Open AccessCharacterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders
Author(s) -
Gonghua Lin,
Qiaofeng Liu,
Antao Dai,
Xiaoqing Cai,
Qingtong Zhou,
Xi Wang,
Yan Chen,
Chenyu Ye,
Jie Li,
Dehua Yang,
Mingwei Wang
Publication year - 2020
Publication title -
biochemical journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.706
H-Index - 265
eISSN - 1470-8728
pISSN - 0264-6021
DOI - 10.1042/bcj20200235
Subject(s) - glucagon receptor , hyperglucagonemia , glucagon , glucose homeostasis , endocrinology , medicine , biology , mutation , homeostasis , receptor , blood sugar regulation , insulin , biochemistry , insulin resistance , gene
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.