Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders
- Biochem J. 2020 Jul 17;477(13):2581-2594. doi: 10.1042/BCJ20200235.
- 1. The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
- 2. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
- 3. University of Chinese Academy of Sciences, Beijing 100049, China.
- 4. School of Pharmacy, Fudan University, Shanghai 201203, China.
- 5. iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
- 6. School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
- # Contributed equally.
Glucagon is a peptide hormone secreted by islet α cells. It plays crucial roles in glucose homeostasis and metabolism by activating its cognate Glucagon Receptor (GCGR). A naturally occurring deleterious mutation V368M in the human GCGR leads to reduced ligand binding and down-regulation of glucagon signaling. To examine the association between this mutation and metabolic disorders, a knock-in mouse model bearing homozygous V369M substitution (equivalent to human V368M) in GCGR was made using CRISPR-Cas9 technology. These GcgrV369M+/+ mice displayed lower fasting blood glucose levels with improved glucose tolerance compared with wild-type controls. They also exhibited hyperglucagonemia, pancreas enlargement and α cell hyperplasia with a lean phenotype. Additionally, V369M mutation resulted in a reduction in adiposity with normal body weight and food intake. Our findings suggest a key role of V369M/V368M mutation in GCGR-mediated glucose homeostasis and pancreatic functions, thereby pointing to a possible interplay between GCGR defect and metabolic disorders.