Glycogen synthase 2 (Gys-2) is the rate-limiting enzyme in the synthesis of glycogen in liver (Figure 3). The activity of Gys-2 is inhibited via phosphorylation by glycogen synthase kinase 3β (GSK-3β). In turn, GSK-3β kinase activity is attenuated after phosphorylation by Akt. Glycogen storage in liver is controlled by many factors, of which the rate of portal venous glucose delivery to the liver and insulin levels are best known. Insulin stimulates glycogen synthesis via Akt-mediated phosphorylation of GSK-3β, while glucagon inhibits Gys-2 activity through cAMP-mediated activation of GSK-3β. In periods of food deprivation, hepatic glycogen is broken down in order to maintain euglycemia. Glycogen phosphorylase (GP), the key enzyme responsible for glycogenolysis, generates glucose-1-phosphate, which is converted to G6P by phosphoglucomutase (Figure 3). Glucose-6-phosphatase (G6Pase), which catalyzes the conversion to glucose, is the rate-limiting enzyme in the regulation of blood glucose levels by breakdown of glycogen. The activity of GP is mainly inhibited by the presence of high levels of glucose.
