Garrett R.H., Grisham C.M. - Biochemistry (1999)(2nd ed.)(en)

FIGURE 23.11

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Regulation of	To bloodstream	Regulation of
glycolysis		gluconeogenesis

[Glucose-6-phosphate

– Glucose-6-phosphate Hexokinase Glucose-6-phosphatase (substrate level control)

Glucose-6-phosphate

			Fructose-6-phosphate
+ Fructose-2,6-bisphosphate
+ AMP	Phosphofructokinase						Fructose-1,6-bisphosphatase			F2, 6BP –
– ATP										AMP	–
– Citrate
		Fructose-1,6-bisphosphate

		Phosphoenolpyruvate
	+ F1, 6BP		Phosphoenolpyruvate
			carboxykinase
	– Acetyl-CoA
		Pyruvate
	– ATP		Oxaloacetate
		kinase

–Alanine

–cAMP-dependent

phosphorylation	Pyruvate carboxylase	Acetyl-CoA +

Pyruvate

23.2 ● Regulation of Gluconeogen

● The principal re mechanisms in glycolysis and gluco Activators are indicated by plus sign inhibitors by minus signs.

[acetyl-CoA] indicates that cellular energy levels are high and that carbon metabolites can be directed to glucose synthesis and storage. When acetyl-CoA levels drop, the activities of pyruvate kinase and pyruvate dehydrogenase increase and flux through the TCA cycle increases, providing needed energy for the cell.

Fructose-1,6-bisphosphatase is another important site of gluconeogenic regulation. This enzyme is inhibited by AMP and activated by citrate. These effects by AMP and citrate are the opposites of those exerted on phosphofructokinase in glycolysis, providing another example of reciprocal regulatory effects. When AMP levels increase, gluconeogenic activity is diminished and glycolysis is stimulated. An increase in citrate concentration signals that TCA cycle activity can be curtailed and that pyruvate should be directed to sugar synthesis instead.

Fructose-2,6-Bisphosphate—Allosteric Regulator of Gluconeogenesis

As described in Chapter 19, Emile Van Schaftingen and Henri-Géry Hers demonstrated in 1980 that fructose-2,6-bisphosphate is a potent stimulator of phosphofructokinase. Cognizant of the reciprocal nature of regulation in glycolysis and gluconeogenesis, Van Schaftingen and Hers also considered the

2–O3POCH2 O OPO23– H HO

H	CH2OH
OH	H

Fructose-2,6-biphosphate

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752 Chapter 23 ● Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway

possibility of an opposite effect—inhibition—for fructose-1,6-bisphosphatase. In 1981 they reported that fructose-2,6-bisphosphate was indeed a powerful inhibitor of fructose-1,6-bisphosphatase (Figure 23.12). Inhibition occurs in either the presence or absence of AMP, and the effects of AMP and fructose- 2,6-bisphosphate are synergistic.

Cellular levels of fructose-2,6-bisphosphate are controlled by phospho- fructokinase-2 (PFK-2), an enzyme distinct from the phosphofructokinase of the glycolytic pathway, and by fructose-2,6-bisphosphatase (F-2,6-BPase).

Remarkably, these two enzymatic activities are both found in the same protein molecule, which is an example of a bifunctional, or tandem, enzyme (Figure 23.13). The opposing activities of this bifunctional enzyme are themselves regulated in two ways. First, fructose-6-phosphate, the substrate of phosphofructokinase and the product of fructose-1,6-bisphosphatase, allosterically activates PFK-2 and inhibits F-2,6-BPase. Second, the phosphorylation by cAMP-depen- dent protein kinase of a single Ser residue on the 49-kD subunit of this dimeric enzyme exerts reciprocal control of the PFK-2 and F-2,6-BPase activities. Phosphorylation then inhibits PFK-2 activity (by increasing the Km for fructose-6- phosphate) and stimulates F-2,6-BPase activity.

