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Tight coupling between glucose and mitochondrial metabolism in clonal beta-cells is required for robust insulin secretion.

Author:
  • Siri Malmgren
  • David Nicholls
  • Jalal Taneera
  • Karl Bacos
  • Thomas Koeck
  • Ashkan Tamaddon
  • Rolf Wibom
  • Leif Groop
  • Charlotte Ling
  • Hindrik Mulder
  • Vladimir Sharoyko
Publishing year: 2009
Language: English
Pages: 32395-32404
Publication/Series: Journal of Biological Chemistry
Volume: 284
Document type: Journal article
Publisher: ASBMB

Abstract english

The biochemical mechanisms underlying glucose-stimulated insulin secretion from pancreatic beta-cells are not completely understood. To identify metabolic disturbances in beta-cells that impair glucose-stimulated insulin secretion, we compared two INS-1-derived clonal beta-cell lines, which are glucose-responsive (832/13) or glucose-unresponsive (832/2). We found that despite a marked impairment of glucose-stimulated insulin secretion, 832/2 cells exhibited a higher rate of glycolysis. Still, no glucose-induced increases in respiratory rate, ATP production or respiratory chain complex I, III and IV activities were seen in the 832/2 cells. Instead, 832/2 cells, which expressed lactate dehydrogenase, released lactate regardless of ambient glucose concentrations. In contrast, the glucose-responsive 832/13 line lacked lactate dehydrogenase and did not produce lactate. Accordingly, in 832/2 cells mRNA expression of genes for glycolytic enzymes were up-regulated, whereas mitochondria-related genes were down-regulated. In human islets, mRNA expression of genes such as lactate dehydrogenase A and hexokinase I correlated positively with long-term glucose homeostasis reflected by HbA1c levels, while that of Slc2a2 (GLUT2) correlated negatively with Hb1Ac. We conclude that tight metabolic regulation enhancing mitochondrial metabolism and restricting glycolysis in 832/13 cells is required for clonal beta-cells to secrete insulin robustly in response to glucose. Moreover, a similar expression pattern of genes controlling glycolytic and mitochondrial metabolism in clonal beta-cells and human islets was observed, suggesting that a similar prioritization of mitochondrial metabolism is required in healthy human beta-cells. The 832 beta-cell lines may be helpful tools to resolve metabolic perturbations occurring in Type 2 Diabetes.

Keywords

  • Endocrinology and Diabetes
  • Neurosciences

Other

Published
  • Brain Repair and Imaging in Neural Systems (BRAINS)
  • Genomics, Diabetes and Endocrinology
  • Diabetes - Molecular Metabolism
  • ISSN: 1083-351X
E-mail: david [dot] nicholls [at] med [dot] lu [dot] se

Visiting research fellow

Diabetes - Molecular Metabolism

33

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00