Identify the primary sites of glycogen storage in the body and the function of glycogen in these tissues.

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Outline the metabolic pathways for synthesis and degradation of glycogen.

Describe the mechanism by which glycogen is mobilized in liver in response to glucagon, in muscle during exercise, and in both tissues in response to epinephrine.

Explain the origin and consequences of glycogen storage diseases in liver and muscle.

Describe the mechanism for counterregulation of glycogenolysis and glycogenesis in liver.

Outline the pathway of gluconeogenesis, including substrates, unique enzymes and regulatory mechanisms.

Describe the complementary roles of glycogenolysis and gluconeogenesis in maintenance of blood glucose concentration.

Introduction

The red cell and the brain have an absolute requirement for blood glucose for energy metabolism. Together, they consume about 80% of the 200 g of glucose consumed in the body per day. There are only about 10 g of glucose in the plasma and extracellular fluid volume, so that blood glucose must be replenished constantly. Otherwise, hypoglycemia develops and compromises brain function, leading to confusion and disorientation, and possibly life-threatening coma at blood glucose concentrations below 2.5 mmol/L (45 mg/dL). We absorb glucose from our intestines for only 2–3 h following a carbohydrate-containing meal, so there must be a mechanism for maintenance of blood glucose between meals.

Glycogen, a polysaccharide storage form of glucose, is our first line of defense against declining blood glucose concentration. During and immediately following a meal, glucose is converted into glycogen, a process known asglycogenesis, in both liver and muscle. The tissue concentration of glycogen is higher in liver than in muscle but because of the relative masses of muscle and liver, the majority of glycogen in the body is stored in muscle (Table 13.1).


Table 13.1


Tissue distribution of carbohydrate energy reserves (70-kg adult)


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Hepatic glycogenolysis and gluconeogenesis are required for maintenance of normal blood glucose concentration

Hepatic glycogen is gradually degraded between meals, by the pathway of glycogenolysis, releasing glucose to maintain blood glucose concentration. However, total hepatic glycogen stores are barely sufficient for maintenance of blood glucose concentration during a 12-h fast.

During sleep, when we are not eating, there is a gradual shift fromglycogenolysisto de novo synthesis of glucose, also an hepatic pathway, known asgluconeogenesis(Fig. 13.1). Gluconeogenesis is essential for survival during fasting or starvation, when glycogen stores are depleted. The liver uses amino acids from muscle protein as the primary precursor of glucose, but also makes use of lactate from glycolysis and glycerol from fat catabolism. Fatty acids, mobilized from adipose tissue triglyceride stores, provide the energy for gluconeogenesis.

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FIG. 13.1Sources of blood glucose during a normal day.Between meals, blood glucose is derived primarily from hepatic glycogen. Depending on the frequency of snacking, glycogenolysis and gluconeogenesis may be more or less active during the day. Late in the night or in early morning, following depletion of a major fraction of hepatic glycogen, gluconeogenesis becomes the primary source of blood glucose.

Glycogen is stored in muscle for use in energy metabolism

Muscle glycogen is not available for maintenance of blood glucose. Glucose obtained from blood and glycogen is used exclusively for energy metabolism in muscle, especially during bursts of physical activity. Although cardiac and skeletal muscles rely on fats as their primary source of energy, some glucose metabolism is essential for efficient fat metabolism in these tissues.

This chapter describes the pathways of glycogenesis and glycogenolysis in liver and muscle, and the pathway of gluconeogenesis in liver.

Structure of glycogen

Glycogen, a highly branched glucan, is the storage form of glucose in tissues

Glycogen is a branched polysaccharide of glucose. It contains only two types of glycosidic linkages, chains of α1→4-linked glucose residues with α1→6 branches spaced about every 4–6 residues along the α1→4 chain (Fig. 13.2). Glycogen is closely related tostarch, the storage polysaccharide of plants, but starch consists of a mixture of amylose and amylopectin. The amylose component contains only linear α1→4 chains; the amylopectin component is more glycogen-like in structure but with fewer α1→6 branches, about one per 12 α1→4-linked glucose residues. The gross structure of glycogen is dendritic in nature, expanding from a core sequence bound to a tyrosine residue in the proteinglycogeninand developing into a final structure resembling a head of cauliflower. The enzymes of glycogen metabolism are bound to the surface of the glycogen particle; many terminal glucose molecules on the surface of the molecule provide ready access for rapid release of glucose from the glycogen polymer.

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FIG. 13.2Close-up of the structure of glycogen.The figure shows α1→4 chains and an α1→6 branch point. Glycogen is stored as granules in liver and muscle cytoplasm.

