Metabolism of Glycogen Chapter 18-20 PDF

C H A P T E R Metabolism of Glycogen David A. Bender, PhD & Peter A. Mayes, PhD, DSc 18 OBJEC TIVES Describe the structure of glycogen and its importance a...

C H A P T E R Metabolism of Glycogen David A. Bender, PhD & Peter A. Mayes, PhD, DSc 18 OBJEC TIVES Describe the structure of glycogen and its importance as a carbohydrate reserve. After studying this chapter, Describe the synthesis and breakdown of glycogen and how the processes are you should be able to: regulated in response to hormone action. Describe the various types of glycogen storage diseases. BIOMEDICAL IMPORTANCE of glucose-1-phosphate. The formation of branch points in glycogen is slower than the addition of glucose units to a linear Glycogen is the major storage carbohydrate in animals, cor- chain, and some endurance athletes practice carbohydrate responding to starch in plants; it is a branched polymer of loading—exercise to exhaustion (when muscle glycogen in α-d-glucose (see Figure 15–12). It occurs mainly in liver and largely depleted) followed by a high-carbohydrate meal, which muscle, with modest amounts in the brain. Although the liver results in rapid glycogen synthesis, with fewer branch points content of glycogen is greater than that of muscle, because than normal. the muscle mass of the body is considerably greater than that of the liver, about three-quarters of total body glycogen is in muscle (Table 18–1). GLYCOGENESIS OCCURS MAINLY Muscle glycogen provides a readily available source of glucose-1-phosphate for glycolysis within the muscle itself. IN MUSCLE & LIVER Liver glycogen functions as a reserve to maintain the blood glucose concentration in the fasting state. The liver concen- Glycogen Biosynthesis Involves tration of glycogen is about 450 mmol /L glucose equivalents UDP-Glucose after a meal, falling to about 200 mmol /L after an overnight As in glycolysis, glucose is phosphorylated to glucose- fast; after 12 to 18 hours of fasting, liver glycogen is almost 6-phosphate, catalyzed by hexokinase in muscle and totally depleted. Although muscle glycogen does not directly glucokinase in liver (Figure 18–1). Glucose-6-phosphate is yield free glucose (because muscle lacks glucose-6-phospha- isomerized to glucose-1-phosphate by phosphoglucomutase. tase), pyruvate formed by glycolysis in muscle can undergo The enzyme itself is phosphorylated, and the phosphate transamination to alanine, which is exported from muscle group takes part in a reversible reaction in which glucose and used for gluconeogenesis in the liver (see Figure 19–4). 1,6-bisphosphate is an intermediate. Next, glucose-1-phosphate Glycogen storage diseases are a group of inherited disorders reacts with uridine triphosphate (UTP) to form the active characterized by deficient mobilization of glycogen or deposi- nucleotide uridine diphosphate glucose (UDPGlc) and tion of abnormal forms of glycogen, leading to liver damage pyrophosphate (Figure 18–2), catalyzed by UDPGlc pyro- and muscle weakness; some glycogen storage diseases result phosphorylase. The reaction proceeds in the direction of in early death. UDPGlc formation because pyrophosphatase catalyzes hydro- The highly branched structure of glycogen (see Figure 15–12) lysis of pyrophosphate to 2 × phosphate, so removing one of the provides a large number of sites for glycogenolysis, permit- reaction products. UDPGlc pyrophosphorylase has a low Km for ting rapid release of glucose-1-phosphate for muscle activity. glucose-1-phosphate and is present in relatively large amounts, Endurance athletes require a slower, more sustained release so that it is not a regulatory step in glycogen synthesis. 176  CHAPTER 18 Metabolism of Glycogen 177 TABLE 181 Storage of Carbohydrate in a 70-kg O Human Being CH2OH Uracil HN O Percentage OH O O O N of Tissue Tissue Body Weight Weight Content (g) OH O P O P O CH2 O O OH O– O– Liver glycogen 5.0 1.8 kg 90 Ribose Muscle glycogen 0.7 35 kg 245 Glucose OH OH Extracellular glucose 0.1 10 L 10 Uridine The initial steps in glycogen synthesis involve the protein FIGURE 182 Uridine diphosphate glucose (UDPGlc). glycogenin, a 37-kDa protein that is glucosylated on a spe- cific tyrosine residue by UDPGlc. Glycogenin catalyzes the transfer of a further seven glucose residues from UDPGlc, in catalyzes the formation of a glycoside bond between C-1 of the 1 → 4 linkage, to form a glycogen primer that is the substrate glucose of UDPGlc and C-4 of a terminal glucose residue of for glycogen synthase. The glycogenin remains at the core of glycogen, liberating uridine diphosphate (UDP). The addition the glycogen granule (see Figure 15–12). Glycogen synthase of a glucose residue to a preexisting glycogen chain, or “primer,” Glycogen (1→4 and 1→6 glucosyl units)x Branching enzyme Pi (1→4 Glucosyl units)x Insulin UDP Glycogen Glycogen synthase cAMP phosphorylase Glycogen primer Glucagon epinephrine Glucan * transferase Glycogenin Debranching Uridine enzyme disphosphate glucose (UDPGlc) To uronic acid Free glucose from pathway debranching UDPGlc pyrophosphorylase enzyme Inorganic pyrophosphatase P Pi 2 Pi Uridine UDP triphosphate (UTP) Glucose-1-phosphate Mg2+ Phosphoglucomutase Glucose-6-phosphate To glycolysis and pentose phosphate pathway H2O ADP Nucleoside diphospho- Glucose-6- ATP ADP Mg2+ Glucokinase kinase phosphatase Pi ATP Glucose FIGURE 181 Pathways of glycogenesis and glycogenolysis in the liver. ( , Stimulation; ⊝, inhibition.) Insulin decreases the level of cAMP only after it has been raised by glucagon or epinephrine; that is, it antagonizes their action. Glucagon is active in heart muscle but not in skeletal muscle. ∗Glucan transferase and debranching enzyme appear to be two separate activities of the same enzyme. 