LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells

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 ORCID: https://orcid.org/0000-0001-5794-748X, Clark, A, Ceresa, CDL, Ray, DW, Hodson, L, Davies, AP, Rutter, GA, Oshima, M, Scharfmann, R, Merrins, MJ, Akerman, I, Tennant, DA, Ludwig, C and Hodson, DJ, 2024. LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells. Cell Reports, 43 (4): 114047. ISSN 2211-1247

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Abstract

Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C 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, cis-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.

Item Type:	Journal article
Publication Title:	Cell Reports
Creators:	Cuozzo, F., Viloria, K., Shilleh, A.H., Nasteska, D., Frazer-Morris, C., Tong, J., Jiao, Z., Boufersaoui, A., Marzullo, B., Rosoff, D.B., Smith, H.R., Bonner, C., Kerr-Conte, J., Pattou, F., Nano, R., Piemonti, L., Johnson, P.R.V., Spiers, R., Roberts, J., Lavery, G.G., Clark, A., Ceresa, C.D.L., Ray, D.W., Hodson, L., Davies, A.P., Rutter, G.A., Oshima, M., Scharfmann, R., Merrins, M.J., Akerman, I., Tennant, D.A., Ludwig, C. and Hodson, D.J.
Publisher:	Elsevier BV
Date:	23 April 2024
Volume:	43
Number:	4
ISSN:	2211-1247
Identifiers:	Number Type 10.1016/j.celrep.2024.114047 DOI 2554315 Other
Rights:	© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Borcherds
Date Added:	09 Jan 2026 09:27
Last Modified:	09 Jan 2026 09:27
URI:	https://irep.ntu.ac.uk/id/eprint/54995

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