TY - JOUR TI - The pore-forming subunit MCU of the mitochondrial Ca2+ uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice AU - Georgiadou, Eleni AU - Haythorne, Elizabeth AU - Dickerson, Matthew T. AU - Lopez-Noriega, Livia AU - Pullen, Timothy J. AU - da Silva Xavier, Gabriela AU - Davis, Samuel P. X. AU - Martinez-Sanchez, Aida AU - Semplici, Francesca AU - Rizzuto, Rosario AU - McGinty, James A. AU - French, Paul M. AU - Cane, Matthew C. AU - Jacobson, David A. AU - Leclerc, Isabelle AU - Rutter, Guy A. T2 - Diabetologia AB - Methods Here, we inactivated the pore-forming subunit of the MCU, encoded by Mcu, selectively in mouse beta cells using Ins1Cre-mediated recombination. Whole or dissociated pancreatic islets were isolated and used for live beta cell fluorescence imaging of cytosolic or mitochondrial Ca2+ concentration and ATP production in response to increasing glucose concentrations. Electrophysiological recordings were also performed on whole islets. Serum and blood samples were collected to examine oral and i.p. glucose tolerance. Results Glucose-stimulated mitochondrial Ca2+ accumulation (p< 0.05), ATP production (p< 0.05) and insulin secretion (p< 0.01) were strongly inhibited in beta cell-specific Mcu-null (βMcu-KO) animals, in vitro, as compared with wild-type (WT) mice. Interestingly, cytosolic Ca2+ concentrations increased (p< 0.001), whereas mitochondrial membrane depolarisation improved in βMcu-KO animals. βMcu-KO mice displayed impaired in vivo insulin secretion at 5 min (p< 0.001) but not 15 min post-i.p. injection of glucose, whilst the opposite phenomenon was observed following an oral gavage at 5 min. Unexpectedly, glucose tolerance was improved (p< 0.05) in young βMcu-KO (<12 weeks), but not in older animals vs WT mice. Conclusions/interpretation MCU is crucial for mitochondrial Ca2+ uptake in pancreatic beta cells and is required for normal GSIS. The apparent compensatory mechanisms that maintain glucose tolerance in βMcu-KO mice remain to be established. DA - 2020/07// PY - 2020 DO - 10.1007/s00125-020-05148-x DP - DOI.org (Crossref) VL - 63 IS - 7 SP - 1368 EP - 1381 J2 - Diabetologia LA - en SN - 0012-186X, 1432-0428 UR - http://link.springer.com/10.1007/s00125-020-05148-x Y2 - 2020/08/03/14:17:50 KW - WP4 ER -