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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

Spégel, Peter LU ; Malmgren, Siri LU ; Sharoyko, Vladimir LU ; Newsholme, Philip; Köck, Thomas LU and Mulder, Hindrik LU (2011) In Biochemical Journal 435. p.277-284
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
hypoxia-inducible factor (HIF), mitochondria, pancreatic islet, insulin, Type 2 diabetes (T2D)
in
Biochemical Journal
volume
435
pages
277 - 284
publisher
Portland Press Limited
external identifiers
  • wos:000289182100026
  • scopus:79952821873
ISSN
0264-6021
DOI
10.1042/BJ20100655
language
English
LU publication?
yes
id
7a0aacd3-8fe3-4a79-ae21-da21d061ec24 (old id 1925543)
date added to LUP
2011-05-02 09:22:17
date last changed
2017-10-08 04:07:54
@article{7a0aacd3-8fe3-4a79-ae21-da21d061ec24,
  abstract     = {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.},
  author       = {Spégel, Peter and Malmgren, Siri and Sharoyko, Vladimir and Newsholme, Philip and Köck, Thomas and Mulder, Hindrik},
  issn         = {0264-6021},
  keyword      = {hypoxia-inducible factor (HIF),mitochondria,pancreatic islet,insulin,Type 2 diabetes (T2D)},
  language     = {eng},
  pages        = {277--284},
  publisher    = {Portland Press Limited},
  series       = {Biochemical Journal},
  title        = {Metabolomic analyses reveal profound differences in glycolytic and tricarboxylic acid cycle metabolism in glucose-responsive and -unresponsive clonal beta-cell lines},
  url          = {http://dx.doi.org/10.1042/BJ20100655},
  volume       = {435},
  year         = {2011},
}