178 SECTION IV Metabolism of Carbohydrates 1→4- Glucosidic bond Unlabeled glucose residue 1→6- Glucosidic bond 14 C-labeled glucose residue 14 C-glucose added New 1→6- bond Glycogen Branching synthase enzyme FIGURE 183 The biosynthesis of glycogen. The mechanism of branching as revealed by feeding 14C-labeled glucose and examining liver glycogen at intervals. occurs at the nonreducing, outer end of the molecule, so that then proceed. The combined action of phosphorylase and these the branches of the glycogen molecule become elongated as other enzymes leads to the complete breakdown of glycogen. successive 1 → 4 linkages are formed (Figure 18–3). The reaction catalyzed by phosphoglucomutase is revers- ible, so that glucose-6-phosphate can be formed from glucose Branching Involves Detachment of 1-phosphate. In liver, but not muscle, glucose-6-phosphatase catalyzes hydrolysis of glucose-6-phosphate, yielding glucose Existing Glycogen Chains that is exported, leading to an increase in the blood glucose When a growing chain is at least 11 glucose residues long, concentration. Glucose-6-phosphatase is in the lumen of the branching enzyme transfers a part of the 1 → 4-chain (at smooth endoplasmic reticulum, and genetic defects of the least six glucose residues) to a neighboring chain to form a glucose-6-phosphate transporter can cause a variant of type I 1 → 6 linkage, establishing a branch point. The branches glycogen storage disease (Table 18–2). grow by further additions of 1 → 4-glucosyl units and further Glycogen granules can also be engulphed by lysosomes, branching. where acid maltase catalyzes the hydrolysis of glycogen to glucose. This may be especially important in glucose homeo- stasis in neonates. Genetic lack of lysosomal acid maltase GLYCOGENOLYSIS IS NOT THE causes type II glycogen storage disease (Pompe disease, Table 18–2). The lysosomal catabolism of glycogen is under REVERSE OF GLYCOGENESIS, hormonal control. BUT IS A SEPARATE PATHWAY Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis—the phosphorolytic cleavage (phosphorolysis; cf hydrolysis) of the 1 → 4 linkages of glycogen to yield glucose 1-phosphate (Figure 18–4). There are different iso- enzymes of glycogen phosphorylase in liver, muscle, and brain, encoded by different genes. Glycogen phosphorylase requires pyridoxal phosphate (see Chapter 44) as its coenzyme. Unlike the reactions of amino acid metabolism (see Chapter 28), in which the aldehyde group of the coenzyme is the reactive group, in phosphorylase it is the phosphate group that is cat- alytically active. The terminal glucosyl residues from the outermost chains of the glycogen molecule are removed sequentially until Phosphorylase Glucan Debranching approximately four glucose residues remain on either side of transferase enzyme a 1 → 6 branch (Figure 18–4). The debranching enzyme has Glucose residues joined by two catalytic sites in a single polypeptide chain. One is a glucan 1 → 4- glucosidic bonds transferase that transfers a trisaccharide unit from one branch Glucose residues joined by to the other, exposing the 1 → 6 branch point. The other is a 1 → 6- glucosidic bonds 1,6-glycosidase that catalyzes hydrolysis of the 1 → 6 glycoside bond to liberate free glucose. Further phosphorylase action can FIGURE 184 Steps in glycogenolysis.  CHAPTER 18 Metabolism of Glycogen 179 TABLE 182 Glycogen Storage Diseases Type Name Enzyme Deficiency Clinical Features 0 — Glycogen synthase Hypoglycemia; hyperketonemia; early death Ia Von Gierke disease Glucose-6-phosphatase Glycogen accumulation in liver and renal tubule cells; hypoglycemia; lactic acidemia; ketosis; hyperlipemia Ib — Endoplasmic reticulum glucose-6- As type Ia; neutropenia and impaired neutrophil function phosphate transporter leading to recurrent infections II Pompe disease Lysosomal α1 → 4 and α1 → 6 Accumulation of glycogen in lysosomes: juvenile onset glucosidase (acid maltase) variant, muscle hypotonia, death from heart failure by age 2; adult onset variant, muscle dystrophy IIIa Limit dextrinosis, Forbe or Cori Liver and muscle debranching Fasting hypoglycemia; hepatomegaly in infancy; disease enzyme accumulation of characteristic branched polysaccharide (limit dextrin); muscle weakness IIIb Limit dextrinosis Liver debranching enzyme As type IIIa, but no muscle weakness IV Amylopectinosis, Andersen Branching enzyme Hepatosplenomegaly; accumulation of polysaccharide with disease few branch points; death from heart or liver failure before age 5 V Myophosphorylase deficiency, Muscle phosphorylase Poor exercise tolerance; muscle glycogen abnormally high McArdle syndrome (2.5%-4%); blood lactate very low after exercise VI Hers disease Liver phosphorylase Hepatomegaly; accumulation of glycogen in liver; mild hypoglycemia; generally good prognosis VII Tarui disease Muscle and erythrocyte Poor exercise tolerance; muscle glycogen abnormally phosphofructokinase 1 high (2.5%-4%); blood lactate very low after exercise; also hemolytic anemia VIII Liver phosphorylase kinase Hepatomegaly; accumulation of glycogen in liver; mild hypoglycemia; generally good prognosis IX Liver and muscle phosphorylase Hepatomegaly; accumulation of glycogen in liver and kinase muscle; mild hypoglycemia; generally good prognosis X cAMP-dependent protein kinase A Hepatomegaly; accumulation of glycogen in liver CYCLIC AMP INTEGRATES Glycogen Phosphorylase Regulation Is Different in Liver & Muscle THE REGULATION OF In the liver, the role of glycogen is to provide free glucose for GLYCOGENOLYSIS & export to maintain the blood concentration of glucose; in GLYCOGENESIS muscle the role of glycogen is to provide a source of glucose- 6-phosphate for glycolysis in response to the need for ATP for The principal enzymes controlling glycogen metabolism— muscle contraction. In both tissues, the enzyme is activated by glycogen phosphorylase and glycogen synthase—are regulated phosphorylation catalyzed by phosphorylase kinase (to yield in opposite directions by allosteric mechanisms and covalent phosphorylase a) and inactivated by dephosphorylation cata- modification by reversible phosphorylation and dephos- lyzed by phosphoprotein phosphatase (to yield phosphorylase phorylation of enzyme protein in response to hormone action b), in response to hormonal and other signals. (see Chapter 9). Phosphorylation of glycogen phosphorylase There is instantaneous overriding of this hormonal con- increases its activity; phosphorylation of glycogen synthase trol. Active phosphorylase a in both tissues is allosterically reduces its activity. inhibited by ATP and glucose-6-phosphate; in liver, but not Phosphorylation is increased in response to cyclic muscle, free glucose is also an inhibitor. Muscle phosphorylase AMP (cAMP) (Figure 18–5) formed from ATP by adenylyl differs from the liver isoenzyme in having a binding site for 5′ cyclase at the inner surface of cell membranes in response AMP (Figure 18–5), which acts as an allosteric activator of the to hormones such as epinephrine, norepinephrine, and (inactive) dephosphorylated b-form of the enzyme. 