Glycogen is stored in two tissues in the body for different reasons: in liver for short-term maintenance of blood glucose homeostasis, and in muscle as a source of energy. Glycogen metabolism in these tissues responds rapidly to both allosteric and hormonal control. In liver, the balance between glycogenolysis and glycogenesis is regulated by the balance between concentrations of glucagon and insulin in the circulation, which controls the state of phosphorylation of enzymes. Phosphorylation of enzymes under the influence of glucagon directs glycogen mobilization and is the most common condition in the liver, e.g. during sleep. Increases in blood insulin during and after meals promote dephosphorylation of the same enzymes, leading to glycogenesis. Insulin also promotes glucose uptake into muscle and adipose tissue for glycogen and triglyceride synthesis following a meal. Epinephrine controls phosphorylation of liver enzymes, enabling a burst in hepatic glycogenolysis and an increase in blood glucose for stress responses. Muscle is also responsive to epinephrine, but not to glucagon; in this case the glucose produced by glycogenolysis is used for energy metabolism. In addition, muscle glycogenolysis is responsive to intracellular Ca2+ and AMP concentrations, providing a mechanism for coupling glycogenolysis to energy consumption during exercise. The actions of insulin, glucagon, and epinephrine illustrate many of the fundamental principles of hormone action (Table 12.5). Gluconeogenesis takes place primarily in liver, and is designed for maintenance of blood glucose during the fasting state. It is essential after 12 h of fasting, when the majority of hepatic glycogen has been consumed. The major substrates for gluconeogenesis are lactate, amino acids, and glycerol; fatty acid metabolism provides the necessary energy. The major control point is at the level of phosphofructokinase-1 (PFK-1), which is activated by the allosteric effector Fru-2,6-BP. The synthesis of Fru-2,6-BP is under control of the bifunctional enzyme, PFK-2/Fru-2,6-BPase, whose kinase and phosphatase activities are regulated by phosphorylation/dephosphorylation, under hormonal control by insulin and glucagon. During fasting and active gluconeogenesis, glucagon mediates phosphorylation and activation of the phosphatase activity of this enzyme, leading to a decrease in the level of Fru-2,6-BP, and a corresponding decrease in glycolysis. Oxidation of pyruvate is also inhibited in the mitochondrion by inhibition of PDH by acetyl-CoA, derived from fat metabolism.
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- The inactivation of glycogenesis in response to epinephrine occurs in a single-step by action of PKA on glycogen synthase, while the activation of glycogenolysis involves an intermediate enzyme, phosphorylate kinase, which phosphorylates phosphorylase. Discuss the metabolic advantages of the two-step activation of glycogenolysis.
- Investigate the use of inhibitors of glycogenolysis and gluconeogenesis for treatment of type 2 diabetes.
- Glucose-6-phosphatase is essential for production of glucose in liver, but is not a cytosolic enzyme. Describe the activity and subcellular localization of this enzyme and the final stages of the pathway for production of glucose in liver.
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