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

Federica Cuozzo, Katrina Viloria, Ali H Shilleh, Daniela Nasteska, Charlotte Frazer-Morris, Jason Tong, Zicong Jiao, Adam Boufersaoui, Bryan Marzullo, Daniel B Rosoff, Hannah R Smith, Caroline Bonner, Julie Kerr-Conte, Francois Pattou, Rita Nano, Lorenzo Piemonti, Paul R V Johnson, Rebecca Spiers, Jennie Roberts, Gareth G LaveryAnne Clark, Carlo D L Ceresa, David W Ray, Leanne Hodson, Amy P Davies, Guy A Rutter, Masaya Oshima, Raphaël Scharfmann, Matthew J Merrins, Ildem Akerman, Daniel A Tennant*, Christian Ludwig*, David J Hodson*

*Corresponding author for this work

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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.

Original languageEnglish
Article number114047
JournalCell Reports
Volume43
Issue number4
Early online date11 Apr 2024
DOIs
Publication statusPublished - 23 Apr 2024

Bibliographical note

D.J.H. was supported by MRC (MR/S025618/1), Diabetes UK (17/0005681 and 22/0006389), and UKRI ERC Frontier Research Guarantee (EP/X026833/1) grants. This work was supported on behalf of the Steve Morgan Foundation Type 1 Diabetes Grand Challenge by Diabetes UK and SMF (grant number 23/0006627). This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). A.H.S. was supported by a Novo Nordisk – Oxford Fellowship. G.G.L. was supported by a Wellcome Trust Senior Fellowship (104612/Z/14/Z). D.N. was supported by a Diabetes UK RD Lawrence Fellowship (23/0006509). L.H. was supported by British Heart Foundation Senior Basic Science Research Fellowships (FS/15/56/31645 and FS/SBSRF/21/31013). C.D.L.C. was supported by a Clinical Research Training Fellowship from the MRC. G.A.R. was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grant (MR/R022259/1), Diabetes UK Project grant (BDA16/0005485), CRCHUM start-up funds, an Innovation Canada John R Evans Leader Award (CFI 42649), an NIH-NIDDK (R01DK135268) project grant, and a CIHR-JDRF team grant (CIHR-IRSC TDP-186358 and JDRF 4-SRA-2023-1182-S-N). R. Scharfmann was supported by the Dutch Diabetes Research Foundation and the DON Foundation. M.J.M. was supported by the NIH/NIDDK (R01DK113013 and R01DK113103) and VA BLR&D (I01BX005113). I.A. was supported by a Diabetes UK RD Lawrence Fellowship (20/0006136) and Academy of Medical Sciences Springboard (SBF006∖1140). D.T. was supported by a Cancer Research UK Programme grant (C42109/A24747). D.W.R. and D.B.R. were supported by a NIHR Oxford Health Biomedical Research Centre grant reference number NIHR203316 and MRC grants MR/W019000/1 and MR/V034049/1. The research was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The project involves an element of animal work not funded by the NIHR but by another funder, as well as an element focused on patients and people appropriately funded by the NIHR. The DRWF Oxford Human Islet Isolation Facility was funded by the Diabetes Research and Wellness Foundation (DRWF) and Juvenile Diabetes Research Foundation (JDRF). Human islets for research were provided by the Alberta Diabetes Institute IsletCore at the University of Alberta in Edmonton (http://www.bcell.org/adi-isletcore.html) with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN), and other Canadian organ procurement organizations. All donors’ families gave informed consent for the use of pancreatic tissue in research. We would like to acknowledge the support and resources of the Birmingham Metabolic Tracer Analysis Core. The graphical abstract was produced in Inkscape, Inkscape Project.

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