Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis
Year: 2021
Type: article
Abstract: 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 abstract
Source: Diabetologia
Authors: S. Neda Mousavy Gharavy, Bryn M. Owen, Steven J. Millership, Pauline Chabosseau, Grazia Pizza, Aida Martinez-Sanchez, Emirhan Tasoez, Eleni Georgiadou, Ming Hu, Nicholas H. F. Fine, David A. Jacobson, Matthew T. Dickerson, Olof Idevall-Hagren, Alex Montoya, Holger Kramer, Zenobia Mehta, Dominic J. Withers, Nikolay Ninov, Paul J. Gadue, Fabian L. Cardenas-Diaz, Céline Cruciani-Guglielmacci, Christophe Magnan, Mark Ibberson, Isabelle Leclerc, Marianne Voz, Guy A. Rutter
Institutions: Hammersmith Hospital, Imperial College London, MRC London Institute of Medical Sciences, Center for Regenerative Therapies Dresden, Technische Universität Dresden, Vanderbilt University, Uppsala University, Children's Hospital of Philadelphia, Centre National de la Recherche Scientifique, Université Paris Cité, Unit of Functional and Adaptive Biology, SIB Swiss Institute of Bioinformatics, University of Liège, Nanyang Technological University
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funders: Wellcome Trust, International Seafood Sustainability Foundation, Diabetes UK, Imperial College London, European Commission, European Association for the Study of Diabetes, Novo Nordisk Fonden, Innovative Medicines Initiative, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Investigating the role of immature beta cells in insulin release from the intact islet, G130968091, G1335979935, G1635243398, Genetic and nutritional control of pancreatic beta cell identity., Roles of GWA genes in controlling pancreatic beta cell function and mass., G2040450235, G2155866234, Control of glucagon secretion by AMPK and related kinases., G2961113885, Role of mitochondrial calcium transport in the regulation of insulin secretion, G3555667338, G3700981753, G434337789, Assessing risk and progression of prediabetes and type 2 diabetes to enable disease modification - Sofia ref.: 115881, G4426574518, AMPK-mediated regulation and roles of miR-125b and miR-184 in pancreatic beta-cell function., HNF1A in human endocrine cell development and function, G4781795914, G4879560972, Two-Pore-Domain Potassium Channels as Novel Targets for Modulating Islet Hormone Secretion, All-optical deconstruction of the islet wiring patterns underlying insulin secretion in health and disease, G5485930741, Targeting etiologic molecular mechanisms to treat human diabetes, G5673545276, The impact of long non-coding RNA at the Pax6 locus on beta cell identity and function, Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes, Molecular mechanisms linking Sorcin to pancreatic beta cell lipotoxicity and ER Ca2+ stores., G7328074751, G8152984508, Roles of the type 2 diabetes (T2D)-associated gene C2cd4a in regulating glucose homeostasis in the mouse, G8635620823, Integrated Training in Engineering and Diabetes, Designing selective TALK-1 inhibitors to reduce beta-cell dysfunction in diabetes
OpenAlex ID: W3124020887