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

The Biochemical Journal
Guangyao LinMing-Wei Wang

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.

References

May 1, 1990·Metabolism: Clinical and Experimental·R C BonadonnaR A DeFronzo
May 1, 1995·Diabetes Care·P J Lefèbvre
Jan 29, 2003·Proceedings of the National Academy of Sciences of the United States of America·R W GellingM J Charron
Mar 11, 2003·American Journal of Physiology. Endocrinology and Metabolism·Guoqiang Jiang, Bei B Zhang
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Feb 23, 2008·Cellular and Molecular Life Sciences : CMLS·F Authier, B Desbuquois
Apr 3, 2008·Nature Reviews. Drug Discovery·Malin C Lagerström, Helgi B Schiöth
Nov 13, 2009·Diabetes Care·Ralph A DeFronzo, Devjit Tripathy
Dec 25, 2009·Circulation. Cardiovascular Genetics·Andrew D Johnson
May 26, 2010·The Journal of Physical Chemistry. B·Jeffery B KlaudaRichard W Pastor
Oct 20, 2010·Nature Reviews. Endocrinology·Kirk M HabeggerMatthias H Tschöp
Jul 23, 2011·The Journal of Clinical Endocrinology and Metabolism·Preethi Srikanthan, Arun S Karlamangla
Mar 13, 2013·Proceedings of the National Academy of Sciences of the United States of America·Denise WoottenPatrick M Sexton
Feb 20, 2015·The Journal of Clinical Endocrinology and Metabolism·Bence SiposGünter Klöppel
Jan 1, 2008·Journal of Chemical Theory and Computation·Berk Hess
Dec 10, 2016·Endocrinology, Diabetes & Metabolism Case Reports·Etienne LargerErica Nishimura
Dec 19, 2017·Cell·Alexander S HauserM Madan Babu
Apr 28, 2018·Pancreas·Run Yu
Jul 23, 2018·The Journal of Clinical Endocrinology and Metabolism·Matti L GildAnthony J Gill

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