CHAPTER 23: GLYCOGEN

Chapter 23: Glycogen

Glycogen is the major carbohydrate storage form in animals, and corresponds to starch in plants. It occurs mainly in liver (up to 6-8% wet weight), and muscle (where it rarely exceeds 1% of wet weight). However, because of its greater mass, the whole body muscle glycogen pool is some 3 to 4 times greater than the liver pool. Glycogen is found in the cytosol of cells, and each molecule can contain up to 60,000 glucose residues. It is a hydrophilic molecule that exists in vivo in highly hydrated glycogen granules. Approximately 65% of glycogen is water. Conversely, triglyceride, the major storage form of fat, is anhydrous and hydrophobic, thus making it lighter than glycogen. If a dog stored the same amount of glycogen as it does fat, it would be nearly twice as heavy, and its mobility would be severely reduced. For this and several other reasons, migrating birds also store potential energy primarily as fat.

Glycogen breakdown (glycogenolysis) occurs in liver during both exercise and starvation, whereas muscle glycogenolysis generally requires exercise. Free glucose can be generated from glycogenolysis in the liver, and thus made available to the rest of the body via the bloodstream. However, this does not occur in muscle (since muscle lacks the enzyme glucose-6-phosphatase (Glc-6-Pase)). Glycogen broken down in muscle cells must be oxidized therein.

Glycogenesis involves the biosynthesis of glycogen from glucose, glucose metabolites, or metabolic precursors of glucose. Glycogen storage diseases are a group of inherited metabolic disorders characterized by deficient mobilization of glycogen or deposition of abnormal forms, leading to muscular weakness, exercise intolerance, and sometimes death. Glycogenesis and glycogenolysis occur via separate metabolic pathways, thereby allowing each to operate independently of the other. They should be viewed as continuous, dynamic physiologic processes that are regulated by the presence or absence of various hormones and neurotransmitters.

Glycogenesis: Branching of the glycogen molecule occurs at an average frequency of every ten glucose residues. Branching increases its solubility as well as the rate at which glucose can be stored and retrieved. Each glycogen molecule has a protein, glycogenin, covalently linked to the polysaccharide. Linear glycogen chains consist of glucose molecules linked together by a-1,4 glycosidic bonds. At each of the branch points, two glucose molecules are linked together by a-1,6 glycosidic bonds. The non-reducing ends of the glycogen molecule are the sites where both synthesis and degradation occur.

The pathway by which glucose-6-phosphate (Glc-6-P) is converted to glycogen. Following glucose phosphorylation by hexokinase (HK) or glucokinase, Glc-6-P may be converted to glucose-1-phosphate (Glc-1-P) by the reversible enzyme, phosphoglucomutase (PGM). This reaction, like that for the phosphorylation of glucose, requires Mg++ as a cofactor. Glc-1-P is next converted to the active nucleotide, uridine diphosphate-glucose (UDP-Glc), by the action of UDPGlc pyrophosphorylase. UDP-glucose now becomes a branch point for entry into the hepatic uronic acid pathway (via UDP-glucuronate), lactose synthesis in the mammary gland (via UDP-galactose), or glycogen synthesis in several tissues (via enhanced activity of glycogen synthase).

Glycogen synthase catalyzes the rate-limiting step in glycogenesis. Being a key enzyme, its activity can be inhibited by phosphorylation, or activated by dephosphorylation. Postprandial (i.e., after a meal) conditions activate glycogen synthase activity in various ways. The parasympathetic nervous system (PNS) has an indirect effect via autonomic stimulation of insulin release from the pancreas. High levels of glucose also stimulate insulin release. Insulin, the anabolic hormone that promotes storage of dietary bounty, stimulates activity of protein phosphatase 1, which in turn stimulates glycogen synthase activity by causing its dephosphorylation.

When the a-1,4 chain of glycogen extends to 11-15 glucose residues from the nearest branch point, branching occurs. A block of 6-7 glucose residues is moved from the end of one chain to another chain, or to an internal position of the same chain. By catalyzing these a-1,4 —> a-1,6 glucan transfers, the non-regulatory branching enzyme helps to create new sites for elongation by glycogen synthase.

