Glycogen Storage Diseases - Chapter 23 PDF

CHAPTER 23 FORMATION AND DEGRADATION OF GLYCOGEN 363 Table 23.1 Glycogen Storage Diseases Primary Organ Type Enzyme Affected Involved Manifestationsa O Glycogen synth...

CHAPTER 23 FORMATION AND DEGRADATION OF GLYCOGEN 363 Table 23.1 Glycogen Storage Diseases Primary Organ Type Enzyme Affected Involved Manifestationsa O Glycogen synthase Liver Hypoglycemia, hyperketonemia, failure to thrive, early death Ib Glucose-6-phosphatase Liver Enlarged liver and kidney, growth (Von Gierke disease) failure, severe fasting hypoglyce- mia, acidosis, lipemia, thrombo- cyte dysfunction II Lysosomal α-glucosidase All organs with Infantile form: early-onset progres- (Pompe disease): may lysosomes sive muscle hypotonia, cardiac see clinical symptoms failure, death before age 2 in childhood, juvenile, or years. Juvenile form: later onset adult life stages, depend- myopathy with variable cardiac ing on the nature of the involvement. Adult form: limb mutation girdle, muscular dystrophy–like features. Glycogen deposits accumulate in lysosomes. III Amylo-1,6-glucosidase Liver, skeletal Fasting hypoglycemia; hepatomeg- (debrancher): form IIIa is muscle, aly in infancy in some myopathic the liver and muscle en- heart features. Glycogen deposits zymes, form IIIb is a liver- have short outer branches. specific form, and IIIc a muscle-specific form. IV Amylo-4,6-glucosidase Liver Hepatosplenomegaly; symptoms (branching enzyme) may arise from a hepatic reac- (Andersen disease) tion to the presence of a foreign body (glycogen with long outer branches). Usually fatal. V Muscle glycogen phosphor- Skeletal Exercise-induced muscular pain, ylase (McArdle disease) muscle cramps, and progressive (expressed as either weakness, sometimes with adult or infantile form) myoglobinuria. VIc Liver glycogen phosphory- Liver Hepatomegaly, mild hypoglycemia; lase (Hers disease) and good prognosis. its activating system (in- cludes mutations in liver phosphorylase kinase and liver protein kinase A) VII Phosphofructokinase-I Muscle, red As in type V; in addition, enzymo- (Tarui syndrome) blood cells pathic hemolysis XI GLUT2 (glucose/galactose Intestine, pan- Glycogen accumulation in liver and transporter); Fanconi- creas, kid- kidney; rickets, growth retarda- Bickel syndrome ney, liver tion, glucosuria a All of these diseases except type O are characterized by increased glycogen deposits. b Glucose-6-phosphatase is composed of several subunits that also transport glucose, glu- cose-6-phosphate (G6P), phosphate, and pyrophosphate across the endoplasmic reticulum membranes. Therefore, there are several subtypes of this disease corresponding to defects in the different subunits. Type Ia is a lack of glucose-6-phosphatase activity; type Ib is a lack of G6P translocase activity; type Ic is a lack of phosphotranslocase activity; type Id is a lack of glucose translocase activity. c Glycogen storage diseases IX (hepatic phosphorylase kinase) and X (hepatic protein kinase A) have been reclassified to VI, which now refers to the hepatic glycogen phosphorylase activat- ing system. (Sources: Parker PH, Ballew M, Greene HL. Nutritional management of glycogen storage disease. Annu Rev Nutr. 1993;13:83–109. Copyright © 1993 by Annual Reviews, Inc; Shin YS. Glycogen storage disease: clinical, biochemical and molecular heterogeneity. Semin Ped Neurol. 2006;13:115–120; Ozen H. Glycogen storage diseases: new perspectives. World J Gastroenterol. 2007;13:2541–2553.) V. REGULATION OF GLYCOGEN SYNTHESIS AND DEGRADATION The regulation of glycogen synthesis in different tissues matches the function of gly- cogen in each tissue. Liver glycogen serves principally for the support of blood glu- cose during fasting or during extreme need (e.g., exercise) and the degradative and biosynthetic pathways are regulated principally by changes in the insulin/glucagon ratio and by blood glucose levels, which reflect the availability of dietary glucose Lieberman_Ch23.indd 363 9/16/14 2:09 AM  364 SECTION V CARBOHYDRATE METABOLISM Table 23.2 Regulation of Liver and Muscle Glycogen Stores State Regulators Response of Tissue Maternal blood glucose readily Liver crosses the placenta to enter the Fasting Blood: glucagon ↑ Glycogen degradation ↑ fetal circulation. During the last 9 or Insulin ↓ Glycogen synthesis ↓ Tissue: cAMP ↑ 10 