Pathway of glycogenesis from blood glucose in liver

Glycogenesis is activated in liver and muscle following a meal

The liver is rich in the high-capacity, low-affinity (Km>10 mmol/L) glucose transporterGLUT-2, making it freely permeable to glucose delivered at high concentration in portal blood during and following a meal (seeTable 8.2). The liver is also rich inglucokinase, an enzyme that is specific for glucose and converts it into glucose 6-phosphate (Glc-6-P). Glucokinase (GK) is inducible by continued consumption of a high-carbohydrate diet. It has a highKm, about 5–7 mmol/L, so that it is poised to increase in activity as portal glucose increases above the normal 5 mmol/L (100 mg/dL) blood glucose concentration. Unlike hexokinase, GK is not inhibited by Glc-6-P, so that the concentration of Glc-6-P increases rapidly in liver following a carbohydrate-rich meal, forcing glucose into all the major pathways of glucose metabolism: glycolysis, the pentose phosphate pathway, and glycogenesis (seeFig. 12.2). Glucose is channeled into glycogen, providing a carbohydrate reserve for maintenance of blood glucose during the postabsorptive state. Excess Glc-6-P in liver, beyond that needed to replenish glycogen reserves, is then funneled into glycolysis, in part for energy production but primarily for conversion into fatty acids and triglycerides, which are exported for storage in adipose tissue. Glucose that passes through the liver causes an increase in peripheral blood glucose concentration following carbohydrate-rich meals. This glucose is used in muscle for synthesis and storage of glycogen and in adipose tissue as a source of glycerol for triglyceride biosynthesis.

The pathway of glycogenesis from glucose (Fig. 13.3A) involves four steps:

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FIG. 13.3Pathways of glycogenesis (A) and glycogenolysis (B).

Conversion of Glc-6-P into glucose-1-phosphate (Glc-1-P) by phosphoglucomutase.

Activation of Glc-1-P to the sugar nucleotide uridine diphosphate (UDP)-glucose by the enzyme UDP-glucose pyrophosphorylase.

Transfer of glucose from UDP-Glc to glycogen in α1→4 linkage by glycogen synthase, a member of the class of enzymes known as glycosyl transferases.

When the α1→4 chain exceeds eight residues in length, glycogen branching enzyme, a transglycosylase, transfers some of the α1→4-linked sugars to an α1→6 branch, setting the stage for continued elongation of both α1→4 chains until they, in turn, become long enough for transfer by branching enzyme.

Glycogen synthaseis the regulatory enzyme for glycogenesis, rather than UDP-glucose pyrophosphorylase, because UDP-glucose is also used for synthesis of other sugars, and as a glycosyl donor for synthesis of glycoproteins, glycolipids and proteoglycans (Chapters 27–29). Pyrophosphate (PPi), the other product of the pyrophosphorylase reaction, is a high energy phosphate anhydride. It is rapidly hydrolyzed to inorganic phosphate by pyrophosphatase, providing the thermodynamic driving force for biosynthesis of glycogen.

Pathway of glycogenolysis in liver

Hepatic glycogen phosphorylase provides for rapid release of glucose into blood during the postabsorptive state

As with most metabolic pathways, separate enzymes, sometimes in separate subcellular compartments, are required for the forward and reverse pathways. The pathway of glycogenolysis (Fig. 13.3B) begins with removal of the abundant, external α1→4-linked glucose residues in glycogen. This is accomplished not by a hydrolase but byglycogen phosphorylase, an enzyme that uses cytosolic phosphate and releases glucose from glycogen in the form of Glc-1-P. The Glc-1-P is isomerized by phosphoglucomutase to Glc-6-P, placing it at the top of the glycolytic pathway; the phosphorylase reaction, in effect, bypasses the requirement for ATP in the hexokinase or glucokinase reactions. In liver, the glucose is released from Glc-6-P by glucose-6-phosphatase (Glc-6-Pase), and the glucose exits via the GLUT-2 transporter into blood. The rate-limiting, regulatory step in glycogenolysis is catalyzed by phosphorylase, the first enzyme in the pathway.

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Phosphorylase is specific for α1→4 glycosidic linkages; it cannot cleave α1→6 linkages. Further, this large enzyme cannot approach the branching glucose residues efficiently. Thus, as shown inFigure 13.3B, phosphorylase cleaves the external glucose residues until the branches are three or four residues long, thendebranching enzyme, which has both transglycosylase and glucosidase activity, moves a short segment of glucose residues bound to the α1→6 branch to the end of an adjacent α1→4 chain, leaving a single glucose residue at the branch point. This glucose is then removed by the exo-1,6-glucosidase activity of debranching enzyme, allowing glycogen phosphorylase to proceed with degradation of the extended α1→4 chain until another branch point is approached, setting the stage for a repeat of the transglycosylase and glucosidase reactions. About 90% of the glucose is released from glycogen as Glc-1-P, and the remainder, derived from the α1→6 branching residues, as free glucose.