Glycogenolysis: Mobilization of glucose from glycogen stores requires two reactions: shortening of the nonreducing ends of a-1,4 glycosidic chains by a regulatory phosphorylase, and disassembly of the a-1,6 branch points by a non-regulatory debranching enzyme. The first reaction adds inorganic phosphate (Pi) rather than H2O across the glycosidic bond, resulting in the release of Glc-1-P which can then be converted to Glc-6- P by PGM. The second reaction removes a free glucose residue from glycogen which can be quickly phosphorylated to Glc-6-P and used in the Embden-Meyerhoff pathway (EMP), or released by liver tissue into blood. Additionally, Glc-6-P may also be dephosphorylated by hepatic Glu-6-Pase, and released as free glucose into blood. Approximately 90% of glycogen degradation results in Glc-1-P formation through reaction one above, and 10% in free glucose formation through reaction two.

Glycogen phosphorylase in muscle is immunologically and genetically distinct from that in liver. It is a dimer, with each monomer containing 1 mol of pyridoxal phosphate (vitamin B6). Indeed, glycogen phosphorylase may account for as much as 70-80% of this water-soluble vitamin in mammals. This enzyme exists in two basic forms, an active phosphorylated form, and an inactive dephosphorylated form. Activation of this enzyme involves a cascade of reactions initiated by an increase in intracellular cyclic-AMP (cAMP). The cascade involves an initial phosphorylation of phosphorylase kinase, which is stimulated by protein kinase A. The active phosphorylase kinase next initiates phosphorylation of glycogen phosphorylase (which becomes active), as well as of glycogen synthase (which becomes inactive). Phosphorylase kinase is activated by hormones that elevate intracellular cAMP (e.g., epinephrine acting on b2-adrenergic receptors, and glucagon), whereas protein phosphatase-1 is activated by insulin. Insulin also activates a cAMP-dependent phosphodiesterase in liver cells, which reduces cAMP to its inactive form (5'-AMP), thus favoring glycogen synthesis.

Phosphorylase kinase can also be allosterically activated by Ca++, a mechanism independent of cAMP. Studies have shown that a1-adrenergic receptor stimulation is also involved in the catecholamine induced stimulation of glycogenolysis in both liver and muscle tissue. This mechanism is particularly important in skeletal muscle, where contraction is initiated by the release of Ca++ from the sarcoplasmic reticulum. It allows glycogen degradation, which normally increases several hundred-fold immediately after the onset of contraction, to be synchronized with the contractile process. Phosphorylase kinase is a complex enzyme having four different subunits, a, b, g, and D. The D subunit is calmodulin, a Ca++-binding protein that sensitizes a number of enzymes to small changes in the intracellular Ca++ concentration.

Glycogen Storage Diseases: Glycogen storage diseases are known to exist in dogs (usually miniature breed puppies), cats, horses, and primates, and are generally characterized by an inability to form or degrade glycogen in normal metabolic pathways. Examples are a type I von Gierke's like disease (a Glc-6-Pase deficiency), and a type II Pompe's-like disease (where glycogen accumulation is minimal due to a glycogen branching enzyme deficiency (GBED)). Clinical signs in type II glycogen storage disease are apparently related to cardiac and skeletal muscle glycogenosis, and include gastric reflux and megaesophagus, systemic muscle weakness, and cardiac abnormalities. A type III Cori's-like disease also exists in dogs, which is a debranching enzyme deficiency. As indicated above, these diseases may result in either the inability to form glycogen, or in glycogen accumulation in the liver, muscles, kidneys, and nervous tissue. Affected patients become exercise intolerant, blood glucose levels are low, and hyperlipidemia, hepatomegaly, and ketonemia develop. Hormones elaborated in response to critically low blood glucose concentrations in affected animals generally prompt increased rates of gluconeogenesis (and lipolysis), generating a great deal of Glc-6-P which can be subsequently stored as glycogen. Definitive diagnosis of these diseases generally requires enzyme assay of affected tissues (type I -- liver, kidneys, and intestinal mucosa; type II -- skeletal muscle, white blood cells, and skin fibroblasts: and type III -- liver, muscle, and skin fibroblasts). The prognosis for all glycogen storage disorders in animals is poor.

Another glycogen storage abnormality is exhibited in dogs with steroid (i.e. glycocorticoid) hepatopathy. Affected animals develop hepatomegaly with excessive glycogen accumulation (vacuolar hepatopathy).