weeks of gestation, glycogen formed from Carbohydrate meal Blood: glucagon ↓ Glycogen degradation ↓ maternal glucose is deposited in the fetal liver Insulin ↑ Glycogen synthesis ↑ under the influence of the insulin-dominated Glucose ↑ Tissue: cAMP ↓ hormonal milieu of that period. At birth, ma- Glucose ↑ ternal glucose supplies cease, causing a tem- Exercise and stress Blood: epinephrine ↑ Glycogen degradation ↑ porary physiological drop in glucose levels in Tissue: cAMP ↑ Glycogen synthesis ↓ Ca2⫹-calmodulin ↑ the newborn’s blood, even in normal healthy Muscle infants. This drop serves as one of the sig- Fasting (rest) Blood: insulin ↓ Glycogen synthesis ↓ nals for glucagon release from the newborn’s Glucose transport ↓ Carbohydrate meal (rest) Blood: insulin ↑ Glycogen synthesis ↑ pancreas, which, in turn, stimulates glycoge- Glucose transport ↑ nolysis. As a result, the glucose levels in the Exercise Blood: epinephrine ↑ Glycogen synthesis ↓ newborn return to normal. Tissue: AMP ↑ Glycogen degradation ↑ Ca2⫹-calmodulin ↑ Glycolysis ↑ Healthy, full-term babies have adequate cAMP ↑ stores of liver glycogen to survive short (12 hours) periods of caloric deprivation pro- ↑, increased compared with other physiological states; ↓, decreased compared with other physiological states. vided other aspects of fuel metabolism are normal. Because Gretchen C.’s mother was markedly anorexic during the critical period (Table 23.2). Degradation of liver glycogen is also activated by epinephrine, which when the fetal liver is normally synthesizing is released in response to exercise, hypoglycemia, or other stress situations in which glycogen from glucose supplied in the maternal there is an immediate demand for blood glucose. In contrast, in skeletal muscles, blood, Gretchen’s liver glycogen stores were glycogen is a reservoir of glucosyl units for the generation of ATP from glycolysis below normal. Thus, because fetal glycogen is and glucose oxidation. As a consequence, muscle glycogenolysis is regulated prin- the major source of fuel for the newborn in the cipally by adenosine monophosphate (AMP), which signals a lack of ATP, and by early hours of life, Gretchen became profoundly Ca2⫹ released during contraction. Epinephrine, which is released in response to ex- hypoglycemic within 5 hours of birth because ercise and other stress situations, also activates skeletal muscle glycogenolysis. The of her low levels of stored carbohydrate. glycogen stores of resting muscle decrease very little during fasting. A. Regulation of Glycogen Metabolism in Liver Liver glycogen is synthesized after a carbohydrate meal, when blood glucose levels are elevated and degraded as blood glucose levels decrease. When an individual eats a carbohydrate-containing meal, blood glucose levels immediately increase, insulin levels increase, and glucagon levels decrease (see Fig. 21.5). The increase of blood glucose levels and the rise of the insulin/glucagon ratio inhibit glycogen degradation and stimulate glycogen synthesis. The immediate increased transport of glucose into A patient was diagnosed as an in- peripheral tissues and storage of blood glucose as glycogen helps to bring circulating fant with type III glycogen storage blood glucose levels back to the normal 80- to 100-mg/dL range of the fasted state. disease, a deficiency of debrancher As the length of time after a carbohydrate-containing meal increases, insulin levels enzyme (see Table 23.1). The patient had hepa- decrease and glucagon levels increase. The fall of the insulin/glucagon ratio results in tomegaly (an enlarged liver) and experienced inhibition of the biosynthetic pathway and activation of the degradative pathway. As a bouts of mild hypoglycemia. To diagnose the result, liver glycogen is rapidly degraded to glucose, which is released into the blood. disease, glycogen was obtained from the pa- Although glycogenolysis and gluconeogenesis are activated together by the same tient’s liver by biopsy after the patient had regulatory mechanisms, glycogenolysis responds more rapidly with a greater outpour- fasted overnight and compared with normal ing of glucose. A substantial proportion of liver glycogen is degraded early within a glycogen. The glycogen samples were treated fast (30% after 4 hours). The rate of glycogenolysis is fairly constant for the first with