LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells
Using <sup>13</sup>C<sub>6</sub> glucose labeling coupled to gas chromatography-mass spectrometry and 2D <sup>1</sup>H-<sup>13</sup>C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Cell Press
2024
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| _version_ | 1826313515737022464 |
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| author | Cuozzo, F Viloria, K Shilleh, AH Nasteska, D Frazer-Morris, C Tong, J Jiao, Z Boufersaoui, A Marzullo, B Rosoff, DB Smith, HR Bonner, C Kerr-Conte, J Pattou, F Nano, R Piemonti, L Johnson, PRV Spiers, R Roberts, J Lavery, GG Clark, A Ceresa, CDL Ray, DW Hodson, L Davies, AP Rutter, GA Oshima, M Scharfmann, R Merrins, MJ Akerman, A Tennant, DA Ludwig, C Hodson, DJ |
| author_facet | Cuozzo, F Viloria, K Shilleh, AH Nasteska, D Frazer-Morris, C Tong, J Jiao, Z Boufersaoui, A Marzullo, B Rosoff, DB Smith, HR Bonner, C Kerr-Conte, J Pattou, F Nano, R Piemonti, L Johnson, PRV Spiers, R Roberts, J Lavery, GG Clark, A Ceresa, CDL Ray, DW Hodson, L Davies, AP Rutter, GA Oshima, M Scharfmann, R Merrins, MJ Akerman, A Tennant, DA Ludwig, C Hodson, DJ |
| author_sort | Cuozzo, F |
| collection | OXFORD |
| description | Using <sup>13</sup>C<sub>6</sub> glucose labeling coupled to gas chromatography-mass spectrometry and 2D <sup>1</sup>H-<sup>13</sup>C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, <i>cis</i>-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release. |
| first_indexed | 2024-09-25T04:15:03Z |
| format | Journal article |
| id | oxford-uuid:2df9f264-69a4-4abb-a7ab-a3c48df87305 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:15:03Z |
| publishDate | 2024 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:2df9f264-69a4-4abb-a7ab-a3c48df873052024-07-20T14:08:45ZLDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2df9f264-69a4-4abb-a7ab-a3c48df87305EnglishSymplectic ElementsCell Press2024Cuozzo, FViloria, KShilleh, AHNasteska, DFrazer-Morris, CTong, JJiao, ZBoufersaoui, AMarzullo, BRosoff, DBSmith, HRBonner, CKerr-Conte, JPattou, FNano, RPiemonti, LJohnson, PRVSpiers, RRoberts, JLavery, GGClark, ACeresa, CDLRay, DWHodson, LDavies, APRutter, GAOshima, MScharfmann, RMerrins, MJAkerman, ATennant, DALudwig, CHodson, DJUsing <sup>13</sup>C<sub>6</sub> glucose labeling coupled to gas chromatography-mass spectrometry and 2D <sup>1</sup>H-<sup>13</sup>C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, <i>cis</i>-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release. |
| spellingShingle | Cuozzo, F Viloria, K Shilleh, AH Nasteska, D Frazer-Morris, C Tong, J Jiao, Z Boufersaoui, A Marzullo, B Rosoff, DB Smith, HR Bonner, C Kerr-Conte, J Pattou, F Nano, R Piemonti, L Johnson, PRV Spiers, R Roberts, J Lavery, GG Clark, A Ceresa, CDL Ray, DW Hodson, L Davies, AP Rutter, GA Oshima, M Scharfmann, R Merrins, MJ Akerman, A Tennant, DA Ludwig, C Hodson, DJ LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells |
| title | LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells |
| title_full | LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells |
| title_fullStr | LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells |
| title_full_unstemmed | LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells |
| title_short | LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells |
| title_sort | ldhb contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells |
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