@article{mousavy_gharavy_sexually_2021,
	title = {Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis},
	volume = {64},
	issn = {0012-186X, 1432-0428},
	url = {http://link.springer.com/10.1007/s00125-020-05350-x},
	doi = {10.1007/s00125-020-05350-x},
	abstract = {Abstract
            
              Aims/hypothesis
              
                Variants close to the
                {VPS}13C
                /
                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
                {VPS}13C
                and
                C2CD4A
                in disease development, none has explored the role of
                C2CD4B
                .
              
            
            
              Methods
              
                {CRISPR}/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.
              
            
            
              Results
              
                Systemic 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
                 {\textless} 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 Ca
                2+
                . Binding partners for both included secretory-granule-localised {PTPRN}2/phogrin.
              
            
            
              Conclusions/interpretation
              
                Our studies suggest that
                C2cd4b
                may act centrally in the pituitary to influence sex-dependent circuits that control pancreatic beta cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for
                C2CD4A
                or
                {VPS}13C
                in the control of glucose homeostasis in humans.
              
            
            
              Data availability
              
                The datasets generated and/or analysed during the current study are available in the Biorxiv repository (
                www.biorxiv.org/content/10.1101/2020.05.18.099200v1
                ). {RNA}-Seq ({GSE}152576) and proteomics ({PXD}021597) data have been deposited to {GEO} (
                www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc={GSE}152576
                ) and {ProteomeXchange} (
                www.ebi.ac.uk/pride/archive/projects/{PXD}021597
                ) repositories, respectively.
              
            
            
              Graphical abstract},
	pages = {850--864},
	number = {4},
	journaltitle = {Diabetologia},
	shortjournal = {Diabetologia},
	author = {Mousavy Gharavy, S. Neda and Owen, Bryn M. and Millership, Steven J. and Chabosseau, Pauline and Pizza, Grazia and Martinez-Sanchez, Aida and Tasoez, Emirhan and Georgiadou, Eleni and Hu, Ming and Fine, Nicholas H. F. and Jacobson, David A. and Dickerson, Matthew T. and Idevall-Hagren, Olof and Montoya, Alex and Kramer, Holger and Mehta, Zenobia and Withers, Dominic J. and Ninov, Nikolay and Gadue, Paul J. and Cardenas-Diaz, Fabian L. and Cruciani-Guglielmacci, Céline and Magnan, Christophe and Ibberson, Mark and Leclerc, Isabelle and Voz, Marianne and Rutter, Guy A.},
	urldate = {2021-12-07},
	date = {2021-04},
	langid = {english},
	keywords = {{WP}4},
}