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

doi:10.1016/j.celrep.2024.114047

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. Epub 2024 Apr 11.

Authors

Federica Cuozzo¹, Katrina Viloria², Ali H Shilleh³, Daniela Nasteska², Charlotte Frazer-Morris³, Jason Tong³, Zicong Jiao⁴, Adam Boufersaoui¹, Bryan Marzullo¹, Daniel B Rosoff⁵, Hannah R Smith¹, Caroline Bonner⁶, Julie Kerr-Conte⁶, Francois Pattou⁶, Rita Nano⁷, Lorenzo Piemonti⁷, Paul R V Johnson⁸, Rebecca Spiers⁸, Jennie Roberts¹, Gareth G Lavery⁹, Anne Clark³, Carlo D L Ceresa³, David W Ray⁵, Leanne Hodson³, Amy P Davies¹⁰, Guy A Rutter¹¹, Masaya Oshima¹², Raphaël Scharfmann¹², Matthew J Merrins¹³, Ildem Akerman¹, Daniel A Tennant¹⁴, Christian Ludwig¹⁵, David J Hodson¹⁶

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].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Citric Acid Cycle
Glucose / metabolism
Humans
Insulin / metabolism
Insulin Secretion*
Insulin-Secreting Cells* / metabolism
Isoenzymes / metabolism
L-Lactate Dehydrogenase* / metabolism
Lactic Acid* / metabolism
Male
Mice
Mice, Inbred C57BL

Substances

L-Lactate Dehydrogenase
Lactic Acid
Glucose
Insulin
Isoenzymes
lactate dehydrogenase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding