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

Mousavy Gharavy, S. Neda (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Owen, Bryn M. (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Invest Med, London, England.
Millership, Steven J. (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.;Imperial Coll London, MRC London Inst Med Sci, Hammersmith Campus, London, England.;Imperial Coll London, Inst Clin Sci, Fac Med, London, England.
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Chabosseau, Pauline (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Pizza, Grazia (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Martinez-Sanchez, Aida (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Tasoez, Emirhan (författare)
Tech Univ Dresden, DFG Ctr Regenerat Therapies, Dresden, Germany.
Georgiadou, Eleni (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Hu, Ming (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Fine, Nicholas H. F. (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Jacobson, David A. (författare)
Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.
Dickerson, Matthew T. (författare)
Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.
Idevall-Hagren, Olof, 1980- (författare)
Uppsala universitet,Institutionen för medicinsk cellbiologi
Montoya, Alex (författare)
Imperial Coll London, MRC London Inst Med Sci, Hammersmith Campus, London, England.
Kramer, Holger (författare)
Imperial Coll London, MRC London Inst Med Sci, Hammersmith Campus, London, England.
Mehta, Zenobia (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Withers, Dominic J. (författare)
Imperial Coll London, MRC London Inst Med Sci, Hammersmith Campus, London, England.;Imperial Coll London, Inst Clin Sci, Fac Med, London, England.
Ninov, Nikolay (författare)
Tech Univ Dresden, DFG Ctr Regenerat Therapies, Dresden, Germany.
Gadue, Paul J. (författare)
Childrens Hosp Philadelphia, CTRB, Philadelphia, PA 19104 USA.
Cardenas-Diaz, Fabian L. (författare)
Childrens Hosp Philadelphia, CTRB, Philadelphia, PA 19104 USA.
Cruciani-Guglielmacci, Celine (författare)
Univ Paris, Regulat Glycemia Cent Nervous Syst, CNRS, BFA,UMR 8251, Paris, France.
Magnan, Christophe (författare)
Univ Paris, Regulat Glycemia Cent Nervous Syst, CNRS, BFA,UMR 8251, Paris, France.
Ibberson, Mark (författare)
SIB Swiss Inst Bioinformat, Vital IT Grp, Lausanne, Switzerland.
Leclerc, Isabelle (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.
Voz, Marianne (författare)
Univ Liege ULg, Lab Zebrafish Dev & Dis Models, Liege, Belgium.
Rutter, Guy A. (författare)
Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England.;Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore.
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Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Cell Biol & Funct Genom, London, England Imperial Coll London, Hammersmith Hosp, Dept Metab Digest & Reprod, Sect Invest Med, London, England. (creator_code:org_t)
2021-01-25
2021
Engelska.
Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 64:4, s. 850-864
Relaterad länk:
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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. 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

C2CD4A/B
Follicle-stimulating hormone
Genome-wide association studies
Glucose homeostasis
Type 2 diabetes

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