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Chronic high Glucose and Pyruvate Levels differentially affect Mitochondrial Bioenergetics and Fuel-stimulated insulin secretion from Clonal INS-1 832/13 Cells. / Göhring, Isabel; Sharoyko, Vladimir V.; Malmgren, Siri; Andersson, Lotta E.; Spégel, Peter; Nicholls, David G.; Mulder, Hindrik.

в: Journal of Biological Chemistry, Том 289, № 6, 07.02.2014, стр. 3786-3798.

Результаты исследований: Научные публикации в периодических изданияхстатьяРецензирование

Harvard

Göhring, I, Sharoyko, VV, Malmgren, S, Andersson, LE, Spégel, P, Nicholls, DG & Mulder, H 2014, 'Chronic high Glucose and Pyruvate Levels differentially affect Mitochondrial Bioenergetics and Fuel-stimulated insulin secretion from Clonal INS-1 832/13 Cells', Journal of Biological Chemistry, Том. 289, № 6, стр. 3786-3798. https://doi.org/10.1074/jbc.M113.507335

APA

Göhring, I., Sharoyko, V. V., Malmgren, S., Andersson, L. E., Spégel, P., Nicholls, D. G., & Mulder, H. (2014). Chronic high Glucose and Pyruvate Levels differentially affect Mitochondrial Bioenergetics and Fuel-stimulated insulin secretion from Clonal INS-1 832/13 Cells. Journal of Biological Chemistry, 289(6), 3786-3798. https://doi.org/10.1074/jbc.M113.507335

Vancouver

Author

Göhring, Isabel ; Sharoyko, Vladimir V. ; Malmgren, Siri ; Andersson, Lotta E. ; Spégel, Peter ; Nicholls, David G. ; Mulder, Hindrik. / Chronic high Glucose and Pyruvate Levels differentially affect Mitochondrial Bioenergetics and Fuel-stimulated insulin secretion from Clonal INS-1 832/13 Cells. в: Journal of Biological Chemistry. 2014 ; Том 289, № 6. стр. 3786-3798.

BibTeX

@article{b9e532fc77ad44738aee1004ed48086d,
title = "Chronic high Glucose and Pyruvate Levels differentially affect Mitochondrial Bioenergetics and Fuel-stimulated insulin secretion from Clonal INS-1 832/13 Cells",
abstract = "Background: Elevated glucose may cause β-cell dysfunction in type 2 diabetes, i.e., glucotoxicity. Results: Elevated glucose, but not pyruvate, perturbed insulin secretion and content, plasma and mitochondrial membrane potentials, and proton leak, while increasing glycolytic metabolites in β-cells. Conclusion: Early metabolism of glucose exerts a toxic effect on clonal insulin-producing cells. Significance: Unraveling these mechanisms may provide protection of β-cells in diabetes. Glucotoxicity in pancreaticβ-cells is a well established pathogenetic process in type 2 diabetes. It has been suggested that metabolism-derived reactive oxygen species perturb the β-cell transcriptional machinery. Less is known about altered mitochondrial function in this condition. We used INS-1 832/13 cells cultured for 48 h in 2.8 mM glucose (low-G), 16.7 mM glucose (high-G), or 2.8 mM glucose plus 13.9 mM pyruvate (high-P) to identify metabolic perturbations. High-G cells showed decreased responsiveness, relative to low-G cells, with respect to mitochondrial membrane hyperpolarization, plasma membrane depolarization, and insulin secretion, when stimulated acutely with 16.7 mM glucose or 10 mM pyruvate. In contrast, high-P cells were functionally unimpaired, eliminating chronic provision of saturating mitochondrial substrate as a cause of glucotoxicity. Although cellular insulin content was depleted in high-G cells, relative to low-G and high-P cells, cellular functions were largely recovered following a further 24-h culture in low-G medium. After 2 h at 2.8 mM glucose, high-G cells did not retain increased levels of glycolytic or TCA cycle intermediates but nevertheless displayed increased glycolysis, increased respiration, and an increased mitochondrial proton leak relative to low-G and high-P cells. This notwithstanding, titration of low-G cells with low protonophore concentrations, monitoring respiration and insulin secretion in parallel, showed that the perturbed insulin secretion of high-G cells could not be accounted for by increased proton leak. The present study supports the idea that glucose-induced disturbances of stimulussecretion coupling by extramitochondrial metabolism upstream of pyruvate, rather than exhaustion from metabolic overload, underlie glucotoxicity in insulin-producing cells.",
keywords = "Beta Cell, Bioenergetics, Insulin Secretion, Metabolomics, Mitochondrial Metabolism, Uncoupling Proteins",
author = "Isabel G{\"o}hring and Sharoyko, {Vladimir V.} and Siri Malmgren and Andersson, {Lotta E.} and Peter Sp{\'e}gel and Nicholls, {David G.} and Hindrik Mulder",
year = "2014",
month = feb,
day = "7",
doi = "10.1074/jbc.M113.507335",
language = "English",
volume = "289",
pages = "3786--3798",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

RIS

TY - JOUR

T1 - Chronic high Glucose and Pyruvate Levels differentially affect Mitochondrial Bioenergetics and Fuel-stimulated insulin secretion from Clonal INS-1 832/13 Cells

AU - Göhring, Isabel

AU - Sharoyko, Vladimir V.

