2. Academic Validation
  3. Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders

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.
Guangyao Lin # 1 2 3,  Qiaofeng Liu # 4,  Antao Dai 1,  Xiaoqing Cai 1,  Qingtong Zhou 5,  Xi Wang 1 3,  Yan Chen 4,  Chenyu Ye 4,  Jie Li 1 3,  Dehua Yang 1 3,  Ming-Wei Wang 1 2 3 4 6
Affiliations

Affiliations

  • 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.
PMID: 32677665 DOI: 10.1042/BCJ20200235
Abstract

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.

Keywords

V368M; glucagon receptor; metabolic disorders; mouse model; mutation.

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