Insulin plays a key role in regulating glucose metabolism in the liver. Glucose enters hepatocytes through insulin-independent GLUT2 transporters. However, insulin increases hepatic retention and utilization of glucose by upregulating the expression of glucokinase. This is achieved through the activation of the transcription factor sterol regulatory element–binding protein 1C (SREBP1C), which acts as a "master switch" in the fed state to increase the levels of enzymes involved in glucose utilization and triglyceride (TG) synthesis. Conversely, hepatocytes also express the enzyme G6Pase, which converts glucose-6-phosphate (G6P) back to glucose. This allows glucose to exit the hepatocyte through the GLUT2 transporter. Insulin prevents the futile cycle of glucose phosphorylation-dephosphorylation by repressing the gene expression of G6Pase. On the other hand, the transcription factor FOXO1 stimulates the gene expression of G6Pase. FOXO1 is inactivated by insulin-activated Akt kinase, which phosphorylates and inactivates FOXO1. During the fasting phase, FOXO1 is active and promotes G6Pase expression, while SREBP1C is inactive and does not stimulate glucokinase expression. The reciprocal regulation of SREBP1C and FOXO1 is primarily determined by the presence or absence of insulin.

Insulin also influences glycogen metabolism in the liver. It indirectly promotes glycogen synthesis by increasing the expression of glucokinase, which allosterically activates glycogen synthase through high levels of G6P. Insulin facilitates the dephosphorylation and activation of glycogen synthase through the stimulation of specific protein phosphatases. Furthermore, insulin inhibits glycogen phosphorylase, preventing the futile cycle of glycogen synthesis to glycogenolysis. In contrast, glucagon-activated PKA phosphorylates phosphorylase kinase, which then activates glycogen phosphorylase.

In addition to its effects on glucose and glycogen metabolism, insulin also stimulates glycolysis in hepatocytes. It activates phosphofructokinase 1 (PFK1), which phosphorylates fructose-6-phosphate (F6P) to fructose-1,6-bisphosphate (F1,6BP). Insulin also inhibits fructose-2,6-bisphosphatase, which catalyzes the dephosphorylation of F1,6BP. This overall effect promotes the glycolytic pathway.
Fig. 39.13 for numbered reactions; D denotes digestive phase, F denotes fasting phase): 1. Trapping vs. releasing intracellular glucose. Although glucose enters hepatocytes through insulin-independent GLUT2 transporters, insulin increases hepatic retention and utilization of glucose by increasing expression of glucokinase (reaction 1D). Insulin increases glucokinase gene expression through increased expression and activation of the transcription factor sterol regulatory element–binding protein 1C (SREBP1C), which acts as a “master switch” in the fed state to coordinately increase levels of several enzymes involved in glucose utilization and TG synthesis. Hepatocytes also express the enzyme G6Pase (reaction 1F), which converts G6P back to glucose, which can then exit the hepatocyte via the GLUT2 transporter. Insulin prevents the futile cycle of glucose phosphorylation-dephosphorylation by repressing gene expression of the enzyme G6Pase. The transcription factor FOXO1 stimulates gene expression of G6Pase. Insulin-activated Akt kinase phosphorylates and inactivates FOXO1. During the fasting phase, FOXO1 is active and promotes G6Pase expression, whereas SREBP1C is inactive and does not stimulate glucokinase expression. The reciprocal regulation of SREBP1C and FOXO1 are thus regulated primarily by the presence or absence of insulin.
2.
Glycogen synthesis vs. breakdown. Insulin indirectly increases glycogen synthesis through increased expression of glucokinase because high levels of G6P allosterically increase glycogen synthase activity. Through stimulation of specific protein phosphatases, insulin promotes dephosphorylation and thereby activation of glycogen synthase (reaction 2D). Insulin also prevents the futile cycle of glycogen synthesis to glycogenolysis through inhibition of glycogen phosphorylase (reaction 2F). Glucagon-activated PKA phosphorylates phosphorylase kinase, which in turn phosphorylates and activates glycogen phosphorylase.
3.
Increasing glycolysis.
A. Activating phosphofructokinase 1 (PFK1) and inhibiting fructose-2,6-bisphosphatase. Insulin increases the activity of PFK1, which phosphorylates •Fig. 39.13 Insulinandcounterregulatoryhormoneregulationofphosphofructokinase1(PFK1;reaction3Din
Fig.39.12) andfructose-1,6-bisphosphatase(F1,6BPase;reaction3Fin