\ SUMMARY

Glycogen is the main carbohydrate storage form in animals, found in the liver and muscles. It is a hydrophilic molecule that exists in highly hydrated glycogen granules. Glycogenolysis, the breakdown of glycogen, occurs in the liver during exercise and starvation, while muscle glycogenolysis requires exercise. Glycogenesis is the biosynthesis of glycogen from glucose or metabolic precursors. Glycogen storage diseases are inherited metabolic disorders that result in deficient mobilization or abnormal deposition of glycogen. Glycogenesis involves branching of the glycogen molecule, while glycogenolysis involves shortening of glycosidic chains and disassembly of branch points. Glycogen phosphorylase is the key enzyme in glycogenolysis and is activated by phosphorylation. Glycogen storage diseases can lead to muscular weakness and exercise intolerance. Steroid hepatopathy in dogs is another glycogen storage abnormality characterized by excessive glycogen accumulation in the liver.

\ OUTLINE

I. Introduction to Glycogen

  • Glycogen is the major carbohydrate storage form in animals
  • It occurs mainly in the liver and muscle
  • Glycogen is a hydrophilic molecule that exists in highly hydrated glycogen granules

II. Glycogen Breakdown (Glycogenolysis)

  • Occurs in the liver during exercise and starvation
  • Muscle glycogenolysis generally requires exercise
  • Free glucose can be generated from glycogenolysis in the liver and made available to the rest of the body

III. Glycogenesis

  • Involves the biosynthesis of glycogen from glucose or metabolic precursors
  • Glycogen storage diseases are inherited metabolic disorders characterized by deficient mobilization or deposition of glycogen

IV. Glycogenesis Process

  • Branching of the glycogen molecule occurs every ten glucose residues
  • Linear glycogen chains consist of glucose molecules linked by a-1,4 glycosidic bonds
  • Branch points are linked by a-1,6 glycosidic bonds
  • Glycogen synthase catalyzes the rate-limiting step in glycogenesis

V. Glycogenolysis Process

  • Mobilization of glucose from glycogen stores requires phosphorylase and debranching enzymes
  • Phosphorylase shortens the nonreducing ends of glycogen chains
  • Debranching enzyme removes a-1,6 branch points

VI. Regulation of Glycogen Metabolism

  • Glycogen phosphorylase is activated by phosphorylation and cAMP
  • Insulin activates glycogen synthase and promotes glycogen synthesis
  • Calcium can also allosterically activate phosphorylase kinase

VII. Glycogen Storage Diseases

  • Inherited metabolic disorders characterized by an inability to form or degrade glycogen
  • Examples include von Gierke's disease, Pompe's disease, and Cori's disease
  • Clinical signs include exercise intolerance, low blood glucose levels, and organ abnormalities

VIII. Steroid Hepatopathy

  • Dogs with steroid hepatopathy develop excessive glycogen accumulation in the liver

IX. Conclusion

  • Understanding glycogen metabolism is important for understanding energy storage and utilization in animals.

\ QUESTIONS

Qcard 1:

Question: What is the major carbohydrate storage form in animals?

Answer: Glycogen

Qcard 2:

Question: Where is glycogen mainly found in the body?

Answer: Liver and muscle

Qcard 3:

Question: How does the glycogen pool in muscle compare to the glycogen pool in the liver?

Answer: The whole body muscle glycogen pool is 3 to 4 times greater than the liver pool.

Qcard 4:

Question: What is the structure of a glycogen molecule?

Answer: Each molecule can contain up to 60,000 glucose residues and has branching at every ten glucose residues.

Qcard 5:

Question: What is the difference between glycogenolysis in the liver and in muscle?

Answer: Glycogenolysis occurs in the liver during both exercise and starvation, while muscle glycogenolysis generally requires exercise.

Qcard 6:

Question: What is the rate-limiting step in glycogenesis?

Answer: Glycogen synthase catalyzes the rate-limiting step in glycogenesis.

Qcard 7:

Question: How is glycogen phosphorylase activated?

Answer: Glycogen phosphorylase is activated by an increase in intracellular cyclic-AMP (cAMP) and phosphorylation by phosphorylase kinase.

Qcard 8:

Question: What are glycogen storage diseases?

Answer: Glycogen storage diseases are inherited metabolic disorders characterized by deficient mobilization of glycogen or deposition of abnormal forms, leading to muscular weakness, exercise intolerance, and sometimes death.

Qcard 9:

Question: What is the prognosis for animals with glycogen storage disorders?

Answer: The prognosis for all glycogen storage disorders in animals is poor.