a preparation of commercial glycogen 23 hours; but in a prolonged fast, the rate decreases significantly as the liver glycogen phosphorylase and commercial debrancher supplies dwindle. Liver glycogen stores are therefore a rapidly rebuilt and degraded enzyme. The amounts of glucose-1-phosphate store of glucose, ever responsive to small and rapid changes of blood glucose levels. and glucose produced in the assay were then measured. The ratio of glucose-1-phosphate to 1. NOMENCLATURE OF ENZYMES METABOLIZING GLYCOGEN glucose for the normal glycogen sample was Both glycogen phosphorylase and glycogen synthase are covalently modified to regu- 9:1, and the ratio for the patient was 3:1. Can late their activity. When activated by covalent modification, glycogen phosphorylase you explain these results? is referred to as glycogen phosphorylase a (remember a for active); when the Lieberman_Ch23.indd 364 9/16/14 2:09 AM  CHAPTER 23 FORMATION AND DEGRADATION OF GLYCOGEN 365 covalent modification is removed, and the enzyme is inactive, it is referred to as With a deficiency of debrancher en- glycogen phosphorylase b. Glycogen synthase, when it is not covalently modi- zyme but normal levels of glycogen fied, is active and can be designated glycogen synthase a or glycogen synthase I phosphorylase, the glycogen chains (the I stands for independent of modifiers for activity). When glycogen synthase is of the patient could be degraded in vivo only covalently modified, it is inactive, in the form of glycogen synthase b or glycogen to within four residues of the branch point. synthase D (for dependent on a modifier for activity). When the glycogen samples were treated with the commercial preparation containing 2. REGULATION OF LIVER GLYCOGEN METABOLISM BY INSULIN normal enzymes, one glucose residue was AND GLUCAGON released for each α-1,6 branch. However, in Insulin and glucagon regulate liver glycogen metabolism by changing the phos- the patient’s glycogen sample, with the short phorylation state of glycogen phosphorylase in the degradative pathway and glyco- outer branches, three glucose-1-phosphates gen synthase in the biosynthetic pathway. An increase of glucagon and decrease of and one glucose residue were obtained for insulin during the fasting state initiates a cyclic adenosine monophosphate (cAMP)- each α-1,6 branch. Normal glycogen has 8 to directed phosphorylation cascade, which results in the phosphorylation of glycogen 10 glucosyl residues per branch and thus gives phosphorylase to an active enzyme, and the phosphorylation of glycogen synthase a ratio of approximately 9 moles of glucose- to an inactive enzyme (Fig. 23.7). As a consequence, glycogen degradation is stimu- 1-phosphate to 1 mole of glucose. lated, and glycogen synthesis is inhibited. Glucagon (liver only) Epinephrine + + Glucose Cell Adenylate Phospho- membrane cyclase diesterase Cytoplasm G- GTP 1 protein + ATP AMP Glucose cAMP Glucokinase Protein Regulatory Glucose 6-phosphate kinase A 2 (inactive) subunit-cAMP Glycogen Pi Phosphorylase synthase– P kinase ATP (inactive) Glucose 1-phosphate (inactive) Protein ADP Protein phosphatase 3 Active protein 5 phosphatase kinase A ATP ADP Glycogen Phosphorylase synthase Pi kinase– P (active) (active) 4 ATP ADP Glycogen UDP-glucose Glycogen Glycogen Pi phosphorylase b phosphorylase a (inactive) (active) P 6 Pi Glucose 1-phosphate Glucose 6-phosphate Protein phosphatase Liver Glucose 6- phosphatase Blood glucose FIG. 23.7. Regulation of glycogen synthesis and degradation in the liver. (1) Glucagon binding to the serpentine glucagon receptor or epineph- rine binding to a serpentine β-receptor in the liver activates adenylate cyclase via G proteins, which synthesizes cAMP from ATP. (2) cAMP binds to PKA (cAMP-dependent protein kinase), thereby activating the catalytic subunits. (3) PKA activates phosphorylase kinase by phosphorylation. (4) Phosphorylase kinase adds a phosphate to specific serine residues on glycogen phosphorylase b, thereby converting it to the active glycogen phosphorylase a. (5) PKA also phosphorylates glycogen synthase, thereby decreasing its activity. (6) Because of the inhibition of glycogen syn- thase and the activation of glycogen phosphorylase, glycogen is degraded to glucose-1-phosphate. The red dashed lines denote reactions that are decreased in the livers of