.1,Goehring Isabel1,Danielsson Anders P. H.1,Malmgren Siri1,Nagorny Cecilia L. F.1,Andersson Lotta E.1,Koeck Thomas1,Sharp Geoffrey W. G.2,Straub Susanne G.2,Wollheim Claes B.13,Mulder Hindrik1

Affiliation:

1. Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden

2. Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, U.S.A.

3. Department of Cell Physiology and Metabolism, University Medical Center, Rue Michel-Servet 1, Geneva 4, Switzerland

Abstract

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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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