Metabolic control by liver-kidney crosstalk and glucagon in health and disease

Gluconeogenesis, nitrogen metabolism and acid-base regulation are fundamental for the maintenance of metabolic homeostasis. These three processes form an interconnected triangle, with liver-kidney crosstalk and the hormone glucagon at its core. Both kidney and liver perform gluconeogenesis, and they function in co-ordination to regulate the formation and excretion of the organic osmolyte urea and the acid equivalent ammonium, and to determine the usage and de novo generation of bicarbonate. Within the liver, glucagon promotes fasting-induced gluconeogenesis and the bicarbonate-consuming formation of urea from amino acid-derived ammonia in response to protein intake and catabolic states. Within the kidney, glucagon facilitates the excretion of urea. In metabolic acidosis, the liver shifts nitrogen metabolism from ureagenesis to glutamine formation for kidney ammoniagenesis. Liver and kidney disease interfere with whole-body homeostasis of glucose, nitrogen and acid-base by promoting hypo- or hyperglycaemia, ammonia and urea toxicity, and metabolic alkalosis or acidosis. Inhibitors of the sodium glucose cotransporter SGLT2 not only cause glucosuria and compensatory hepatic gluconeogenesis but also interfere with kidney bicarbonate reabsorption, leading to compensatory kidney ammoniagenesis, bicarbonate formation and gluconeogenesis, which mitigates lactate accumulation and is associated with improved kidney health. Glucagon receptor agonists, in combination with GLP1 receptor agonists, also hold therapeutic promise in obesity and fatty liver and potentially kidney disease, but a better understanding of their effects is needed in the pathophysiological setting.