Different forms of metabolic stress, including SARS-CoV-2 infection, fasting or high-fat diet feeding, induce the expression and secretion of GP73 from a variety of tissues depending on the context. Circulating GP73 travels to the liver, where it activates PKA and its downstream signalling molecules, increases the expression of gluconeogenic genes and augments hepatic glucose release. GP73 also impairs insulin-mediated glucose utilization, which, when combined with the above, elevates blood glucose.