Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

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

Summary, in 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.

Department/s

  • Diabetes - Molecular Metabolism
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2011

Language

English

Pages

277-284

Publication/Series

Biochemical Journal

Volume

435

Document type

Journal article

Publisher

Portland Press

Topic

  • Biochemistry and Molecular Biology

Keywords

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

Status

Published

Research group

  • Diabetes - Molecular Metabolism

ISBN/ISSN/Other

  • ISSN: 0264-6021