First Author | Lin G | Year | 2020 |
Journal | Biochem J | Volume | 477 |
Issue | 13 | Pages | 2581-2594 |
PubMed ID | 32677665 | Mgi Jnum | J:300368 |
Mgi Id | MGI:6492112 | Doi | 10.1042/BCJ20200235 |
Citation | Lin G, et al. (2020) Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders. Biochem J 477(13):2581-2594 |
abstractText | Glucagon is a peptide hormone secreted by islet alpha 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 alpha 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. |