A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells.
Cytosolic NADPH may act as one of the signals that couple glucose metabolism to insulin secretion in the pancreatic ß-cell. NADPH levels in the cytoplasm are largely controlled by the cytosolic isoforms of malic enzyme and isocitrate dehydrogenase (IDHc). Some studies have provided evidence for a ro...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3795013?pdf=render |
| _version_ | 1818537956383653888 |
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| author | Claudiane Guay Erik Joly Emilie Pepin Annie Barbeau Lisa Hentsch Marco Pineda S R Murthy Madiraju Henri Brunengraber Marc Prentki |
| author_facet | Claudiane Guay Erik Joly Emilie Pepin Annie Barbeau Lisa Hentsch Marco Pineda S R Murthy Madiraju Henri Brunengraber Marc Prentki |
| author_sort | Claudiane Guay |
| collection | DOAJ |
| description | Cytosolic NADPH may act as one of the signals that couple glucose metabolism to insulin secretion in the pancreatic ß-cell. NADPH levels in the cytoplasm are largely controlled by the cytosolic isoforms of malic enzyme and isocitrate dehydrogenase (IDHc). Some studies have provided evidence for a role of malic enzyme in glucose-induced insulin secretion (GIIS) via pyruvate cycling, but the role of IDHc in ß-cell signaling is unsettled. IDHc is an established component of the isocitrate/α-ketoglutarate shuttle that transfers reducing equivalents (NADPH) from the mitochondrion to the cytosol. This shuttle is energy consuming since it is coupled to nicotinamide nucleotide transhydrogenase that uses the mitochondrial proton gradient to produce mitochondrial NADPH and NAD(+) from NADP(+) and NADH. To determine whether flux through IDHc is positively or negatively linked to GIIS, we performed RNAi knockdown experiments in ß-cells. Reduced IDHc expression in INS 832/13 cells and isolated rat islet ß-cells resulted in enhanced GIIS. This effect was mediated at least in part via the KATP-independent amplification arm of GIIS. IDHc knockdown in INS 832/13 cells did not alter glucose oxidation but it reduced fatty acid oxidation and increased lipogenesis from glucose. Metabolome profiling in INS 832/13 cells showed that IDHc knockdown increased isocitrate and NADP(+) levels. It also increased the cellular contents of several metabolites linked to GIIS, in particular some Krebs cycle intermediates, acetyl-CoA, glutamate, cAMP and ATP. The results identify IDHc as a component of the emerging pathways that negatively regulate GIIS. |
| first_indexed | 2024-12-11T18:57:23Z |
| format | Article |
| id | doaj.art-fc9c21b5e2474577b5507612818a8807 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T18:57:23Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-fc9c21b5e2474577b5507612818a88072022-12-22T00:54:06ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01810e7709710.1371/journal.pone.0077097A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells.Claudiane GuayErik JolyEmilie PepinAnnie BarbeauLisa HentschMarco PinedaS R Murthy MadirajuHenri BrunengraberMarc PrentkiCytosolic NADPH may act as one of the signals that couple glucose metabolism to insulin secretion in the pancreatic ß-cell. NADPH levels in the cytoplasm are largely controlled by the cytosolic isoforms of malic enzyme and isocitrate dehydrogenase (IDHc). Some studies have provided evidence for a role of malic enzyme in glucose-induced insulin secretion (GIIS) via pyruvate cycling, but the role of IDHc in ß-cell signaling is unsettled. IDHc is an established component of the isocitrate/α-ketoglutarate shuttle that transfers reducing equivalents (NADPH) from the mitochondrion to the cytosol. This shuttle is energy consuming since it is coupled to nicotinamide nucleotide transhydrogenase that uses the mitochondrial proton gradient to produce mitochondrial NADPH and NAD(+) from NADP(+) and NADH. To determine whether flux through IDHc is positively or negatively linked to GIIS, we performed RNAi knockdown experiments in ß-cells. Reduced IDHc expression in INS 832/13 cells and isolated rat islet ß-cells resulted in enhanced GIIS. This effect was mediated at least in part via the KATP-independent amplification arm of GIIS. IDHc knockdown in INS 832/13 cells did not alter glucose oxidation but it reduced fatty acid oxidation and increased lipogenesis from glucose. Metabolome profiling in INS 832/13 cells showed that IDHc knockdown increased isocitrate and NADP(+) levels. It also increased the cellular contents of several metabolites linked to GIIS, in particular some Krebs cycle intermediates, acetyl-CoA, glutamate, cAMP and ATP. The results identify IDHc as a component of the emerging pathways that negatively regulate GIIS.http://europepmc.org/articles/PMC3795013?pdf=render |
| spellingShingle | Claudiane Guay Erik Joly Emilie Pepin Annie Barbeau Lisa Hentsch Marco Pineda S R Murthy Madiraju Henri Brunengraber Marc Prentki A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells. PLoS ONE |
| title | A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells. |
| title_full | A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells. |
| title_fullStr | A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells. |
| title_full_unstemmed | A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells. |
| title_short | A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells. |
| title_sort | role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ss cells |
| url | http://europepmc.org/articles/PMC3795013?pdf=render |
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