fasting individuals. Lieberman_Ch23.indd 365 9/16/14 2:09 AM  366 SECTION V CARBOHYDRATE METABOLISM 3. ACTIVATION OF A PHOSPHORYLATION CASCADE BY GLUCAGON Glucagon regulates glycogen metabolism through its intracellular second messen- ger cAMP and protein kinase A (PKA) (see Chapter 21). Glucagon, by binding to its cell membrane receptor, transmits a signal through G proteins that activates adenylate cyclase, causing cAMP levels to increase (see Fig. 23.7). cAMP binds to the regulatory subunits of PKA, which dissociate from the catalytic subunits. The catalytic subunits of PKA are activated by the dissociation and phosphorylate the enzyme phosphorylase kinase, activating it. Phosphorylase kinase is the protein ki- nase that converts the inactive liver glycogen phosphorylase b conformer to the ac- tive glycogen phosphorylase a conformer by transferring a phosphate from ATP to a specific serine residue on the phosphorylase subunits. Because of the activation of glycogen phosphorylase, glycogenolysis is stimulated. 4. INHIBITION OF GLYCOGEN SYNTHASE BY GLUCAGON- DIRECTED PHOSPHORYLATION When glycogen degradation is activated by the cAMP-stimulated phosphorylation cascade, glycogen synthesis is simultaneously inhibited. The enzyme glycogen syn- thase is also phosphorylated by PKA, but this phosphorylation results in a less active form, glycogen synthase b. The phosphorylation of glycogen synthase is far more complex than that of gly- cogen phosphorylase. Glycogen synthase has multiple phosphorylation sites and is acted on by up to 10 different protein kinases. Phosphorylation by PKA does not, by itself, inactivate glycogen synthase. Instead, phosphorylation by PKA facilitates the subsequent addition of phosphate groups by other kinases, and these inactivate the enzyme. A term that has been applied to changes of activity resulting from multiple phosphorylation is “hierarchical” or “synergistic” phosphorylation; the phosphory- lation of one site makes another site more reactive and easier to phosphorylate by a different protein kinase. 5. REGULATION OF PROTEIN PHOSPHATASES At the same time that PKA and phosphorylase kinase are adding phosphate groups to enzymes, the protein phosphatases that remove this phosphate are inhibited. Pro- tein phosphatases remove the phosphate groups, bound to serine or other residues of enzymes, by hydrolysis. Hepatic protein phosphatase-1 (hepatic PP-1), one of the major protein phosphatases involved in glycogen metabolism, removes phos- Most of the enzymes that are regu- phate groups from phosphorylase kinase, glycogen phosphorylase, and glycogen lated by phosphorylation also can be synthase. During fasting, hepatic PP-1 is inactivated by several mechanisms. One is converted to the active conforma- dissociation from the glycogen particle, such that substrates are no longer available tion by allosteric effectors. Glycogen synthase to the phosphatase. A second is the binding of inhibitor proteins, such as the protein b, the less active form of glycogen synthase, called inhibitor-1, which, when phosphorylated by a glucagon (or epinephrine)- can be activated by the accumulation of G6P directed mechanism, binds to and inhibits phosphatase action. Insulin indirectly above physiological levels. The activation of activates hepatic PP-1 through its own signal transduction cascade initiated at the glycogen synthase by G6P may be important in insulin receptor tyrosine kinase. individuals with glucose-6-phosphatase defi- ciency, a disorder known as type I or von Gierke 6. INSULIN IN LIVER GLYCOGEN METABOLISM glycogen storage disease (see Table 23.1). Insulin is antagonistic to glucagon in the degradation and synthesis of glycogen. The When G6P produced from gluconeogenesis glucose level in the blood is the signal controlling the secretion of insulin and glu- accumulates in the liver, it activates glycogen cagon. Glucose stimulates insulin release and suppresses glucagon release; one in- synthesis even though the individual may be creases whereas the other decreases. However, insulin levels in the blood change to hypoglycemic and have low insulin levels. G6P a greater degree with the fasting-feeding cycle than do the glucagon levels, and thus, is also elevated, resulting in the inhibition of insulin is considered the principal regulator of glycogen synthesis and