Studies on the effects of glucagon on the liver typically focus on the role of gluconeogenic genes and their products, but these genes and proteins do not explain the acute effects of glucagon on hepatic metabolism. Now, a new study reports that elevated levels of glucagon promote the release of glutamine from the liver and increase gluconeogenesis. In addition, the authors show that reducing glutamine metabolism in the liver reduces the severity of hyperglycaemia.

“Among the early studies on the hepatic actions of glucagon, there are numerous reports detailing rapid metabolic changes, some studies even showed increases in glutamine metabolism,” explains Russell Miller, lead author on the study. “In the present study, we used stable isotope-based mass spectrometry, which tracks heavy isotopes through metabolic pathways, to analyse the metabolic changes that occur in the liver in response to glucagon.”

The team found that hepatic glucose release following stimulation with glucagon was concomitant with a large increase in hepatic glutaminolysis. Further analysis revealed that a marked proportion of this metabolized glutamine contributed to the carbons of glucose generated during the glucagon-stimulated gluconeogenesis.

The authors then genotyped cryopreserved human hepatocytes and identified the L581P variant of liver-expressed glutaminase 2 (GLS2) as a gain-of-function variant. Importantly, loss-of-function of GLS2 in mice recapitulated the L581P GLS2 phenotype observed in humans (low fasting levels of glucose and increased plasma levels of glutamine).

“There are a number of paths forward,” concludes Miller. “Levels of plasma glutamine and the L581P GLS2 variant could potentially be used in future clinical work to inform therapeutic approaches to type 2 diabetes mellitus. For example, plasma levels of glutamine could possibly be used to identify populations of patients who will respond to treatment with a glucagon antagonist.”