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Metabolomic analyses reveal profound differences in glycolytic and tricarboxylic acid cycle metabolism in glucose-responsive and -unresponsive clonal beta-cell lines

Author:
  • Peter Spégel
  • Siri Malmgren
  • Vladimir Sharoyko
  • Philip Newsholme
  • Thomas Köck
  • Hindrik Mulder
Publishing year: 2011
Language: English
Pages: 277-284
Publication/Series: Biochemical Journal
Volume: 435
Document type: Journal article
Publisher: Portland Press Limited

Abstract english

Insulin secretion from pancreatic beta-cells is controlled by complex metabolic and energetic changes provoked by exposure to metabolic fuels. Perturbations in these processes lead to impaired insulin secretion, the ultimate cause of T2D (Type 2 diabetes). To increase our understanding of stimulus secretion coupling and metabolic processes potentially involved in the pathogenesis of T2D, a comprehensive investigation of the metabolic response in the glucose-responsive INS-1 832/13 and glucose-unresponsive INS-1 832/2 beta-cell lines was performed. For this metabolomics analysis, we used GC/MS (gas chromatography/mass spectrometry) combined with multivariate statistics. We found that perturbed secretion in the 832/2 line was characterized by disturbed coupling of glycolytic and TCA (tricarboxylic acid)-cycle metabolism. The importance of this metabolic coupling was reinforced by our observation that insulin secretion partially could be reinstated by stimulation of the cells with mitochondrial fuels which bypass glycolytic metabolism. Furthermore, metabolic and functional profiling of additional beta-cell lines (INS-1, INS-1 832/1) confirmed the important role of coupled glycolytic and TCA-cycle metabolism in stimulus-secretion coupling. Dependence of the unresponsive clones on glycolytic metabolism was paralleled by increased stabilization of HIF-1 alpha (hypoxia-inducible factor 1 alpha). The relevance of a similar perturbation for human T2D was suggested by increased expression of HIF-1 alpha target genes in islets from T2D patients.

Keywords

  • Biochemistry and Molecular Biology
  • hypoxia-inducible factor (HIF)
  • mitochondria
  • pancreatic islet
  • insulin
  • Type 2 diabetes (T2D)

Other

Published
  • Molecular Metabolism
  • ISSN: 0264-6021
Peter Spegel
E-mail: peter [dot] spegel [at] chem [dot] lu [dot] se

Researcher

Centre for Analysis and Synthesis

1

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00