5′ AMP glucagon. cAMP is hydrolyzed by phosphodiesterase, so acts as a potent signal of the energy state of the muscle cell; it is terminating hormone action; in liver insulin increases the formed as the concentration of ADP begins to increase (indi- activity of phosphodiesterase. cating the need for increased substrate metabolism to permit 180 SECTION IV Metabolism of Carbohydrates NH2 N N O O O − N N O P O P O P O CH 2 O − − − O O O OH OH Adenosine triphosphate (ATP) Adenylyl cyclase Pyrophosphate NH2 NH 2 N N N N O N N H2O − N N O CH 2 O O P O CH 2 O Phosphodiesterase − − O O P O O OH OH OH Cyclic adenosine monophosphate (cAMP) Adenosine monophosphate (5'AMP) FIGURE 185 The formation and hydrolysis of cyclic AMP (3′,5′-adenylic acid, cAMP). ATP formation), as a result of the reaction of adenylate kinase: to the Ca2+-binding protein calmodulin (see Chapter 42), 2 × ADP ↔ ATP + 5′ AMP. and binds four Ca2+. The binding of Ca2+ activates the cata- lytic site of the γ subunit even while the enzyme is in the dephosphorylated b state; the phosphorylated a form is only cAMP ACTIVATES GLYCOGEN fully activated in the presence of high concentrations of Ca2+. PHOSPHORYLASE Phosphorylase kinase is activated in response to cAMP Glycogenolysis in Liver Can Be (Figure 18–6). Increasing the concentration of cAMP acti- cAMP-Independent vates cAMP-dependent protein kinase, which catalyzes the In the liver, there is cAMP-independent activation of glycoge- phosphorylation by ATP of inactive phosphorylase kinase b nolysis in response to stimulation of α1 adrenergic recep- to active phosphorylase kinase a, which in turn, phosphory- tors by epinephrine and norepinephrine. This involves lates phosphorylase b to phosphorylase a. In the liver, cAMP is mobilization of Ca2+ into the cytosol, followed by the formed in response to glucagon, which is secreted in response stimulation of a Ca2+/calmodulin-sensitive phosphorylase to falling blood glucose. Muscle is insensitive to glucagon; in kinase. cAMP-independent glycogenolysis is also activated muscle, the signal for increased cAMP formation is the action by vasopressin, oxytocin, and angiotensin II acting either of norepinephrine, which is secreted in response to fear or through calcium or the phosphatidylinositol bisphosphate fright, when there is a need for increased glycogenolysis to pathway (see Figure 42–10). permit rapid muscle activity. Protein Phosphatase-1 Inactivates Ca2+ Synchronizes the Activation of Glycogen Phosphorylase Glycogen Phosphorylase With Muscle Both phosphorylase a and phosphorylase kinase a are dephos- Contraction phorylated and inactivated by protein phosphatase-1. Protein Glycogenolysis in muscle increases several hundred-fold at phosphatase-1 is inhibited by a protein, inhibitor-1, which is the onset of contraction; the same signal (increased cyto- active only after it has been phosphorylated by cAMP-depen- solic Ca2+ ion concentration) is responsible for initiation of dent protein kinase. Thus, cAMP controls both the activation both contraction and glycogenolysis. Muscle phosphorylase and inactivation of phosphorylase (Figure 18–6). Insulin rein- kinase, which activates glycogen phosphorylase, is a tetra- forces this effect by inhibiting the activation of phosphorylase b. mer of four different subunits, α, β, γ, and δ. The α and β It does this indirectly by increasing uptake of glucose, leading subunits contain serine residues that are phosphorylated by to increased formation of glucose-6-phosphate, which is an cAMP-dependent protein kinase. The δ subunit is identical inhibitor of phosphorylase kinase.  Epinephrine β Receptor + Inactive Active adenylyl adenylyl cyclase cyclase Glycogen(n) + + Phosphodiesterase Glycogen(n+1) Glucose-1-phosphate ATP cAMP 5′-AMP + Active Pi Inactive cAMP-dependent cAMP-dependent protein kinase protein kinase ADP Phosphorylase a Calmodulin (active) ADP H2O component of Inhibitor-1 phosphorylase kinase (inactive) ATP – + Phosphorylase kinase b Phosphorylase kinase a G6P Insulin Protein (inactive) Ca2+ (active) phosphatase-1 ATP – + –Ca2+ ATP Pi Phosphorylase b ADP (inactive) Pi H 2O Protein phosphatase-1 – Inhibitor-1-phosphate (active) FIGURE 186 Control of glycogen phosphorylase in muscle. The sequence of reactions arranged as a cascade allows amplification of the hormonal signal at each step. (G6P, glucose 6-phosphate; n, number of glucose residues.) 181 182 SECTION IV Metabolism of Carbohydrates The Activities of Glycogen Synthase protein phosphatase-1, which is under the control of cAMP- dependent protein kinase. & Phosphorylase Are Reciprocally Regulated There are different isoenzymes of glycogen synthase in liver, GLYCOGEN METABOLISM IS muscle, and brain. Like phosphorylase, glycogen synthase exists in both phosphorylated and nonphosphorylated states, REGULATED BY A BALANCE IN and the effect of phosphorylation is the reverse of that seen ACTIVITIES BETWEEN GLYCOGEN in phosphorylase (Figure 18–7). Active glycogen synthase a is dephosphorylated and inactive glycogen synthase b is SYNTHASE & PHOSPHORYLASE phosphorylated. At the same time as phosphorylase is activated by a rise in Six different protein kinases act on glycogen synthase, concentration of cAMP (via phosphorylase kinase), glycogen and there are at least nine different serine residues in the synthase is converted to the inactive form; both effects are enzyme that can be phosphorylated. Two of the protein mediated via cAMP-dependent protein kinase (Figure 18–8). kinases are Ca2+/calmodulin dependent (one of these is phos- Thus, inhibition of glycogenolysis enhances net glycogenesis, phorylase kinase). Another kinase is cAMP-dependent pro- and inhibition of glycogenesis enhances net glycogenolysis. tein kinase, which allows cAMP-mediated hormonal action Also, the dephosphorylation of phosphorylase a, phosphorylase to inhibit glycogen synthesis synchronously with the activa- kinase, and glycogen synthase b is catalyzed by a single enzyme tion of glycogenolysis. Insulin also promotes glycogenesis in with broad specificity—protein phosphatase-1. In turn, pro- muscle at the same time as inhibiting glycogenolysis by rais- tein phosphatase-1 is inhibited by cAMP-dependent protein ing glucose-6-phosphate concentrations, which stimulates kinase via inhibitor-1. Thus, glycogenolysis can be terminated the dephosphorylation and activation of glycogen synthase. and glycogenesis can be stimulated, or vice versa, synchro- Dephosphorylation of glycogen synthase b is carried out by nously, because both processes are dependent on the activity of Epinephrine β Receptor + Inactive Active adenylyl adenylyl cyclase cyclase + Phosphodiesterase ATP cAMP 5′-AMP Phosphorylase kinase Ca2+ + + Inactive Active cAMP-dependent cAMP-dependent protein kinase protein kinase ATP Glycogen(n+1) Inhibitor-1 GSK (inactive) ADP Calmodulin-dependent protein kinase ATP Glycogen synthase Glycogen synthase + b a (inactive) Ca2+ (active) + Insulin G6P + + ADP Protein phosphatase Glycogen(n) H2O Pi + UDPG Inhibitor-1-phosphate Protein phosphatase-1 (active) – FIGURE 187 Control of glycogen synthase in muscle. (G6P, glucose-6-phosphate; GSK, glycogen synthase kinase; n, number of glucose residues.)  CHAPTER 18 Metabolism of Glycogen 183 Epinephrine Phosphodiesterase (liver, muscle) Inhibitor-1 cAMP 5′-AMP Inhibitor-1 Glucagon phosphate (liver) Glycogen Phosphorylase synthase b kinase b Protein cAMP- Protein phosphatase-1 dependent phosphatase-1 protein kinase Glycogen Phosphorylase synthase a kinase a Glycogen Glycogen Phosphorylase Phosphorylase UDPGIc a b cycle Glucose-1-phosphate Protein phosphatase-1 Glucose (liver) Glucose Lactate (muscle) FIGURE 188 Coordinated control of glycogenolysis and glycogenesis by cAMP-dependent protein kinase. The reactions that lead to glycogenolysis as a result of an increase in cAMP concentrations are shown with bold arrows, and those that are inhibited by activation of protein phosphatase-1 are shown with dashed arrows. The reverse occurs when cAMP concentrations decrease as a result of phosphodiesterase activity, leading to glycogenesis. cAMP-dependent protein kinase. Both phosphorylase kinase and glycogen synthase may be reversibly phosphorylated at SUMMARY Glycogen represents the principal storage carbohydrate in the more than one site by separate kinases and phosphatases. These body, mainly in the liver and muscle. secondary phosphorylations modify the sensitivity of the pri- In the liver, its major function is to provide glucose for mary sites to phosphorylation and dephosphorylation (mul- tisite phosphorylation). Also, they allow insulin, by way of extrahepatic tissues. In muscle, it serves mainly as a ready source of metabolic fuel for use in muscle. Muscle lacks increased glucose 6-phosphate, to have effects that act recipro- glucose-6-phosphatase and cannot release free glucose from cally to those of cAMP (see Figures 18–6 and 18–7). glycogen. Glycogen is synthesized from glucose by the pathway of CLINICAL ASPECTS glycogenesis. It is broken down by a separate pathway, glycogenolysis. Glycogen Storage Diseases Cyclic AMP integrates the regulation of glycogenolysis and glycogenesis by promoting the simultaneous activation of Are Inherited phosphorylase and inhibition of glycogen synthase. Insulin “Glycogen storage disease” is a generic term to describe a group acts reciprocally by inhibiting glycogenolysis and stimulating of inherited disorders characterized by deposition of an abnor- glycogenesis. mal type or quantity of glycogen in tissues, or failure to mobilize Inherited deficiencies of enzymes of glycogen metabolism in glycogen. The principal diseases are summarized in Table 18–2. both liver and muscle cause glycogen storage diseases. 184 SECTION IV Metabolism of Carbohydrates REFERENCES Ozen H: Glycogen storage diseases: new perspectives. World J Gastroenterol 2007;13:2541. Alanso MD, Lomako J, Lomako WM, et al: A new look at the Palm DC, Rohwer JM: Regulation of glycogen synthase from biogenesis of glycogen. FASEB J 1995;9:1126. mammalian skeletal muscle—a unifying view of allosteric and Bollen M, Keppens S, Stalmans W: Specific features of glycogen covalent regulation. FEBS J 2013;280:2. metabolism in the liver. Biochem J 1998;336:19. Philp A, Hargreaves M: More than a store: regulatory roles for DiMauro S, Spiegel R: Progress and problems in muscle glycogen in skeletal muscle adaptation to exercise. Am J Physiol glycogenoses. Acta Myol 2011;30:96. Endocrinol Metab 2012;302:E1343. Ferrer JC, Favre C, Gomis RR, et al: Control of glycogen deposition. Radziuk J, Pye S: Hepatic glucose uptake, gluconeogenesis and FEBS Lett 2003;546:127–132. the regulation of glycogen synthesis. Diabetes Metab Res Rev Forde JE, Dale TC: Glycogen synthase kinase 3: a key regulator of 2001;17(4):250. cellular fate. Cell Mol Life Sci 2007;64:1930. Roach PJ, Depaoli-Roach AA: Glycogen and its metabolism: Gazzerro E, Andreu AL: Neuromuscular disorders of glycogen some new developments and old themes. Biochem J metabolism. Curr Neurol Neurosci Rep 2013;13:333. 2012;441:763. Graham TE, Yuan Z, Hill AK, et al: The regulation of muscle glycogen: Roden M, Bernroider E: Hepatic glucose metabolism in humans— the granule and its proteins. Acta Physiol (Oxf) 2010;199:489. its role in health and disease. Best Pract Res Clin Endocrinol Greenberg CC, Jurczak MJ, Danos AM, et al: Glycogen branches Metab 2003;17:365. out: new perspectives on the role of glycogen metabolism in the Rybicka KK: Glycosomes—the organelles of glycogen metabolism. integration of metabolic pathways. Am J Physiol Endocrinol Tissue Cell 1996;28:254. Metab 2006;291:E1. Shearer J, Graham TE: New perspectives on the storage and Jensen J, Lai YC: Regulation of muscle glycogen synthase organization of muscle glycogen. Can J Appl Physiol 2002;27:179. phosphorylation and kinetic properties by insulin, exercise, Shin YS: Glycogen storage disease: clinical, biochemical, and adrenaline and role in insulin resistance. Arch Physiol Biochem molecular heterogeneity. Semin Pediatr Neurol 2006;13:115. 