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

Qiaofeng Liu,Jianjun Lyu,Dehua Yang,Ming-Wei Wang,Yan Chen,Wenbo Feng,Yingna Xu,Guangyao Lin

doi:10.1042/bsr20210758

Qiaofeng Liu, Jianjun Lyu + Show 6 more

Open Access

https://doi.org/10.1042/bsr20210758

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Abstract

Glucagon plays an important role in glucose homeostasis and amino acid metabolism. It regulates plasma amino acid levels which in turn modulate glucagon secretion from the pancreatic α-cell, thereby establishing a liver–α-cell axis described recently. We reported previously that the knock-in mice bearing homozygous V369M substitution (equivalent to a naturally occurring mutation V368M in the human glucagon receptor, GCGR) led to hypoglycemia with improved glucose tolerance. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia. Here, we investigated the effect of V369M/V368M mutation on glucagon-mediated amino acid metabolism. It was found that GcgrV369M+/+ mice displayed increased plasma amino acid levels in general, but significant accumulation of the ketogenic/glucogenic amino acids was observed in animals fed with a high-fat diet (HFD), resulting in deleterious metabolic consequence characteristic of α-cell proliferation and hyperglucagonemia.

Highlights

Glucagon, a peptide hormone secreted by the pancreatic islet α-cell, regulates carbohydrate homeostasis and lipid metabolism through its cognate glucagon receptor (GCGR) [1,2,3]
GcgrV369M+/+ mice receiving high-fat diet (HFD) showed statistically significant increases in total α-amino acid (TAA) (Figure 1A), essential amino acid (EAA) (Figure 1C), glucogenic amino acids (GAA), glucogenic and ketogenic amino acids (G&KAA), the summation of GAA and G&KAA (G G&KAA), ketogenic amino acids (KAA) and the summation of KAA and G&KAA (K G&KAA) (Figure 1E) levels compared with the WT
42 types of amino acids were examined and the results show that among GcgrV369M+/+ mice fed with standard chow diet (SCD), there was a significant decline in plasma Cth (−20.75%) and 3MHis (−17.14%) concentrations along with marked accumulation of Ser (+31.59%) and GABA (+89.16%) compared with the WT mice (Table 1 and Figure 2A)

Summary

Introduction

A peptide hormone secreted by the pancreatic islet α-cell, regulates carbohydrate homeostasis and lipid metabolism through its cognate glucagon receptor (GCGR) [1,2,3]. It releases glucose from the liver by glycogenolysis and stimulates hepatic amino acid uptake [3,4,5]. GcgrV369M+/+ mice displayed lower fasting blood glucose levels with improved glucose tolerance compared with the wildtype (WT) controls They exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia [22]. Plasma abnormal amino acid levels, marked accumulation of the ketogenic/glucogenic amino acids was noted in HFD-fed animals accompanied by hyperglucagonemia and α-cell hyperplasia

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