degradation. glycogen phosphorylase. As a consequence, The role of insulin in glycogen metabolism is often overlooked because the mecha- large glycogen deposits accumulate and hepa- nism by which insulin reverses all of the effects of glucagon on individual meta- tomegaly occurs. bolic enzymes is still under investigation. In addition to the activation of hepatic Lieberman_Ch23.indd 366 9/16/14 2:09 AM  CHAPTER 23 FORMATION AND DEGRADATION OF GLYCOGEN 367 PP-1 through the insulin-receptor tyrosine kinase phosphorylation cascade, insulin An inability of liver and muscle to may activate the phosphodiesterase that converts cAMP to AMP, thereby decreasing store glucose as glycogen contrib- cAMP levels and inactivating PKA. Regardless of the mechanisms involved, insulin utes to the hyperglycemia in pa- is able to reverse all of the effects of glucagon and is the most important hormonal tients, such as Dianne A., with type 1 diabetes regulator of blood glucose levels. mellitus and in patients, such as Deborah S., with type 2 diabetes mellitus. The absence of 7. BLOOD GLUCOSE LEVELS AND GLYCOGEN SYNTHESIS insulin in type 1 diabetes mellitus patients and AND DEGRADATION the high levels of glucagon result in decreased When an individual eats a high-carbohydrate meal, glycogen degradation immedi- activity of glycogen synthase. Glycogen syn- ately stops. Although the changes in insulin and glucagon levels are relatively rapid thesis in skeletal muscles of type 1 patients is (10 to 15 minutes), the direct inhibitory effect of rising glucose levels on glycogen also limited by the lack of insulin-stimulated degradation is even more rapid. Glucose, as an allosteric effector, inhibits liver gly- glucose transport. Insulin resistance in type 2 cogen phosphorylase a by stimulating dephosphorylation of this enzyme. As insulin patients has the same effect. levels rise and glucagon levels fall, cAMP levels decrease and PKA reassociates An injection of insulin suppresses glucagon with its inhibitory subunits and becomes inactive. The protein phosphatases are acti- release and alters the insulin/glucagon ratio. vated, and phosphorylase a and glycogen synthase b are dephosphorylated. The col- The result is rapid uptake of glucose into skel- lective result of these effects is rapid inhibition of glycogen degradation and rapid etal muscle and rapid conversion of glucose to activation of glycogen synthesis. glycogen in skeletal muscle and liver. 8. EPINEPHRINE AND CALCIUM IN THE REGULATION OF LIVER GLYCOGEN LEVELS Epinephrine, the fight-or-flight hormone, is released from the adrenal medulla in In the neonate, the release of epi- response to neural signals reflecting an increased demand for glucose. To flee from nephrine during labor and birth nor- a dangerous situation, skeletal muscles use increased amounts of blood glucose mally contributes to restoring blood to generate ATP. As a result, liver glycogenolysis must be stimulated. In the liver, glucose levels. Unfortunately, Gretchen C. did epinephrine stimulates glycogenolysis through two different types of receptors, the not have adequate liver glycogen stores to α- and β-agonist receptors. support a rise in her blood glucose levels. a. Epinephrine Acting at a-Receptors Epinephrine, acting at the β-receptors, transmits a signal through G proteins to ad- enylate cyclase, which increases cAMP and activates PKA. Hence, regulation of glycogen degradation and synthesis in liver by epinephrine and glucagon are similar (see Fig. 23.7). b. Epinephrine Acting at `-Receptors Epinephrine also binds to α-receptors in the hepatocyte. This binding activates A series of inborn errors of metabo- glycogenolysis and inhibits glycogen synthesis principally by increasing the Ca2⫹ lism, the glycogen storage diseases, levels in the liver. The effects of epinephrine at the α-agonist receptor are mediated result from deficiencies in the en- by the phosphatidylinositol bisphosphate (PIP2)-Ca2⫹ signal transduction system, zymes of glycogenolysis (see Table 23.1). Mus- one of the principal intracellular second messenger systems employed by many hor- cle glycogen phosphorylase, the key regulatory mones (Fig. 23.8) (also see Chapter 8). enzyme of glycogen degradation, is genetically In the PIP2-Ca2⫹ signal transduction system, the signal is transferred from the different from liver glycogen