2009;115:13. Wolfsdorf JI, Holm IA: Glycogen storage diseases. Phenotypic, Jensen TE, Richter EA: Regulation of glucose and glycogen genetic, and biochemical characteristics, and therapy. Endocrinol metabolism during and after exercise. J Physiol 2012;590:1069. Metab Clin North Am 1999;28:801. McGarry JD, Kuwajima M, Newgard CB, et al: From dietary glucose Yeaman SJ, Armstrong JL, Bonavaud SM, et al: Regulation of to liver glycogen: the full circle round. Annu Rev Nutr 1987;7:51. glycogen synthesis in human muscle cells. Biochem Soc Trans Meléndez-Hevia E, Waddell TG, Shelton ED: Optimization of 2001;29:537. molecular design in the evolution of metabolism: the glycogen molecule. Biochem J 1993;295:477.  C H A P T E R Gluconeogenesis & the Control of Blood Glucose David A. Bender, PhD & Peter A. Mayes, PhD, DSc 19 OBJEC TIVES Explain the importance of gluconeogenesis in glucose homeostasis. Describe the pathway of gluconeogenesis, how irreversible enzymes of After studying this chapter, glycolysis are bypassed, and how glycolysis and gluconeogenesis are regulated you should be able to: reciprocally. Explain how plasma glucose concentration is maintained within narrow limits in the fed and fasting states. BIOMEDICAL IMPORTANCE coagulation. Excessive gluconeogenesis is also a contributory factor to hyperglycemia in type 2 diabetes because of impaired Gluconeogenesis is the process of synthesizing glucose or downregulation in response to insulin. glycogen from noncarbohydrate precursors. The major sub- strates are the glucogenic amino acids (see Chapter 29), lac- tate, glycerol, and propionate. Liver and kidney are the major GLUCONEOGENESIS INVOLVES gluconeogenic tissues; the kidney may contribute up to 40% of total glucose synthesis in the fasting state and more in star- GLYCOLYSIS, THE CITRIC ACID vation. The key gluconeogenic enzymes are expressed in the CYCLE, PLUS SOME SPECIAL small intestine, but it is unclear whether or not there is signifi- cant glucose production by the intestine in the fasting state. REACTIONS A supply of glucose is necessary especially for the nervous system and erythrocytes. After an overnight fast, glycogenolysis Thermodynamic Barriers Prevent a (see Chapter 18) and gluconeogenesis make approximately equal Simple Reversal of Glycolysis contributions to blood glucose; as glycogen reserves are depleted, Three nonequilibrium reactions in glycolysis (see Chapter 17), so gluconeogenesis becomes progressively more important. catalyzed by hexokinase, phosphofructokinase and pyruvate Failure of gluconeogenesis is usually fatal. Hypoglycemia kinase, prevent simple reversal of glycolysis for glucose syn- causes brain dysfunction, which can lead to coma and death. thesis (Figure 19–1). They are circumvented as follows. Glucose is also important in maintaining adequate concentra- tions of intermediates of the citric acid cycle (see Chapter 16) even when fatty acids are the main source of acetyl-CoA in the Pyruvate & Phosphoenolpyruvate tissues. In addition, gluconeogenesis clears lactate produced by Reversal of the reaction catalyzed by pyruvate kinase in gly- muscle and erythrocytes, and glycerol produced by adipose tis- colysis involves two endothermic reactions. Mitochondrial sue. In ruminants, propionate is a product of rumen metabolism pyruvate carboxylase catalyzes the carboxylation of pyru- of carbohydrates, and is a major substrate for gluconeogenesis. vate to oxaloacetate, an ATP-requiring reaction in which the Excessive gluconeogenesis occurs in critically ill patients vitamin biotin is the coenzyme. Biotin binds CO2 from bicar- in response to injury and infection, contributing to hypergly- bonate as carboxybiotin prior to the addition of the CO2 to cemia which is associated with a poor outcome. Hyperglycemia pyruvate (see Figure 44–17). The resultant oxaloacetate is leads to changes in osmolality of body fluids, impaired blood reduced to malate, exported from the mitochondrion into flow, intracellular acidosis and increased superoxide radical the cytosol and there oxidized back to oxaloacetate. A sec- production (see Chapter 45), resulting in deranged endo- ond enzyme, phosphoenolpyruvate carboxykinase, catalyzes thelial and immune system function and impaired blood the decarboxylation and phosphorylation of oxaloacetate to oxaloacetate cannot just pass thru the membrane to cytosol; it has to be converted to malate then oxidized back to oxalo 185 186 SECTION IV Metabolism of Carbohydrates Pi Glucose ATP Glucokinase Glucose-6-phosphatase Hexokinase Glucose-6- H2 O ADP phosphate Glycogen AMP AMP Pi Fructose-6- ATP phosphate Fructose 1,6- bisphosphatase Phosphofructokinase Fructose 1,6- H2 O ADP bisphosphate Fructose cAMP 2,6-bisphosphate (glucagon) Fructose 2,6-bisphosphate Glyceraldehyde-3-phosphate Dihydroxyacetone phosphate NAD + Pi NADH + H+ Glycerol-3-phosphate NADH + H + dehydrogenase cAMP (glucagon) 1,3-Bisphosphoglycerate NAD+ ADP Glycerol-3-phosphate ADP ATP Glycerol kinase 3-Phosphoglycerate ATP Glycerol 2-Phosphoglycerate cAMP (glucagon) Phosphoenolpyruvate ADP Pyruvate kinase Alanine GDP + CO2 Fatty ATP acids Phosphoenolpyruvate Pyruvate Lactate carboxykinase Citrate + GTP NADH + H NAD+ sol to Pyruvate Cy n dehydrogenase Oxaloacetate drio on Pyruvate Acetyl-CoA ch NADH + H + ito CO2 + ATP M Mg 2 + Pyruvate carboxylase NAD + ADP + Pi NADH + H+ Oxaloacetate NAD + Malate Malate Citrate Citric acid cycle α- Ketoglutarate Fumarate Succinyl-CoA Propionate FIGURE 191 Major pathways and regulation of gluconeogenesis and glycolysis in the liver. Entry points of glucogenic amino acids after transamination are indicated by arrows extended from circles (see also Figure 16–4). The key gluconeogenic enzymes are enclosed in double-bordered boxes. The ATP required for gluconeogenesis is supplied by the oxidation of fatty acids. Propionate is of quantitative importance only in ruminants. Arrows with wavy shafts signify allosteric effects; dash-shafted arrows, covalent modification by reversible phosphorylation. High concentrations of alanine act as a “gluconeo- genic signal” by inhibiting glycolysis at the pyruvate kinase step. phosphoenolpyruvate using GTP as the phosphate donor. In of phosphoenolpyruvate carboxykinase, thus providing a link liver and kidney, the reaction of succinate thiokinase in the between citric acid cycle activity and gluconeogenesis, to pre- citric acid cycle (see Chapter 16) produces GTP (rather than vent excessive removal of oxaloacetate for gluconeogenesis, ATP as in other tissues), and this GTP is used for the reaction which would impair citric acid cycle activity.  CHAPTER 19 Gluconeogenesis & the Control of Blood Glucose 187 Fructose 1,6-Bisphosphate & Fructose-6- by methylmalonyl-CoA mutase. In nonruminants, includ- Phosphate ing human beings, propionate arises from the β-oxidation of odd-chain fatty acids that occur in ruminant lipids (see The conversion of fructose 1,6-bisphosphate to fructose-6- Chapter 22), as well as the oxidation of isoleucine and the side phosphate, for the reversal of glycolysis, is catalyzed by fructose chain of cholesterol, and is a (relatively minor) substrate for r a t e - 1,6-bisphosphatase. Its presence determines whether a tissue limitiing gluconeogenesis. Methylmalonyl-CoA mutase is a vitamin B12- step is capable of synthesizing glucose (or glycogen) not only from dependent enzyme, and in deficiency methylmalonic acid is pyruvate, but also from triose phosphates. It is present in liver, excreted in the urine (methylmalonic aciduria). kidney, and skeletal muscle, but is probably absent from heart Glycerol is released from adipose tissue as a result of lipolysis and smooth muscle. of lipoprotein triacylglycerol in the fed state; it may be used for reesterification of free fatty acids to triacylglycerol, or may be a Glucose-6-Phosphate & Glucose substrate for gluconeogenesis in the liver. In the fasting state, glyc- The conversion of glucose-6-phosphate to glucose is catalyzed erol released from lipolysis of adipose tissue triacylglycerol is used by glucose-6-phosphatase. It is present in liver and kidney, as a substrate for gluconeogenesis in the liver and kidneys. but absent from muscle, which, therefore, cannot export glu- cose into the bloodstream. GLYCOLYSIS & GLUCONEOGENESIS Glucose-1-Phosphate & Glycogen SHARE THE SAME PATHWAY BUT The breakdown of glycogen to glucose-1-phosphate is cata- lyzed by phosphorylase. Glycogen synthesis involves a differ- IN OPPOSITE DIRECTIONS, AND ent pathway via uridine diphosphate glucose and glycogen ARE RECIPROCALLY REGULATED synthase (see Figure 18–1). Changes in the availability of substrates are responsible for The relationships between gluconeogenesis and the glyco- most changes in metabolism either directly or indirectly act- lytic pathway are shown in Figure 19–1. After transamination ing via changes in hormone secretion. Three mechanisms are or deamination, glucogenic amino acids yield either pyruvate responsible for regulating the activity of enzymes concerned or intermediates of the citric acid cycle. Therefore, the reac- in carbohydrate metabolism: (1) changes in the rate of enzyme tions described above can account for the conversion of both synthesis, (2) covalent modification by reversible phosphory- lactate and glucogenic amino acids to glucose or glycogen. lation, and (3) allosteric effects. Propionate is a major precursor of glucose in rumi- nants; it enters gluconeogenesis via the citric acid cycle. After esterification with CoA, propionyl-CoA is carboxyl- Induction & Repression of Key Enzymes ated to d-methylmalonyl-CoA, catalyzed by propionyl-CoA Requires Several Hours carboxylase, a biotin-dependent enzyme (Figure 19–2). The changes in enzyme activity in the liver that occur under Methylmalonyl-CoA racemase catalyzes the conversion various metabolic conditions are listed in Table 19–1. The of d-methylmalonyl-CoA to l-methylmalonyl-CoA, which enzymes involved catalyze physiologically irreversible non- then undergoes isomerization to succinyl-CoA catalyzed equilibrium reactions. The effects are generally reinforced CoA SH Acyl-CoA CO2 + H2O Propionyl-CoA CH3 synthetase CH3 carboxylase CH3 CH2 CH2 H C COO– Mg2+ Biotin COO– CO S CoA CO S CoA ATP AMP + PPi ATP ADP + Pi Propionate Propionyl-CoA D-Methyl- malonyl-CoA Methylmalonyl-CoA racemase COO– Methylmalonyl- CoA mutase CH3 CH2 Intermediates – OOC C H of citric acid cycle CH2 B12 coenzyme CO S CoA CO S CoA L-Methyl- Succinyl-CoA malonyl-CoA FIGURE 192 Metabolism of propionate. 188 SECTION IV Metabolism of Carbohydrates TABLE 191 Regulatory and Adaptive Enzymes Associated with Carbohydrate Metabolism Activity in Fasting Carbohydrate and Feeding Diabetes Inducer Repressor Activator Inhibitor Glycogenolysis, glycolysis, and pyruvate oxidation Glycogen synthase ↑ ↓ Insulin, glucose-6- Glucagon phosphate Hexokinase Glucose-6- phosphate Glucokinase ↑ ↓ Insulin Glucagon Phosphofructokinase-1 ↑ ↓ Insulin Glucagon 5′ AMP, fructose- Citrate, ATP, 6-phosphate, glucagon fructose 2,6-bisphosphate, Pi Pyruvate kinase ↑ ↓ Insulin, fructose Glucagon Fructose ATP, alanine, 1,6-bisphosphate, glucagon, insulin norepinephrine Pyruvate dehydrogenase ↑ ↓ CoA, NAD+, insulin, Acetyl CoA, NADH, ADP, pyruvate ATP (fatty acids, ketone bodies) Gluconeogenesis Pyruvate carboxylase ↓ ↑ Glucocorticoids, Insulin Acetyl CoA ADP glucagon, epinephrine Phosphoenolpyruvate ↓ ↑ Glucocorticoids, Insulin Glucagon carboxykinase glucagon, epinephrine Glucose 6-phosphatase ↓ ↑ Glucocorticoids, Insulin glucagon, epinephrine because the activity of the enzymes catalyzing the reactions Allosteric Modification Is Instantaneous in the opposite direction varies reciprocally (see Figure 19–1). In gluconeogenesis, pyruvate carboxylase, which catalyzes the The enzymes involved in the utilization of glucose (ie, those synthesis of oxaloacetate from pyruvate, requires acetyl-CoA of glycolysis and lipogenesis) become more active when there as an allosteric activator. The addition of acetyl-CoA results is a superfluity of glucose, and under these conditions the in a change in the tertiary structure of the protein, lower- enzymes of gluconeogenesis have low activity. Insulin, secreted ing the Km for bicarbonate. This means that as acetyl-CoA is in response to increased blood glucose, enhances the synthesis formed from pyruvate, it automatically ensures the provision of the key enzymes in glycolysis. It also antagonizes the effect of oxaloacetate and, therefore, its further oxidation in the cit- of the glucocorticoids and glucagon-stimulated cAMP, which ric acid cycle, by activating pyruvate carboxylase. The acti- induce synthesis of the key enzymes of gluconeogenesis. vation of pyruvate carboxylase and the reciprocal inhibition of pyruvate dehydrogenase by acetyl-CoA derived from the Covalent Modification by Reversible oxidation of fatty acids explain the action of fatty acid oxida- Phosphorylation Is Rapid tion in sparing the oxidation of pyruvate (and hence glucose) Glucagon and epinephrine, hormones that are responsive to a and in stimulating gluconeogenesis. The reciprocal relation- decrease in blood glucose, inhibit glycolysis and stimulate gluco- ship between these two enzymes alters the metabolic fate of pyrv carboxy and pyrv dehyd neogenesis in the liver by increasing the concentration of cAMP. pyruvate as the tissue changes from carbohydrate oxidation This in turn activates cAMP-dependent protein kinase, leading (glycolysis) to gluconeogenesis during the transition from the to the phosphorylation and inactivation of pyruvate kinase. fed to fasting state (see Figure 19–1). A major role of fatty acid They also affect the concentration of fructose 2,6-bisphosphate oxidation in promoting gluconeogenesis is to supply the ATP and therefore glycolysis and gluconeogenesis, as described below. that is required.  CHAPTER 19 Gluconeogenesis & the Control of Blood Glucose 189 + 5’AMP Relative activity No AMP 0 1 2 3 4 5 ATP (mmol /L) Normal intracellular [ATP] FIGURE 193 The inhibition of phosphofructokinase-1 by ATP and relief of inhibition by ATP. inhib: cit, ATP activ: 5’AMP allosteric; activ of PFK-1 and inhib of F-1.6-BP Phosphofructokinase (phosphofructokinase-1) occu- liver is fructose 2,6-bisphosphate. It relieves inhibition of pies a key position in regulating glycolysis and is also subject phosphofructokinase-1 by ATP and increases the affinity for to feedback control. It is inhibited by citrate and by normal fructose-6-phosphate. It inhibits fructose 1,6-bisphosphatase intracellular concentrations of ATP and is activated by 5′ AMP. by increasing the Km for fructose 1,6-bisphosphate. Its con- At the normal intracellular [ATP] the enzyme is about 90% centration is under both substrate (allosteric) and hormonal inhibited; this inhibition is reversed by 5′AMP (Figure 19-3). control (covalent modification) (Figure 19–4). 5′ AMP acts as an indicator of the energy status of the cell. Fructose 2,6-bisphosphate is formed by phosphoryla- The presence of adenylyl kinase in liver and many other tis- tion of fructose-6-phosphate by phosphofructokinase-2. sues allows rapid equilibration of the reaction The same enzyme protein is also responsible for its break- 2ADP ↔ ATP + 5′ AMP down, since it has fructose 2,6-bisphosphatase activity. This bifunctional enzyme is under the allosteric control Thus, when ATP is used in energy-requiring processes, of fructose-6-phosphate, which stimulates the kinase and resulting in formation of ADP, [AMP] increases. A relatively inhibits the phosphatase. Hence, when there is an abundant small decrease in [ATP] causes a several-fold increase in [AMP], supply of glucose, the concentration of fructose 2,6-bispho- so that [AMP] acts as a metabolic amplifier of a small change sphate increases, stimulating glycolysis by activating in [ATP], and hence a sensitive signal of the energy state of the phosphofructokinase-1 and inhibiting fructose 1,6-bispho- cell. The activity of phosphofructokinase-1 is thus regulated in sphatase. In the fasting state, glucagon stimulates the pro- response to the energy status of the cell to control the quantity duction of cAMP, activating cAMP-dependent protein of carbohydrate undergoing glycolysis prior to its entry into the kinase, which in turn inactivates phosphofructokinase-2 citric acid cycle. At the same time, AMP activates glycogen phos- and activates fructose 2,6-bisphosphatase by phosphoryla- phorylase, so increasing glycogenolysis. A consequence of the tion. Hence, gluconeogenesis is stimulated by a decrease in inhibition of phosphofructokinase-1 by ATP is an accumulation the concentration of fructose 2,6-bisphosphate, which inac- of glucose-6-phosphate, which in turn inhibits further uptake of tivates phosphofructokinase-1 and relieves the inhibition of glucose in extrahepatic tissues by inhibition of hexokinase. fructose 1,6-bisphosphatase. Xylulose 5-phosphate, an inter- mediate of the pentose phosphate pathway (see Chapter 20) Fructose 2,6-Bisphosphate Plays a Unique activates the protein phosphatase that dephosphorylates the bifunctional enzyme, so increasing the formation of Role in the Regulation of Glycolysis & fructose 2,6-bisphosphate and increasing the rate of gly- Gluconeogenesis in Liver colysis. This leads to increased flux through glycolysis and The most potent positive allosteric activator of phosphofruc- the pentose phosphate pathway and increased fatty acid tokinase-1 and inhibitor of fructose 1,6-bisphosphatase in synthesis (see Chapter 23). 190 SECTION IV Metabolism of Carbohydrates Glycogen of phosphofructokinase activity is some 10-fold higher than glucose that of fructose 1,6-bisphosphatase; in anticipation of muscle contraction, the activity of both enzymes increases, fructose Fructose-6-phosphate 1,6-bisphosphatase 10 times more than phosphofructoki- Glucagon nase, maintaining the same net rate of glycolysis. At the start of muscle contraction, the activity of phosphofructokinase Pi cAMP increases further, and that of fructose 1,6-bisphosphatase falls, so increasing the net rate of glycolysis (and hence ATP forma- cAMP-dependent tion) as much as a 1000-fold. protein kinase ADP ATP THE BLOOD CONCENTRATION OF Active Inactive GLUCOSE IS REGULATED WITHIN Gluconeogenesis F-2,6-pase F-2,6-pase NARROW LIMITS Glycolysis P Inactive Active PFK-2 PFK-2 In the postabsorptive state, the concentration of blood glucose in most mammals is maintained between 4.5 and 5.5 mmol/L. H2O Pi After the ingestion of a carbohydrate meal, it may rise to 6.5 to 7.2 mmol/L, and in starvation, it may fall to 3.3 to 3.9 mmol/L. Protein phosphatase-2 ADP A sudden decrease in blood glucose (eg, in response to insulin Citrate overdose) causes convulsions, because of the dependence of Fructose 2,6 -bisphosphate the brain on a supply of glucose. However, much lower con- Pi ATP centrations can be tolerated if hypoglycemia develops slowly F-1,6-pase PFK-1 enough for adaptation to occur. The blood glucose level in birds is considerably higher (14.0 mmol/L) and in ruminants H2O ADP