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Aims/hypothesis  Variants 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 .    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  < 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 PTPRN2/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  VPS13C  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 (GSE152576) and proteomics (PXD021597) data have been deposited to GEO ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152576 ) and ProteomeXchange ( www.ebi.ac.uk/pride/archive/projects/PXD021597 ) repositories, respectively.    Graphical abstractSupplementary Information  The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-020-05350-x.

Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis