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.
Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders
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Guangyao Lin, Qiaofeng Liu, Antao Dai, Xiaoqing Cai, Qingtong Zhou, Xi Wang, Yan Chen, Chenyu Ye, Jie Li, Dehua Yang, Ming-Wei Wang; Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders. Biochem J 17 July 2020; 477 (13): 2581–2594. doi: https://doi.org/10.1042/BCJ20200235
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