Substrate Cycles Provide Metabolic Control Mechanisms

If fructose-1,6-bisphosphatase and phosphofructokinase acted simultaneously, they would constitute a substrate cycle in which fructose-1,6-bisphosphate and fructose-6-phosphate became interconverted with net consumption of ATP:

Fructose-1,6-bisP H2O 88n fructose-6-P Pi

Fructose-6-P ATP 88n fructose-1,6-bisP ADP

Net: ATP H2O 88n ADP Pi

Because substrate cycles such as this appear to operate with no net benefit to the cell, they were once regarded as metabolic quirks and were referred to as futile cycles. More recently, substrate cycles have been recognized as important devices for controlling metabolite concentrations.

-1,6-bisphosphatase	units/mg protein
Fructose	activity,

(a)
20
15	0
	1
10	5
5
	25
0
0	50	100	200
	Fructose-1,6-bisphosphate, M

	(b)						(c)
1,6-Fructose-bisphosphatase units/mgactivity,protein	15						100
							Relativeactivity
				5							0
							75
	10			0
				0.2			50
				1							10
	5			2.5			25
											25
	0						0
	0			50	100	200	0			1	2	3	4	5
			Fructose-1,6-bisphosphate, M							Fructose-2,6-bisphosphate, M
FIGURE 23.12 ●				Inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate
in the (a) absence and (b) presence of 25							M AMP. In (a) and (b), enzyme activity is
plotted against substrate (fructose-1,6-bisphosphate) concentration. Concentrations of

fructose-2,6-bisphosphate (in M) are indicated above each curve. (c) The effect of AMP (0, 10, and 25 M) on the inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphos- phate. Activity was measured in the presence of 10 M fructose-1,6-bisphosphate.

(Adapted from Van Schaftingen, E., and Hers, H.-G., 1981. Inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bis- phosphate. Proceedings of the National Academy of Science, USA 78:2861–2863.)

FIGURE 23.13

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Glucagon

cAMP-dep. PK

F6P	ATP	ATP	ADP	H2O	F2,6BP
	PFK-2			F2,6BPase
F2,6BP	ADP			Pi	– F6P

+

PFK-1

–

F1,6B Pase

The three steps in glycolysis and gluconeogenesis that differ constitute three such substrate cycles, each with its own particular metabolic raison d’être. Consider, for example, the regulation of the fructose-1,6-bisP–fructose-6-P cycle by fructose-2,6-bisphosphate. As already noted, fructose-1,6-bisphosphatase is subject to allosteric inhibition by fructose-2,6-bisphosphate, whereas phosphofructokinase is allosterically activated by fructose-2,6-bisP. The combination of these effects should permit either phosphofructokinase or fructose-1,6-bisphos- phatase (but not both) to operate at any one time and should thus prevent futile cycling. For instance, in the fasting state, when food (i.e., glucose) intake is zero, phosphofructokinase (and therefore glycolysis) is inactive due to the low concentration of fructose-2,6-bisphosphate. In the liver, gluconeogenesis operates to provide glucose for the brain. However, in the fed state, up to 30% of fructose-1,6-bisphosphate formed from phosphofructokinase is recycled back to fructose-6-P (and then to glucose). Because the dependence of fruc- tose-1,6-bisphosphatase activity on fructose-1,6-bisphosphate is sigmoidal in the presence of fructose-2,6-bisphosphate (Figure 23.12), substrate cycling occurs only at relatively high levels of fructose-1,6-bisphosphate. Substrate cycling in this case prevents the accumulation of excessively high levels of fructose-1,6- bisphosphate.

23.3 ● Glycogen Catabolism

Dietary Glycogen and Starch Breakdown

As noted earlier, well-fed adult human beings normally metabolize about 160 g of carbohydrates each day. A balanced diet easily provides this amount, mostly in the form of starch, with smaller amounts of glycogen. If too little carbohydrate is supplied by the diet, glycogen reserves in liver and muscle tissue can also be mobilized. The reactions by which ingested starch and glycogen are digested are shown in Figure 23.14. The enzyme known as -amylase is an important component of saliva and pancreatic juice. ( -Amylase is found in plants. The - and -designations for these enzymes serve only to distinguish the two, and do not refer to glycosidic linkage nomenclature.) -Amylase is an endoglycosidase that hydrolyzes -(1 n 4) linkages of amylopectin and glycogen at random positions, eventually producing a mixture of maltose, maltotriose [with three -(1 n 4)-linked glucose residues], and other small oligosaccharides. -Amylase can cleave on either side of a glycogen or amylopectin branch point, but activity is reduced in highly branched regions of the polysaccharide and stops four residues from any branch point.

