Glucagon Receptor Inhibition Reduces Hyperammonemia and Lethality in Male Mice with Urea Cycle Disorder

Author:

Cavino Katie1,Sung Biin1,Su Qi1,Na Erqian1,Kim Jinrang1,Cheng Xiping1,Gromada Jesper1,Okamoto Haruka1ORCID

Affiliation:

1. Regeneron Pharmaceuticals, Tarrytown, New York USA

Abstract

Abstract The liver plays a critical role in maintaining ammonia homeostasis. Urea cycle defects, liver injury, or failure and glutamine synthetase (GS) deficiency result in hyperammonemia, serious clinical conditions, and lethality. In this study we used a mouse model with a defect in the urea cycle enzyme ornithine transcarbamylase (Otcspf-ash) to test the hypothesis that glucagon receptor inhibition using a monoclonal blocking antibody will reduce the hyperammonemia and associated lethality induced by a high-protein diet, which exacerbates disease. We found reduced expression of glutaminase, which degrades glutamine and increased expression of GS in livers of Otcspf-ash mice treated with the glucagon receptor blocking antibody. The gene expression changes favor ammonia consumption and were accompanied by increased circulating glutamine levels and diminished hyperammonemia. Otcspf-ash mice treated with the glucagon receptor-blocking antibody gained lean and body mass and had increased survival. These data suggest that glucagon receptor inhibition using a monoclonal antibody could reduce the risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle, liver injury, or failure and GS deficiency.

Funder

Regeneron Pharmaceuticals

Publisher

The Endocrine Society

Subject

Endocrinology

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