AU - Malmgren, Siri

AU - Andersson, Lotta E.

AU - Spégel, Peter

AU - Nicholls, David G.

AU - Mulder, Hindrik

PY - 2014/2/7

Y1 - 2014/2/7

N2 - Background: Elevated glucose may cause β-cell dysfunction in type 2 diabetes, i.e., glucotoxicity. Results: Elevated glucose, but not pyruvate, perturbed insulin secretion and content, plasma and mitochondrial membrane potentials, and proton leak, while increasing glycolytic metabolites in β-cells. Conclusion: Early metabolism of glucose exerts a toxic effect on clonal insulin-producing cells. Significance: Unraveling these mechanisms may provide protection of β-cells in diabetes. Glucotoxicity in pancreaticβ-cells is a well established pathogenetic process in type 2 diabetes. It has been suggested that metabolism-derived reactive oxygen species perturb the β-cell transcriptional machinery. Less is known about altered mitochondrial function in this condition. We used INS-1 832/13 cells cultured for 48 h in 2.8 mM glucose (low-G), 16.7 mM glucose (high-G), or 2.8 mM glucose plus 13.9 mM pyruvate (high-P) to identify metabolic perturbations. High-G cells showed decreased responsiveness, relative to low-G cells, with respect to mitochondrial membrane hyperpolarization, plasma membrane depolarization, and insulin secretion, when stimulated acutely with 16.7 mM glucose or 10 mM pyruvate. In contrast, high-P cells were functionally unimpaired, eliminating chronic provision of saturating mitochondrial substrate as a cause of glucotoxicity. Although cellular insulin content was depleted in high-G cells, relative to low-G and high-P cells, cellular functions were largely recovered following a further 24-h culture in low-G medium. After 2 h at 2.8 mM glucose, high-G cells did not retain increased levels of glycolytic or TCA cycle intermediates but nevertheless displayed increased glycolysis, increased respiration, and an increased mitochondrial proton leak relative to low-G and high-P cells. This notwithstanding, titration of low-G cells with low protonophore concentrations, monitoring respiration and insulin secretion in parallel, showed that the perturbed insulin secretion of high-G cells could not be accounted for by increased proton leak. The present study supports the idea that glucose-induced disturbances of stimulussecretion coupling by extramitochondrial metabolism upstream of pyruvate, rather than exhaustion from metabolic overload, underlie glucotoxicity in insulin-producing cells.

AB - Background: Elevated glucose may cause β-cell dysfunction in type 2 diabetes, i.e., glucotoxicity. Results: Elevated glucose, but not pyruvate, perturbed insulin secretion and content, plasma and mitochondrial membrane potentials, and proton leak, while increasing glycolytic metabolites in β-cells. Conclusion: Early metabolism of glucose exerts a toxic effect on clonal insulin-producing cells. Significance: Unraveling these mechanisms may provide protection of β-cells in diabetes. Glucotoxicity in pancreaticβ-cells is a well established pathogenetic process in type 2 diabetes. It has been suggested that metabolism-derived reactive oxygen species perturb the β-cell transcriptional machinery. Less is known about altered mitochondrial function in this condition. We used INS-1 832/13 cells cultured for 48 h in 2.8 mM glucose (low-G), 16.7 mM glucose (high-G), or 2.8 mM glucose plus 13.9 mM pyruvate (high-P) to identify metabolic perturbations. High-G cells showed decreased responsiveness, relative to low-G cells, with respect to mitochondrial membrane hyperpolarization, plasma membrane depolarization, and insulin secretion, when stimulated acutely with 16.7 mM glucose or 10 mM pyruvate. In contrast, high-P cells were functionally unimpaired, eliminating chronic provision of saturating mitochondrial substrate as a cause of glucotoxicity. Although cellular insulin content was depleted in high-G cells, relative to low-G and high-P cells, cellular functions were largely recovered following a further 24-h culture in low-G medium. After 2 h at 2.8 mM glucose, high-G cells did not retain increased levels of glycolytic or TCA cycle intermediates but nevertheless displayed increased glycolysis, increased respiration, and an increased mitochondrial proton leak relative to low-G and high-P cells. This notwithstanding, titration of low-G cells with low protonophore concentrations, monitoring respiration and insulin secretion in parallel, showed that the perturbed insulin secretion of high-G cells could not be accounted for by increased proton leak. The present study supports the idea that glucose-induced disturbances of stimulussecretion coupling by extramitochondrial metabolism upstream of pyruvate, rather than exhaustion from metabolic overload, underlie glucotoxicity in insulin-producing cells.

KW - Beta Cell

KW - Bioenergetics

KW - Insulin Secretion

KW - Metabolomics

KW - Mitochondrial Metabolism

KW - Uncoupling Proteins

UR - http://www.scopus.com/inward/record.url?scp=84893653671&partnerID=8YFLogxK

U2 - 10.1074/jbc.M113.507335

DO - 10.1074/jbc.M113.507335

M3 - Article

C2 - 24356960

VL - 289

SP - 3786

EP - 3798

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -

ID: 5716033