Qcard 10:

Question: What is exhibited in dogs with steroid hepatopathy?

Answer: Excessive glycogen accumulation in the liver (vacuolar hepatopathy).

Mind Map: Chapter 23: Glycogen

Central Idea: Glycogen is the major carbohydrate storage form in animals and plays a crucial role in energy metabolism.

Main Branches:
  1. Introduction to Glycogen
  2. Glycogenesis
  3. Glycogenolysis
  4. Glycogen Storage Diseases
1. Introduction to Glycogen
  • Definition and function of glycogen
  • Occurrence and distribution in the body
  • Comparison with other energy storage forms (triglycerides)
2. Glycogenesis
  • Biosynthesis of glycogen from glucose and glucose metabolites
  • Role of glycogenin and branching in glycogen structure
  • Regulation of glycogen synthase activity
  • Factors that stimulate glycogen synthesis (postprandial conditions, insulin)
Sub-branches:
  • Conversion of glucose-6-phosphate to glycogen
  • Role of UDP-glucose in glycogen synthesis
  • Activation and inhibition of glycogen synthase
3. Glycogenolysis
  • Breakdown of glycogen to release glucose
  • Differences in glycogenolysis between liver and muscle
  • Role of glycogen phosphorylase and debranching enzyme
Sub-branches:
  • Mobilization of glucose from glycogen stores
  • Formation of Glc-1-P and Glc-6-P
  • Activation and regulation of glycogen phosphorylase
  • Role of hormones and intracellular signaling pathways
4. Glycogen Storage Diseases
  • Inherited metabolic disorders affecting glycogen metabolism
  • Deficiencies in glycogen mobilization or deposition
  • Clinical signs and symptoms in affected animals
  • Diagnosis and prognosis of glycogen storage diseases
Sub-branches:
  • Types of glycogen storage diseases in animals (von Gierke's, Pompe's, Cori's)
  • Impact on glycogen formation and accumulation
  • Relationship to exercise intolerance and low blood glucose levels
  • Diagnostic methods and poor prognosis
Note: The mind map provides a brief overview of the chapter and does not cover all details. Further reading is recommended for a comprehensive understanding of glycogen metabolism.

Study Plan: Chapter 23: Glycogen

Day 1:

  1. Read and understand the introduction and overview of glycogen (paragraph 1).
  2. Focus on the structure and distribution of glycogen in animals (paragraph 2).
  3. Take notes on the differences between glycogen and triglyceride as storage forms (paragraph 2).
  4. Study the process of glycogen breakdown (glycogenolysis) in the liver and muscle (paragraph 3).
  5. Understand the significance of glucose-6-phosphatase in glycogenolysis (paragraph 3).

Day 2:

  1. Review the process of glycogenesis and the role of glycogen synthase (paragraph 4).
  2. Take note of the regulation of glycogen synthase activity (paragraph 5).
  3. Study the branching of glycogen molecules and its importance (paragraph 6).
  4. Understand the pathway of glucose-6-phosphate conversion to glycogen (paragraph 7).
  5. Take note of the different metabolic pathways involving UDP-glucose (paragraph 7).

Day 3:

  1. Review the role of glycogen phosphorylase in glycogenolysis (paragraph 8).
  2. Understand the activation and inhibition of glycogen phosphorylase (paragraph 8).
  3. Study the role of phosphorylase kinase and its regulation (paragraph 9).
  4. Take note of the involvement of hormones and intracellular signaling in glycogenolysis (paragraph 9).
  5. Understand the role of Ca++ in the allosteric activation of phosphorylase kinase (paragraph 10).

Day 4:

  1. Review the concept of glycogen storage diseases and their characteristics (paragraph 11).
  2. Focus on the examples of glycogen storage diseases in animals (paragraph 11).
  3. Study the clinical signs and symptoms associated with glycogen storage diseases (paragraph 11).
  4. Understand the impact of glycogen storage diseases on glucose metabolism (paragraph 11).
  5. Take note of the diagnostic methods for glycogen storage diseases (paragraph 11).

Day 5:

  1. Review the glycogen storage abnormality in dogs with steroid hepatopathy (paragraph 12).
  2. Understand the development and characteristics of steroid hepatopathy (paragraph 12).
  3. Study the excessive glycogen accumulation in dogs with steroid hepatopathy (paragraph 12).
  4. Review the overall content of Chapter 23 and summarize key

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