phosphorylase, epinephrine receptor to membrane-bound phospholipase C by G proteins. Phospho- and thus, a person may have a defect in one and lipase C hydrolyzes PIP2 to form diacylglycerol (DAG) and inositol trisphosphate not the other. Why do you think that a genetic (IP3). IP3 stimulates the release of Ca2⫹ from the endoplasmic reticulum. Ca2⫹ and deficiency in muscle glycogen phosphorylase DAG activate protein kinase C. The amount of calcium bound to one of the calcium- (McArdle disease) is a mere inconvenience, binding proteins, calmodulin, is also increased. whereas a deficiency of liver glycogen phos- Calcium/calmodulin associates as a subunit with a number of enzymes and phorylase (Hers disease) can be lethal? modifies their activities. It binds to inactive phosphorylase kinase, thereby partially activating this enzyme. (The fully activated enzyme is both bound to the calcium- calmodulin subunit and phosphorylated.) Phosphorylase kinase then phosphorylates glycogen phosphorylase b, thereby activating glycogen degradation. Calcium/cal- modulin is also a modifier protein that activates one of the glycogen synthase ki- nases (calcium-calmodulin synthase kinase). Protein kinase C, calcium-calmodulin synthase kinase, and phosphorylase kinase all phosphorylate glycogen synthase at Lieberman_Ch23.indd 367 9/16/14 2:09 AM  368 SECTION V CARBOHYDRATE METABOLISM Epinephrine ␣-Agonist 1 Phospholipase C Protein kinase C Extracellular receptor + + Cell membrane G PIP2 DAG + Cytoplasm GTP 2 IP3 + 4 P + Glycogen synthase Ca2+ Calmodulin- P dependent (inactive) P protein kinase Glycogen synthase (active) Endoplasmic Ca2+-calmodulin reticulum 5 Glycogen 3 Phosphorylase phosphorylase a P (active) + kinase Glycogen phosphorylase b (inactive) FIG. 23.8. Regulation of glycogen synthesis and degradation by epinephrine and Ca2⫹. (1) The effect of epinephrine binding to α-agonist recep- tors in liver transmits a signal via G proteins to phospholipase C, which hydrolyzes PIP2 to DAG and IP3. (2) IP3 stimulates the release of Ca2⫹ from the endoplasmic reticulum. (3) Ca2⫹ binds to the modifier protein calmodulin, which activates calmodulin-dependent protein kinase and phosphorylase kinase. Both Ca2⫹ and DAG activate protein kinase C. (4) These three kinases phosphorylate glycogen synthase at different sites and decrease its activity. (5) Phosphorylase kinase phosphorylates glycogen phosphorylase b to the active form. It therefore activates glycoge- nolysis as well as inhibiting glycogen synthesis. Muscle glycogen is used within the different serine residues on the enzyme, thereby inhibiting glycogen synthase and muscle to support exercise. Thus, thus glycogen synthesis. an individual with McArdle’s disease The effect of epinephrine in the liver, therefore, enhances or is synergistic with (type V glycogen storage disease) experiences the effects of glucagon. Epinephrine release during bouts of hypoglycemia or during no other symptoms but unusual fatigue and exercise can stimulate hepatic glycogenolysis and inhibit glycogen synthesis very muscle cramps during exercise. These symp- rapidly. toms may be accompanied by myoglobinuria and release of muscle creatine kinase into the B. Regulation of Glycogen Synthesis and Degradation in blood. Skeletal Muscle Liver glycogen is the first reservoir for the The regulation of glycogenolysis in skeletal muscle is related to the availability support of blood glucose levels, and a defi- of ATP for muscular contraction. Skeletal muscle glycogen produces glucose-1- ciency in glycogen phosphorylase or any of the phosphate and a small amount of free glucose. Glucose-1-phosphate is converted other enzymes of liver glycogen degradation to G6P, which is committed to the glycolytic pathway; the absence of glucose- can result in fasting hypoglycemia. The hypo- 6-phosphatase in skeletal muscle prevents conversion of the glucosyl units from glycemia is usually mild because patients can glycogen to blood glucose. Skeletal muscle glycogen is therefore degraded only still synthesize glucose from gluconeogenesis when the demand for ATP generation from glycolysis is high. The highest de- (see Table 23.1). mands occur during anaerobic glycolysis, which requires more moles of glucose for each ATP produced than oxidation of glucose to CO2 (see Chapter 19). Anaer- obic glycolysis occurs in tissues that have fewer mitochondria, a higher content of glycolytic enzymes, and higher levels of glycogen or fast-twitch glycolytic fibers. It occurs most frequently at the onset of exercise—before vasodilation occurs to bring in blood-borne fuels. The regulation of skeletal muscle glycogen degradation therefore must respond very rapidly to the need for ATP, indicated by the increase in AMP. The regulation of skeletal muscle glycogen synthesis and degradation differs from that in liver in several important respects: 1. Glucagon has no effect on muscle, and thus glycogen levels in muscle do not vary with the fasting or feeding state. Lieberman_Ch23.indd 368 9/16/14 2:09 AM  CHAPTER 23 FORMATION AND DEGRADATION OF GLYCOGEN 369 Epinephrine Jim B. gradually regained conscious- ness with continued infusions of Nerve impulse high-concentration glucose titrated Sarcoplasmic cAMP to keep his serum glucose level between 120 reticulum Ca2+ 3 2 and 160 mg/dL. Although he remained somno- Ca2+ Protein kinase A lent and moderately confused over the next + 12 hours, he was eventually able to tell his phy- ATP Myosin sicians that he had self-injected approximately ATPase Ca2+-calmodulin 25 units of regular (short-acting) insulin every ADP 6 hours while eating a high-carbohydrate diet Phosphorylase Adenylate kinase P for the last 2 days preceding his seizure. Nor- Muscle kinase contraction AMP mal subjects under basal conditions secrete an + average of 40 units of insulin daily. He had last 1 + P injected insulin just before exercising. An arti- Glycogen Glycogen cle in a body-building magazine that he had re- phosphorylase b phosphorylase a cently read cited the anabolic effects of insulin on increasing muscle mass. He had purchased Pi the insulin and necessary syringes from the same underground drug source from whom he FIG. 23.9. Activation of muscle glycogen phosphorylase during exercise. Glycogenolysis in regularly bought his anabolic steroids. skeletal muscle is initiated by muscle contraction, neural impulses, and epinephrine. (1) AMP Normally, muscle glycogenolysis supplies produced from the degradation of ATP during muscular contraction allosterically activates glycogen phosphorylase b. (2) The neural impulses that initiate contraction release Ca2⫹ from the glucose required for the kinds of high- the sarcoplasmic reticulum. The Ca2⫹ binds to calmodulin, which is a modifier protein that intensity exercise that require anaerobic gly- activates phosphorylase kinase. (3) Phosphorylase kinase is also activated through phosphor- colysis, such as weight-lifting. Jim’s treadmill ylation by PKA. The formation of cAMP and the resultant activation of PKA are initiated by exercise also uses blood glucose, which is the binding of epinephrine to plasma membrane receptors. supplied by liver glycogenolysis. The high serum insulin levels, resulting from the injec- tion he gave himself just before his workout, activated both glucose transport into skeletal 2. AMP is an allosteric activator of the muscle isozyme of glycogen phosphorylase muscle and glycogen synthesis while inhibit- but not liver glycogen phosphorylase (Fig. 23.9). ing glycogen degradation. His exercise, which 3. The effects of Ca2⫹ in muscle result principally from the release of Ca2⫹ from would continue to use blood glucose, could the sarcoplasmic reticulum after neural stimulation and not from epinephrine- normally be supported by breakdown of liver stimulated uptake. glycogen. However, glycogen synthesis in his 4. Glucose is not a physiological inhibitor of glycogen phosphorylase a in liver was activated, and glycogen degradation muscle. was inhibited by the insulin injection. 5. Glycogen is a stronger feedback inhibitor of muscle glycogen synthase than of liver glycogen synthase, resulting in a smaller amount of stored glycogen per gram weight of muscle tissue. However, the effects of epinephrine-stimulated phosphorylation by PKA on skel- etal muscle glycogen degradation and glycogen synthesis are similar to those occur- ring in liver (see Fig. 23.7). Muscle glycogen phosphorylase is a genetically distinct isoenzyme of liver gly- cogen phosphorylase and contains an amino acid sequence that has a purine nucle- otide-binding site. When AMP binds to this site, it changes the conformation at the catalytic site to a structure very similar to