Glucagon Receptor Inhibition Reduces Hyperammonemia and Lethality in Male Mice with Urea Cycle Disorder.
2020
The liver plays a critical role in maintaining ammonia homeostasis. Urea cycle defects, liver injury or failure and glutamine synthetase 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 (Otc spf-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 glutamine synthetase in livers of Otc spf-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. The Otc spf-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 risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle, liver injury or failure and glutamine synthetase deficiency.
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