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@article{Mousavy:2021:10.1007/s00125-020-05350-x,
author = {Mousavy, Gharavy SN and Owen, BM and Millership, SJ and Chabosseau, P and Pizza, G and Martinez-Sanchez, A and Tasoez, E and Georgiadou, E and Hu, M and Fine, NHF and Jacobson, DA and Dickerson, MT and Idevall-Hagren, O and Montoya, A and Kramer, H and Mehta, Z and Withers, DJ and Ninov, N and Gadue, PJ and Cardenas-Diaz, FL and Cruciani-Guglielmacci, C and Magnan, C and Ibberson, M and Leclerc, I and Voz, M and Rutter, GA},
doi = {10.1007/s00125-020-05350-x},
journal = {Diabetologia},
pages = {850--864},
title = {Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis},
url = {http://dx.doi.org/10.1007/s00125-020-05350-x},
volume = {64},
year = {2021}
}

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TY  - JOUR
AB  - Aims/hypothesisVariants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. While previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B.MethodsCRISPR/Cas9-induced global C2cd4b-knockout mice and zebrafish larvae with c2cd4a deletion were used to study the role of this gene in glucose homeostasis. C2 calcium dependent domain containing protein (C2CD)4A and C2CD4B constructs tagged with FLAG or green fluorescent protein were generated to investigate subcellular dynamics using confocal or near-field microscopy and to identify interacting partners by mass spectrometry.ResultsSystemic inactivation of C2cd4b in mice led to marked, but highly sexually dimorphic changes in body weight and glucose homeostasis. Female C2cd4b mice displayed unchanged body weight compared with control littermates, but abnormal glucose tolerance (AUC, p = 0.01) and defective in vivo, but not in vitro, insulin secretion (p = 0.02). This was associated with a marked decrease in follicle-stimulating hormone levels as compared with wild-type (WT) littermates (p = 0.003). In sharp contrast, male C2cd4b null mice displayed essentially normal glucose tolerance but an increase in body weight (p < 0.001) and fasting blood glucose (p = 0.003) after maintenance on a high-fat and -sucrose diet vs WT littermates. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic beta cell function at larval stages in C2cd4a null zebrafish. Fasting blood glucose levels were also unaltered in adult C2cd4a-null fish. C2CD4B and C2CD4A were partially localised to the plasma membrane, with the latter under the control of intracellular Ca2+. Binding partners for both included secretory-granule-localised PTPRN2/phogrin.Conclusions/interpretationOur studies sugge
AU  - Mousavy,Gharavy SN
AU  - Owen,BM
AU  - Millership,SJ
AU  - Chabosseau,P
AU  - Pizza,G
AU  - Martinez-Sanchez,A
AU  - Tasoez,E
AU  - Georgiadou,E
AU  - Hu,M
AU  - Fine,NHF
AU  - Jacobson,DA
AU  - Dickerson,MT
AU  - Idevall-Hagren,O
AU  - Montoya,A
AU  - Kramer,H
AU  - Mehta,Z
AU  - Withers,DJ
AU  - Ninov,N
AU  - Gadue,PJ
AU  - Cardenas-Diaz,FL
AU  - Cruciani-Guglielmacci,C
AU  - Magnan,C
AU  - Ibberson,M
AU  - Leclerc,I
AU  - Voz,M
AU  - Rutter,GA
DO  - 10.1007/s00125-020-05350-x
EP  - 864
PY  - 2021///
SN  - 0012-186X
SP  - 850
TI  - Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis
T2  - Diabetologia
UR  - http://dx.doi.org/10.1007/s00125-020-05350-x
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000611486300001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://link.springer.com/article/10.1007%2Fs00125-020-05350-x
UR  - http://hdl.handle.net/10044/1/92690
VL  - 64
ER  -

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