2. Academic Validation
  3. LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells

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

  • Cell Rep. 2024 Apr 23;43(4):114047. doi: 10.1016/j.celrep.2024.114047.
Federica Cuozzo 1,  Katrina Viloria 2,  Ali H Shilleh 3,  Daniela Nasteska 2,  Charlotte Frazer-Morris 3,  Jason Tong 3,  Zicong Jiao 4,  Adam Boufersaoui 1,  Bryan Marzullo 1,  Daniel B Rosoff 5,  Hannah R Smith 1,  Caroline Bonner 6,  Julie Kerr-Conte 6,  Francois Pattou 6,  Rita Nano 7,  Lorenzo Piemonti 7,  Paul R V Johnson 8,  Rebecca Spiers 8,  Jennie Roberts 1,  Gareth G Lavery 9,  Anne Clark 3,  Carlo D L Ceresa 3,  David W Ray 5,  Leanne Hodson 3,  Amy P Davies 10,  Guy A Rutter 11,  Masaya Oshima 12,  Raphaël Scharfmann 12,  Matthew J Merrins 13,  Ildem Akerman 1,  Daniel A Tennant 14,  Christian Ludwig 15,  David J Hodson 16
Affiliations

Affiliations

  • 1 Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK.
  • 2 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.
  • 3 Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 4 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.
  • 5 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.
  • 6 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.
  • 7 San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
  • 8 Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • 9 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.
  • 10 Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
  • 11 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.
  • 12 Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, 75014 Paris, France.
  • 13 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.
  • 14 Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK. Electronic address: [email protected].
  • 15 Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK. Electronic address: [email protected].
  • 16 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. Electronic address: [email protected].
PMID: 38607916 DOI: 10.1016/j.celrep.2024.114047
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.

Keywords

CP: Metabolism; GC-MS; LDH; NMR; glucose tracing; imaging; islet; lactate; metabolism; pyruvate; pyruvate dehydrogenase.

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