@article{georgiadou_pore-forming_2020,
	title = {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},
	volume = {63},
	issn = {0012-186X, 1432-0428},
	url = {http://link.springer.com/10.1007/s00125-020-05148-x},
	doi = {10.1007/s00125-020-05148-x},
	abstract = {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{\textless} 0.05), {ATP} production (p{\textless} 0.05) and insulin secretion (p{\textless} 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{\textless} 0.001), whereas mitochondrial membrane depolarisation improved in βMcu-{KO} animals. βMcu-{KO} mice displayed impaired in vivo insulin secretion at 5 min (p{\textless} 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{\textless} 0.05) in young βMcu-{KO} ({\textless}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.},
	pages = {1368--1381},
	number = {7},
	journaltitle = {Diabetologia},
	shortjournal = {Diabetologia},
	author = {Georgiadou, Eleni and Haythorne, Elizabeth and Dickerson, Matthew T. and Lopez-Noriega, Livia and Pullen, Timothy J. and da Silva Xavier, Gabriela and Davis, Samuel P. X. and Martinez-Sanchez, Aida and Semplici, Francesca and Rizzuto, Rosario and {McGinty}, James A. and French, Paul M. and Cane, Matthew C. and Jacobson, David A. and Leclerc, Isabelle and Rutter, Guy A.},
	urldate = {2020-08-03},
	date = {2020-07},
	langid = {english},
	keywords = {{WP}4},
}