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

Research output: Contribution to journalResearch articleContributedpeer-review


  • S. Neda Mousavy Gharavy - , Imperial College London (Author)
  • Bryn M. Owen - , Imperial College London (Author)
  • Steven J. Millership - , Imperial College London (Author)
  • Pauline Chabosseau - , Imperial College London (Author)
  • Grazia Pizza - , Imperial College London (Author)
  • Aida Martinez-Sanchez - , Imperial College London (Author)
  • Emirhan Tasoez - , Chair of Cell Biology and Regeneration of β-Cells, German Research Foundation (DFG), Center for Regenerative Therapies Dresden (CRTD) (Author)
  • Eleni Georgiadou - , Imperial College London (Author)
  • Ming Hu - , Imperial College London (Author)
  • Nicholas H. F. Fine - , Imperial College London (Author)
  • David A. Jacobson - , Vanderbilt University (Author)
  • Matthew T. Dickerson - , Vanderbilt University (Author)
  • Olof Idevall-Hagren - , Uppsala University (Author)
  • Alex Montoya - , Imperial College London (Author)
  • Holger Kramer - , Imperial College London (Author)
  • Zenobia Mehta - , Imperial College London (Author)
  • Dominic J. Withers - , Imperial College London (Author)
  • Nikolay Ninov - , Chair of Cell Biology and Regeneration of β-Cells, German Research Foundation (DFG), Center for Regenerative Therapies Dresden (CRTD) (Author)
  • Paul J. Gadue - , University of Pennsylvania (Author)
  • Fabian L. Cardenas-Diaz - , University of Pennsylvania (Author)
  • Celine Cruciani-Guglielmacci - , French National Centre for Scientific Research (CNRS) (Author)
  • Christophe Magnan - , French National Centre for Scientific Research (CNRS) (Author)
  • Mark Ibberson - , Swiss Institute of Bioinformatics (Author)
  • Isabelle Leclerc - , Imperial College London (Author)
  • Marianne Voz - , University of Liege (Author)
  • Guy A. Rutter - , Imperial College London, Nanyang Technological University (Author)


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 Ca2+. 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. RNA-Seq (GSE152576) and proteomics (PXD021597) data have been deposited to GEO ( and ProteomeXchange ( archive/projects/PXD021597) repositories, respectively.


Original languageEnglish
Pages (from-to)850-864
Number of pages15
Issue number4
Publication statusPublished - Apr 2021

External IDs

PubMed 33492421
Scopus 85099920375


Sustainable Development Goals


  • C2cd4a/b, Follicle-stimulating hormone, Genome-wide association studies, Glucose homeostasis, Type 2 diabetes

Library keywords