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

Malmgren, Siri LU ; Nicholls, David LU ; Taneera, Jalal LU ; Bacos, Karl LU orcid ; Koeck, Thomas ; Tamaddon, Ashkan LU ; Wibom, Rolf ; Groop, Leif LU ; Ling, Charlotte LU and Mulder, Hindrik LU orcid , et al. (2009) In Journal of Biological Chemistry 284. p.32395-32404
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
284
pages
32395 - 32404
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • wos:000272028400022
  • pmid:19797055
  • scopus:70450285188
  • pmid:19797055
ISSN
1083-351X
DOI
10.1074/jbc.M109.026708
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Neuronal Survival (013212041), Brain Repair and Imaging in Neural Systems (BRAINS) (013212027), Molecular Metabolism (013212001), Diabetes and Endocrinology (013241530), Molecular Metabolism (013244000)
id
0d31d49e-f074-4728-9740-86973ecd143e (old id 1500778)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19797055?dopt=Abstract
date added to LUP
2016-04-04 08:49:08
date last changed
2021-10-06 03:25:27
@article{0d31d49e-f074-4728-9740-86973ecd143e,
  abstract     = {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.},
  author       = {Malmgren, Siri and Nicholls, David and Taneera, Jalal and Bacos, Karl and Koeck, Thomas and Tamaddon, Ashkan and Wibom, Rolf and Groop, Leif and Ling, Charlotte and Mulder, Hindrik and Sharoyko, Vladimir},
  issn         = {1083-351X},
  language     = {eng},
  pages        = {32395--32404},
  publisher    = {American Society for Biochemistry and Molecular Biology},
  series       = {Journal of Biological Chemistry},
  title        = {Tight coupling between glucose and mitochondrial metabolism in clonal beta-cells is required for robust insulin secretion.},
  url          = {http://dx.doi.org/10.1074/jbc.M109.026708},
  doi          = {10.1074/jbc.M109.026708},
  volume       = {284},
  year         = {2009},
}