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 P. Marzullo, Daniel B. Rosoff, Hannah Smith, Caroline Bonner, J. Kerr–Conte, François Pattou, Rita Nano, Lorenzo Piemonti, Paul Johnson, Rebecca Spiers, Jennie Roberts, Gareth G. Lavery, Anne Clark, Carlo Ceresa, David Ray, Leanne Hodson, A. Davies, Guy A. Rutter, Masaya Oshima, Raphaël Scharfmann, Matthew J. Merrins, İldem Akerman, Daniel A. Tennant, Christian Ludwig, David J. Hodson
Abstract
C 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.