Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders

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.

Deleterious mutation V369M in the mouse GCGR gene causes abnormal plasma amino acid levels indicative of a possible liver–α-cell axis

“…V368M (c.1102G > A, p.V368M), a naturally occurring GCGR single nucleotide polymorphism (SNP), was identified as a mild deleterious mutation leading to reduced ligand binding and down-regulation of glucagon signaling. Our previous studies confirmed that mice bearing homozygous V369M (c.1105G > A, p.V369M) substitution in the GCGR ( Gcgr V369M+/+ ) display lower fasting blood glucose levels with improved glucose tolerance, hyperglucagonemia, pancreas enlargement and α-cell hyperplasia [ 22 ].…”

“…Generation of Gcgr V369M+/+ mice was described previously [ 22 ]. The genotypes of all the mice were verified by PCR and confirmed by DNA sequencing (Supplementary Figure S1).…”

“…Gcgr V369M+/+ mice displayed lower fasting blood glucose levels with improved glucose Downloaded from http://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20210758/911211/bsr-2021-0758-t.pdf by guest on 24 May 2021 tolerance compared to the wild-type (WT) controls. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia [22].…”

“…It manifests itself as hyperglucagonemia without glucagonoma syndrome, hyperaminoacidemia, α-cell proliferation and hereditary pancreatic neuroendocrine tumor (PNET) [17][18][19][20][21]. We reported previously that a naturally occurring mutation V368M (equivalent to mouse V369M) in the human GCGR led to reduced ligand binding and down-regulation of glucagon signaling [22]. Gcgr V369M+/+ mice displayed lower fasting blood glucose levels with improved glucose Downloaded from http://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20210758/911211/bsr-2021-0758-t.pdf by guest on 24 May 2021 tolerance compared to the wild-type (WT) controls.…”

“…Gcgr V369M+/+ mice displayed lower fasting blood glucose levels with improved glucose tolerance compared with the wildtype (WT) controls. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia [ 22 ].…”