{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:58:29Z","timestamp":1790380709782,"version":"4.1.0"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T00:00:00Z","timestamp":1611532800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T00:00:00Z","timestamp":1611532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2021,4]]},"abstract":"Abstract<\/jats:title>\n \n Aims\/hypothesis<\/jats:title>\n \n Variants close to the\n VPS13C<\/jats:italic>\n \/\n C2CD4A\/C2CD4B<\/jats:italic>\n locus are associated with altered risk of type 2 diabetes in genome-wide association studies. While previous functional work has suggested roles for\n VPS13C<\/jats:italic>\n and\n C2CD4A<\/jats:italic>\n in disease development, none has explored the role of\n C2CD4B<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n CRISPR\/Cas9-induced global\n C2cd4b<\/jats:italic>\n -knockout mice and zebrafish larvae with\n c2cd4a<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Systemic inactivation of\n C2cd4b<\/jats:italic>\n in mice led to marked, but highly sexually dimorphic changes in body weight and glucose homeostasis. Female\n C2cd4b<\/jats:italic>\n mice displayed unchanged body weight compared with control littermates, but abnormal glucose tolerance (AUC,\n p<\/jats:italic>\n \u2009=\u20090.01) and defective in vivo, but not in vitro, insulin secretion (\n p<\/jats:italic>\n \u2009=\u20090.02). This was associated with a marked decrease in follicle-stimulating hormone levels as compared with wild-type (WT) littermates (\n p<\/jats:italic>\n \u2009=\u20090.003). In sharp contrast, male\n C2cd4b<\/jats:italic>\n null mice displayed essentially normal glucose tolerance but an increase in body weight (\n p<\/jats:italic>\n \u2009<\u20090.001) and fasting blood glucose (\n p<\/jats:italic>\n \u2009=\u20090.003) after maintenance on a high-fat and -sucrose diet vs WT littermates. No metabolic disturbances were observed after global inactivation of\n C2cd4a<\/jats:italic>\n in mice, or in pancreatic beta cell function at larval stages in\n C2cd4a<\/jats:italic>\n null zebrafish. Fasting blood glucose levels were also unaltered in adult\n C2cd4a<\/jats:italic>\n -null fish. C2CD4B and C2CD4A were partially localised to the plasma membrane, with the latter under the control of intracellular Ca\n 2+<\/jats:sup>\n . Binding partners for both included secretory-granule-localised PTPRN2\/phogrin.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions\/interpretation<\/jats:title>\n \n Our studies suggest that\n C2cd4b<\/jats:italic>\n 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\n C2CD4A<\/jats:italic>\n or\n VPS13C<\/jats:italic>\n in the control of glucose homeostasis in humans.\n <\/jats:p>\n <\/jats:sec>\n \n Data availability<\/jats:title>\n \n The datasets generated and\/or analysed during the current study are available in the Biorxiv repository (\n www.biorxiv.org\/content\/10.1101\/2020.05.18.099200v1<\/jats:ext-link>\n ). RNA-Seq (GSE152576) and proteomics (PXD021597) data have been deposited to GEO (\n www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE152576<\/jats:ext-link>\n ) and ProteomeXchange (\n www.ebi.ac.uk\/pride\/archive\/projects\/PXD021597<\/jats:ext-link>\n ) repositories, respectively.\n <\/jats:p>\n <\/jats:sec>\n \n Graphical abstract<\/jats:title>\n <\/jats:sec>","DOI":"10.1007\/s00125-020-05350-x","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T03:05:19Z","timestamp":1611543919000},"page":"850-864","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis"],"prefix":"10.1007","volume":"64","author":[{"given":"S. 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