Cell Reports (Apr 2024)
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. Lavery,
- Anne 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
Affiliations
- Federica Cuozzo
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Katrina Viloria
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Ali H. Shilleh
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Daniela Nasteska
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Charlotte Frazer-Morris
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Jason Tong
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Zicong Jiao
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Geneplus-Beijing, Changping District, Beijing 102206, China
- Adam Boufersaoui
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Bryan Marzullo
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Daniel B. Rosoff
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
- Hannah R. Smith
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Caroline Bonner
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU Lille), Institute Pasteur Lille, U1190 -European Genomic Institute for Diabetes (EGID), F59000 Lille, France
- Julie Kerr-Conte
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU Lille), Institute Pasteur Lille, U1190 -European Genomic Institute for Diabetes (EGID), F59000 Lille, France
- Francois Pattou
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU Lille), Institute Pasteur Lille, U1190 -European Genomic Institute for Diabetes (EGID), F59000 Lille, France
- Rita Nano
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
- Lorenzo Piemonti
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
- Paul R.V. Johnson
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Rebecca Spiers
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Jennie Roberts
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Gareth G. Lavery
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Centre for Systems Health and Integrated Metabolic Research (SHiMR), Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Anne Clark
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Carlo D.L. Ceresa
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- David W. Ray
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
- Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Amy P. Davies
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; CHUM Research Centre and Faculty of Medicine, University of Montreal, Montreal, QC, Canada; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Masaya Oshima
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, 75014 Paris, France
- Raphaël Scharfmann
- Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, 75014 Paris, France
- Matthew J. Merrins
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA
- Ildem Akerman
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Daniel A. Tennant
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Corresponding author
- Christian Ludwig
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Corresponding author
- David J. Hodson
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 4
p. 114047
Abstract
Summary: 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.
