| Title: |
Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis |
| Authors: |
Mousavy Gharavy, SN; Owen, BM; Millership, SJ; Chabosseau, P; Pizza, G; Martinez-Sanchez, A; Tasoez, E; Georgiadou, E; Hu, M; Fine, NHF; Jacobson, DA; Dickerson, MT; Idevall-Hagren, O; Montoya, A; Kramer, H; Mehta, Z; Withers, DJ; Ninov, N; Gadue, PJ; Cardenas-Diaz, FL; Cruciani-Guglielmacci, C; Magnan, C; Ibberson, M; Leclerc, I; Voz, M; Rutter, GA |
| Contributors: |
Medical Research Council (MRC); Wellcome Trust; Medical Research Council |
| Source: |
864 ; 850 |
| Publisher Information: |
Springer |
| Publication Year: |
2020 |
| Collection: |
Imperial College London: Spiral |
| Subject Terms: |
Science & Technology; Life Sciences & Biomedicine; Endocrinology & Metabolism; C2CD4A/B; Follicle-stimulating hormone; Genome-wide association studies; Glucose homeostasis; Type 2 diabetes; 1103 Clinical Sciences; 1114 Paediatrics and Reproductive Medicine; 1117 Public Health and Health Services |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Diabetologia; http://hdl.handle.net/10044/1/92690; MR/P023223/1; 093082/Z/10/Z; 511377; MR/R022259/1 |
| DOI: |
10.1007/s00125-020-05350-x |
| Availability: |
http://hdl.handle.net/10044/1/92690; https://doi.org/10.1007/s00125-020-05350-x |
| Rights: |
© The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Accession Number: |
edsbas.6BC62B77 |
| Database: |
BASE |