considerably lower (approximately 2.2 mmol/L in sheep and 3.3 mmol/L in cattle). These lower normal levels appear to Fructose 1,6-bisphosphate be associated with the fact that ruminants ferment virtually all dietary carbohydrate to short-chain fatty acids, and these Pyruvate largely replace glucose as the main metabolic fuel of the tissues in the fed state. FIGURE 194 Control of glycolysis and gluconeogenesis in the liver by fructose 2,6-bisphosphate and the bifunctional enzyme PFK-2/F-2,6-Pase (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase). (F-1,6-Pase, fructose 1,6-bisphosphatase; BLOOD GLUCOSE IS PFK-1, phosphofructokinase-1 [6-phosphofructo-1-kinase].) Arrows with wavy shafts indicate allosteric effects. DERIVED FROM THE DIET, GLUCONEOGENESIS, & Substrate (Futile) Cycles Allow Fine Tuning GLYCOGENOLYSIS & Rapid Response The digestible dietary carbohydrates yield glucose, galactose, The control points in glycolysis and glycogen metabolism and fructose that are transported to the liver via the hepatic involve a cycle of phosphorylation and dephosphorylation portal vein. Galactose and fructose are readily converted to catalyzed by glucokinase and glucose-6-phosphatase; phos- glucose in the liver (see Chapter 20). phofructokinase-1 and fructose 1,6-bisphosphatase; pyru- Glucose is formed from two groups of compounds that vate kinase, pyruvate carboxylase, and phosphoenolpyruvate undergo gluconeogenesis (see Figures 16–4 and 19–1): (1) those carboxykinase; and glycogen synthase and phosphorylase. It which involve a direct net conversion to glucose, including most would seem obvious that these opposing enzymes are regu- amino acids and propionate; and (2) those which are the prod- lated in such a way that when those involved in glycolysis are ucts of the metabolism of glucose in tissues. Thus lactate, formed active, those involved in gluconeogenesis are inactive, since by glycolysis in skeletal muscle and erythrocytes, is transported otherwise there would be cycling between phosphorylated to the liver and kidney where it reforms glucose, which again and nonphosphorylated intermediates, with net hydrolysis becomes available via the circulation for oxidation in the tissues. of ATP. While this is so, in muscle both phosphofructoki- This process is known as the Cori cycle, or the lactic acid cycle nase and fructose 1,6-bisphosphatase have some activity at all (Figure 19–5). times, so that there is indeed some measure of (wasteful) sub- In the fasting state, there is a considerable output of ala- strate cycling. This permits the very rapid increase in the rate nine from skeletal muscle, far in excess of the amount in the of glycolysis necessary for muscle contraction. At rest the rate muscle proteins that are being catabolized. It is formed by opposing enzymes: - glucokin & G6P - PFK-1 & F16BPase - PK, PC, PEPC - GS & Phosp  CHAPTER 19 Gluconeogenesis & the Control of Blood Glucose 191 Blood Glucose Liver Muscle Glucose-6-phosphate Glycogen Glycogen Glucose-6-phosphate Urea Pyruvate Lactate Lactate Pyruvate Tra –NH2 –NH2 n tio n sa Lactate na mi mi na sa Blood tio n Tra n Pyruvate Alanine Alanine Alanine FIGURE 195 The lactic acid (Cori cycle) and glucose-alanine cycles. transamination of pyruvate produced by glycolysis of muscle direction (via the GLUT 2 transporter), whereas cells of extra- glycogen, and is exported to the liver, where, after transami- hepatic tissues (apart from pancreatic β-islets) are relatively nation back to pyruvate, it is a substrate for gluconeogenesis. impermeable, and their unidirectional glucose transporters This glucose-alanine cycle (see Figure 19–5) thus provides an are regulated by insulin. As a result, uptake from the blood- indirect way of utilizing muscle glycogen to maintain blood stream is the rate-limiting step in the utilization of glucose in glucose in the fasting state. The ATP required for the hepatic extrahepatic tissues. The role of various glucose transporter synthesis of glucose from pyruvate is derived from the oxida- proteins found in cell membranes is shown in Table 19–2. tion of fatty acids. Glucose is also formed from liver glycogen by glycoge- Glucokinase Is Important in Regulating nolysis (see Chapter 18). Blood Glucose After a Meal Metabolic & Hormonal Mechanisms Hexokinase has a low Km for glucose, and in the liver it is sat- urated and acting at a constant rate under all normal condi- Regulate the Concentration of Blood tions. It thus acts to ensure an adequate rate of glycolysis to Glucose meet the liver’s needs. Glucokinase has a considerably higher The maintenance of a stable blood glucose concentration is Km (lower affinity) for glucose, so that its activity increases one of the most finely regulated of all homeostatic mecha- with increases in the concentration of glucose in the hepatic nisms, involving the liver, extrahepatic tissues, and several portal vein (Figure 19–6). It permits hepatic uptake of large hormones. Liver cells are freely permeable to glucose in either amounts of glucose after a carbohydrate meal, for glycogen TABLE 192 Major Glucose Transporters Tissue Location Functions Facilitative bidirectional transporters GLUT 1 Brain, kidney, colon, placenta, erythrocytes Glucose uptake GLUT 2 Liver, pancreatic β cell, small intestine, kidney Rapid uptake or release of glucose GLUT 3 Brain, kidney, placenta Glucose uptake GLUT 4 Heart and skeletal muscle, adipose tissue Insulin-stimulated glucose uptake GLUT 5 Small intestine Absorption of fructose Sodium-dependent unidirectional transporter SGLT 1 Small intestine and kidney Active uptake of glucose against a concentration gradient 192 SECTION IV Metabolism of Carbohydrates Vmax 100 Hexokinase the cell membrane, which increases Ca2+ influx via voltage- sensitive Ca2+ channels, stimulating exocytosis of insulin. Thus, the concentration of insulin in the blood parallels that of the blood glucose. Other substances causing release of insu- lin from the pancreas include amino acids, nonesterified fatty Activity 50 Glucokinase acids, ketone bodies, glucagon, secretin, and the sulfonylurea drugs tolbutamide and glyburide. These drugs are used to stimulate insulin secretion in type 2 diabetes mellitus via the ATP-sensitive K+ channels. Epinephrine and norepinephrine