Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis
In this study, we investigated a consanguineous family in whom normal-weight individuals had hepatic steatosis and cirrhosis. Using whole-exome sequencing we found two rare homozygous variants in the glucagon receptor (GCGR) gene that cosegregated with the phenotype. In cells, the GCGR mutations result in a loss of function and increased lipid accumulation. These results highlight the potential risks associated with GCGR antagonists and the benefits of GCGR agonists, currently in clinical trials.
Authors
- I. Sadaf Farooqi (ORCID: https://orcid.org/0000-0001-7609-3504)
- Katherine Lawler (ORCID: https://orcid.org/0000-0003-4188-1804)
- Rebecca Bounds (ORCID: https://orcid.org/0000-0001-8830-9456)
- Edmund Godfrey (ORCID: https://orcid.org/0000-0002-4268-8494)
- Adam Duckworth
- Alastair Baker (ORCID: https://orcid.org/0000-0001-6630-7388)
- D. J. Harman (ORCID: https://orcid.org/0000-0002-7544-0284)
- Miriam Smith
- Edson Mendes de Oliveira (ORCID: https://orcid.org/0000-0002-7330-7826)
- Matthew Hoare (ORCID: https://orcid.org/0000-0001-5990-9604)
- S. Tamir Rashid (ORCID: https://orcid.org/0000-0001-6779-2506)
- Elana Henning (ORCID: https://orcid.org/0000-0001-9463-794X)
- Julia M. Keogh (ORCID: https://orcid.org/0000-0002-0399-4114)
- Laura Watson
- Kevin M. Méndez-Acevedo (ORCID: https://orcid.org/0000-0001-9872-7192)
- Adam Syanda (ORCID: https://orcid.org/0000-0003-2297-6146)
- Tessa Cacciottolo (ORCID: https://orcid.org/0000-0002-6646-5498)
- Benedict C. Jones (ORCID: https://orcid.org/0000-0001-7777-0220)
- Daniyal Ashraf (ORCID: https://orcid.org/0009-0001-1011-7793)
Institutions
- Royal Berkshire NHS Foundation Trust (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- National Institute for Health and Care Research (GB)
- Cancer Research UK Cambridge Center (GB)
- Hutchison/MRC Research Centre (GB)
- King's College Hospital (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Diabetes
- Published
- 2025-08-25
- DOI
- https://doi.org/10.2337/db25-0209
- Citations
- 4
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 8.03
Funders
- Eli Lilly and Company
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Diabetes UK
- Fondation Leducq
- Novo Nordisk
- Fondation Botnar
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre