Allosteric and Hormonal Signals Coordinate Carbohydrate Metabolism

Having looked at the mechanisms that regulate individual enzymes, we can now consider the overall shifts in carbohydrate metabolism that occur in the well-fed state, during fasting, and in the fight-or-flight response—signaled by insulin, glucagon, and epinephrine, respectively. We need to contrast two cases in which regulation serves different ends: (1) the role of hepatocytes in supplying glucose to the blood, and (2) the selfish use of carbohydrate fuels by nonhepatic tissues, typified by skeletal muscle (the myocyte), to support their own activities.

After ingestion of a carbohydrate-rich meal, the elevation of blood glucose triggers insulin release (Fig. 15-31, top). In a hepatocyte, insulin has two immediate effects: it inactivates GSK3, acting through the cascade shown in Figure 15-29, and activates a protein phosphatase, perhaps PP1. These two actions fully activate glycogen synthase. PP1 also inactivates glycogen phosphorylase a and phosphorylase kinase by dephosphory-lating both, effectively stopping glycogen breakdown. Glucose enters the hepatocyte through the high-capacity transporter GLUT2, always present in the plasma membrane, and the elevated intracellular glucose leads to dissociation of hexokinase IV (glucokinase) from its nuclear regulator protein. Hexokinase IV enters the cytosol and phosphorylates glucose, stimulating glycolysis and supplying the precursor for glycogen synthesis. Under these conditions, hepatocytes use the excess glucose in the blood to synthesize glycogen, up to the limit of about 10% of the total weight of the liver.

Glycogen granule insulin epinephrine

FIGURE 15-30 Glycogen-targeting protein GM. The glycogen-targeting protein Gm is one of a family of proteins that bind other proteins (including PP1) to glycogen particles. Gm can be phosphorylated in two different positions in response to insulin or epinephrine. (1 Insulin-stimulated phosphorylation of Gm site 1 activates PP1, which dephosphorylates phosphorylase kinase, glycogen phosphorylase, and glycogen synthase. @ Epinephrine-stimulated phosphorylation of Gm site 2 causes dissociation of PP1 from the glycogen particle, preventing its access to glycogen phosphorylase and glycogen synthase. PKA also phosphorylates a protein (inhibitor 1) that, when phosphorylated, inhibits PP1. By these means, insulin inhibits glycogen breakdown and stimulates glycogen synthesis, and epinephrine (or glucagon in the liver) has the opposite effects.

insulin epinephrine

FIGURE 15-30 Glycogen-targeting protein GM. The glycogen-targeting protein Gm is one of a family of proteins that bind other proteins (including PP1) to glycogen particles. Gm can be phosphorylated in two different positions in response to insulin or epinephrine. (1 Insulin-stimulated phosphorylation of Gm site 1 activates PP1, which dephosphorylates phosphorylase kinase, glycogen phosphorylase, and glycogen synthase. @ Epinephrine-stimulated phosphorylation of Gm site 2 causes dissociation of PP1 from the glycogen particle, preventing its access to glycogen phosphorylase and glycogen synthase. PKA also phosphorylates a protein (inhibitor 1) that, when phosphorylated, inhibits PP1. By these means, insulin inhibits glycogen breakdown and stimulates glycogen synthesis, and epinephrine (or glucagon in the liver) has the opposite effects.

Glycogen Synthesis

Inhibitor 1

Phosphorylated inhibitor 1 binds and inactivates PP1

Phosphorylase kinase

Phosphorylase kinase

Inhibitor 1

Phosphorylated inhibitor 1 binds and inactivates PP1

15.4 Coordinated Regulation of Glycogen Synthesis and Breakdown

Essentials of Human Physiology

Essentials of Human Physiology

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