23.3 ● Glycogen Catabol

● Synthesis and de of fructose-2,6-bisphosphate are cata the same bifunctional enzyme.

β

α –Amylase

α -(1 6)-glucosidase

FIGURE 23.14 ● Hydrolysis of gly starch by -amylase and -amylase.

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754 Chapter 23 ● Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway

The highly branched polysaccharides that are left after extensive exposure to -amylase are called limit dextrins. These structures can be further degraded by the action of a debranching enzyme, which carries out two distinct reactions. The first of these, known as oligo( 1,4 n 1,4) glucantransferase activity, removes a trisaccharide unit and transfers this group to the end of another, nearby branch (Figure 23.15). This leaves a single glucose residue in -(1 n 6) linkage to the main chain. The -(1 n 6) glucosidase activity of the debranching enzyme then cleaves this residue from the chain, leaving a polysaccharide chain with one branch fewer. Repetition of this sequence of events leads to complete degradation of the polysaccharide.

-Amylase is an exoglycosidase that cleaves maltose units from the free, nonreducing ends of amylopectin branches, as in Figure 23.14. Like -amylase, however, -amylase does not cleave either the -(1 n 6) bonds at the branch points or the -(1 n 4) linkages near the branch points.

Metabolism of Tissue Glycogen

Digestion itself is a highly efficient process in which almost 100% of ingested food is absorbed and metabolized. Digestive breakdown of starch and glycogen is an unregulated process. On the other hand, tissue glycogen represents an important reservoir of potential energy, and it should be no surprise that the reactions involved in its degradation and synthesis are carefully controlled and regulated. Glycogen reserves in liver and muscle tissue are stored in the cytosol as granules exhibiting a molecular weight range from 6 106 to 1600 106. These granular aggregates contain the enzymes required to synthesize and catabolize the glycogen, as well as all the enzymes of glycolysis.

FIGURE 23.15 ● The reactions of glycogen debranching enzyme. Transfer of a group of three -(1 n 4)-linked glucose residues from a limit branch to another branch is followed by cleavage of the -(1 n 6) bond of the residue that remains at the branch point.

HO

HO

O

Limit branch

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

HO

O

O

O

O

O

O

Limit dextrin

Glycogen debranching enzyme

α− (1 6)-glucosidase activity

of debranching enzyme cleaves

O

this residue

H

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

Further cleavage by α -amylase

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23.4 ● Glycogen Synth

		CH2OH		CH2OH		CH2OH		CH2OH
		O		O		O		O
	HO	OH	O	OH	O	OH	O	OH	O
		OH		OH		OH		OH	n
	Nonreducing end								residues
						P
	CH2OH			CH2OH		CH2OH		CH2OH
	O		+	O		O		O
HO	OH	OPO3H2		OH	O	OH	O	OH	O
			HO
	OH			OH		OH		OH	n–1
α -D-Glucose-1-phosphate									residues

FIGURE 23.16 ● The glycogen phosphorylase reaction.

The principal enzyme of glycogen catabolism is glycogen phosphorylase, a highly regulated enzyme that was discussed extensively in Chapter 15. The glycogen phosphorylase reaction (Figure 23.16) involves phosphorolysis at a nonreducing end of a glycogen polymer. The standard-state free energy change for this reaction is 3.1 kJ/mol, but the intracellular ratio of [Pi] to [glucose- 1-P] approaches 100, and thus the actual G in vivo is approximately 6 kJ/mol. There is an energetic advantage to the cell in this phosphorolysis reaction. If glycogen breakdown were hydrolytic and yielded glucose as a product, it would be necessary to phosphorylate the product glucose (with the expenditure of a molecule of ATP) to initiate its glycolytic degradation.

