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NNT reverse mode of...
NNT reverse mode of operation mediates glucose control of mitochondrial NADPH and glutathione redox state in mouse pancreatic β-cells
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- Santos, Laila R.B. (författare)
- Catholic University of Louvain
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- Muller, Carole (författare)
- Catholic University of Louvain
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- de Souza, Arnaldo H. (författare)
- Catholic University of Louvain
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- Takahashi, Hilton K. (författare)
- Catholic University of Louvain
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- Spégel, Peter (författare)
- Lund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Diabetes - Molecular Metabolism,Lund University Research Groups,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Sweet, Ian R. (författare)
- University of Washington
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- Chae, Heeyoung (författare)
- Catholic University of Louvain
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- Mulder, Hindrik (författare)
- Lund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups
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- Jonas, Jean Christophe (författare)
- Catholic University of Louvain
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(creator_code:org_t)
- Elsevier BV, 2017
- 2017
- Engelska 13 s.
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 6:6, s. 535-547
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Objective: The glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and δpH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets. Methods: Islets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N-islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures. Results: NNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in β-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification. Conclusion: These results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Nyckelord
- C57BL/6J mice
- C57BL/6N mice
- Glucose metabolism
- GRX1-roGFP2
- Insulin secretion
- Mitochondrial shuttles
- Pancreatic islet
- Redox-sensitive GFP
- Stimulus-secretion coupling
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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