Imperial College London
Alternate

DrIsabelleLeclerc

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3354i.leclerc

 
 
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Location

 

323ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Georgiadou:2020:10.1007/s00125-020-05148-x,
author = {Georgiadou, E and Haythorne, E and Dickerson, MT and Lopez-Noriega, L and Pullen, TJ and da, Silva Xavier G and Davis, SPX and Martinez-Sanchez, A and Semplici, F and Rizzuto, R and McGinty, JA and French, PM and Cane, MC and Jacobson, DA and Leclerc, I and Rutter, GA},
doi = {10.1007/s00125-020-05148-x},
journal = {Diabetologia},
pages = {1368--1381},
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},
url = {http://dx.doi.org/10.1007/s00125-020-05148-x},
volume = {63},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Aims/hypothesisMitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca2+ uptake into pancreatic beta cell mitochondria potentiates or antagonises this process is still a matter of debate. Although the mitochondrial Ca2+ importer (MCU) complex is thought to represent the main route for Ca2+ transport across the inner mitochondrial membrane, its role in beta cells has not previously been examined in vivo.MethodsHere, 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.ResultsGlucose-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/interpretationMCU 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
AU  - Georgiadou,E
AU  - Haythorne,E
AU  - Dickerson,MT
AU  - Lopez-Noriega,L
AU  - Pullen,TJ
AU  - da,Silva Xavier G
AU  - Davis,SPX
AU  - Martinez-Sanchez,A
AU  - Semplici,F
AU  - Rizzuto,R
AU  - McGinty,JA
AU  - French,PM
AU  - Cane,MC
AU  - Jacobson,DA
AU  - Leclerc,I
AU  - Rutter,GA
DO  - 10.1007/s00125-020-05148-x
EP  - 1381
PY  - 2020///
SN  - 0012-186X
SP  - 1368
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
T2  - Diabetologia
UR  - http://dx.doi.org/10.1007/s00125-020-05148-x
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000529847900002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://link.springer.com/article/10.1007%2Fs00125-020-05148-x
UR  - http://hdl.handle.net/10044/1/79453
VL  - 63
ER  -
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