that in the phosphorylated enzyme. Thus, hydrolysis of ATP to adenosine diphosphate (ADP) and the consequent increase of AMP generated by adenylate kinase during muscular contraction can directly stimu- late glycogenolysis to provide fuel for the glycolytic pathway. AMP also stimulates glycolysis by activating phosphofructokinase-1, so this one effector activates both glycogenolysis and glycolysis. The activation of the calcium-calmodulin subunit of phosphorylase kinase by the Ca2⫹ released from the sarcoplasmic reticulum during muscle contraction also provides a direct and rapid means of stimulating glycogen degradation. Lieberman_Ch23.indd 369 9/16/14 2:09 AM  370 SECTION V CARBOHYDRATE METABOLISM CLINICAL COMMENTS Diseases discussed in this chapter are summarized in Table 23.3. Gretchen C. Gretchen C.’s hypoglycemia illustrates the importance of glycogen stores in the neonate. At birth, the fetus must make two major adjustments in the way fuels are used: it must adapt to using a greater vari- ety of fuels than were available in utero, and it must adjust to intermittent feeding. In utero, the fetus receives a relatively constant supply of glucose from the maternal circulation through the placenta, producing a level of glucose in the fetus that ap- proximates 75% of maternal blood levels. With regard to the hormonal regulation of fuel utilization in utero, fetal tissues function in an environment dominated by insu- lin, which promotes growth. During the last 10 weeks of gestation, this hormonal milieu leads to glycogen formation and storage. At birth, the infant’s diet changes to one containing greater amounts of fat and lactose (galactose and glucose in equal ratio), presented at intervals rather than in a constant fashion. At the same time, the neonate’s need for glucose is relatively larger than that of the adult because the new- born’s ratio of brain to liver weight is greater. Thus, the infant has even greater dif- ficulty in maintaining glucose homeostasis than the adult. At the moment that the umbilical cord is clamped, the normal neonate is faced with a metabolic problem: the high insulin levels of late fetal existence must be quickly reversed to prevent hypoglycemia. This reversal is accomplished through the secretion of the counterregulatory hormones epinephrine and glucagon. Glucagon release is triggered by the normal decline of blood glucose after birth. The neural response that stimulates the release of both glucagon and epinephrine is activated by the anoxia, cord clamping, and tactile stimulation that are part of a normal delivery. These responses have been referred to as the “normal sensor function” of the neonate. Within 3 to 4 hours of birth, these counterregulatory hormones reestablish normal serum glucose levels in the newborn’s blood through their glycogenolytic and glu- coneogenic actions. The failure of Gretchen’s normal “sensor function” was partly the result of maternal malnutrition, which resulted in an inadequate deposition of glycogen in Gretchen’s liver before birth. The consequence was a serious degree of postnatal hypoglycemia. The ability to maintain glucose homeostasis during the first few days of life also depends on the activation of gluconeogenesis and the mobilization of fatty acids. Fatty acid oxidation in the liver not only promotes gluconeogenesis (see Chapter 26) but also generates ketone bodies. The neonatal brain has an enhanced capacity to use ketone bodies relative to that of infants (4-fold) and adults (40-fold). This ability is consistent with the relatively high fat content of breast milk. Table 23.3 Diseases Discussed in Chapter 23 Environmental Disease or Disorder or Genetic Comments Newborn hypoglycemia Environmental Poor maternal nutrition may lead to inad- equate glycogen levels in the newborn, resulting in hypoglycemia during the early fasting period after birth. Insulin overdose Environmental Insulin taken without carbohydrate inges- tion will lead to severe hypoglycemia, due to stimulation of glucose uptake by peripheral tissues, leading to insufficient glucose in the circulation for proper func- tioning of the nervous system. Glycogen storage diseases Genetic These have been summarized in Table 23.1. Affect storage and use of glycogen, with different levels of severity, from mild to fatal. Lieberman_Ch23.indd 370 9/16/14 2:09 AM