ArticleDiabetologia2021
Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis.
Article in Diabetologia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 12 citations in OpenAlex.
- Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility.bioRxiv : the preprint server for biology · 2025Article
- Lack of glutamate neurotransmission in melanin-concentrating hormone neurons alters mouse reproduction and metabolism in a sex-specific manner.Biology of sex differences · 2025Article
- Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function.Nature communications · 2024Article
- Selective Transcription Factor Blockade Reduces Human Retinal Endothelial Cell Expression of Intercellular Adhesion Molecule-1 and Leukocyte Binding.International journal of molecular sciences · 2023Article
- Pancreatic microexons regulate islet function and glucose homeostasis.Nature metabolism · 2023Article
- Sex Differences in Glucose Homeostasis.Handbook of experimental pharmacology · 2023Article
- Reflections on the state of diabetes research and prospects for treatment.Diabetology international · 2023Review
- Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase.Diabetologia · 2022Article
- Article
- Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research.Frontiers in endocrinology · 2020Review
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Authors and funding
26 authors at 11 institutions in 8 countries.
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Abstract
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 Ca CONCLUSIONS/
interpretationOur 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.
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