The glycogen phosphorylase reaction degrades glycogen to produce limit dextrins, which are further degraded by debranching enzyme, as already described.

23.4 ● Glycogen Synthesis

Animals synthesize and store glycogen when glucose levels are high, but the synthetic pathway is not merely a reversal of the glycogen phosphorylase reaction. High levels of phosphate in the cell favor glycogen breakdown and prevent the phosphorylase reaction from synthesizing glycogen in vivo, in spite of the fact that G° for the phosphorylase reaction actually favors glycogen synthesis. Hence, another reaction pathway must be employed in the cell for the net synthesis of glycogen. In essence, this pathway must activate glucose units for transfer to glycogen chains.

Glucose Units Are Activated for Transfer by

Formation of Sugar Nucleotides

We are familiar with several examples of chemical activation as a strategy for group transfer reactions. Acetyl-CoA is an activated form of acetate, biotin and tetrahydrofolate activate one-carbon groups for transfer, and ATP is an activated form of phosphate. Luis Leloir, a biochemist in Argentina, showed in the 1950s that glycogen synthesis depended upon sugar nucleotides, which may be

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756 Chapter 23 ● Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway

						O
HOCH2	O					HN
H H		H	O	O
						O N
OH	H
		O	P O
HO				P O	CH2	O
H	OH		O–	O–	H	H
					H	H
					HO	OH

Uridine diphosphate glucose (UDPG)

FIGURE 23.17 ● The structure of UDP-glu- cose, a sugar nucleotide.

FIGURE 23.18 ● The UDP-glucose pyrophosphorylase reaction is a phosphoanhydride exchange, with a phosphoryl oxygen of glu- cose-1-P attacking the -phosphorus of UTP to form UDP-glucose and pyrophosphate.

thought of as activated forms of sugar units (Figure 23.17). For example, formation of an ester linkage between the C-1 hydroxyl group and the -phos- phate of UDP activates the glucose moiety of UDP-glucose.

UDP-Glucose Synthesis Is Driven by Pyrophosphate Hydrolysis

Sugar nucleotides are formed from sugar-1-phosphates and nucleoside triphosphates by specific pyrophosphorylase enzymes (Figure 23.18). For example, UDP-glucose pyrophosphorylase catalyzes the formation of UDP-glucose from glucose-1-phosphate and uridine 5 -triphosphate:

Glucose-1-P UTP 88n UDP-glucose pyrophosphate

						O
					HN
O	O		O		O	N
–O P	O P	O	P	OCH2	O
–O	–O		–O	H	H	H
				H
CH2OH				HO	OH
				UTP
HO	O	O
HO
	OH O		O–
		P
Glucose-1-P		O–
UDP-glucose			P P			2 P
pyrophosphorylase
						O
CH2OH						HN
HO	O	O		O
HO						O N
	OH O
		P	O	P OCH2		O
		–O		–O	H	H
				H		H
					HO	OH

UDP–glucose

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23.4 ● Glycogen Synth

The reaction proceeds via attack by a phosphate oxygen of glucose-1-phosphate on the -phosphorus of UTP, with departure of the pyrophosphate anion. The reaction is a reversible one, but—as is the case for many biosynthetic reactions —it is driven forward by subsequent hydrolysis of pyrophosphate:

Pyrophosphate H2O 88n 2 Pi

The net reaction for sugar nucleotide formation (combining the preceding two equations) is thus

Glucose-1-P UTP H2O 88n UDP-glucose 2 Pi

Sugar nucleotides of this type act as donors of sugar units in the biosynthesis of oligoand polysaccharides. In animals, UDP-glucose is the donor of glucose units for glycogen synthesis, but ADP-glucose is the glucose source for starch synthesis in plants.

Glycogen Synthase Catalyzes Formation of

-(1 n 4) Glycosidic Bonds in Glycogen

The very large glycogen polymer is built around a tiny protein core. The first glucose residue is covalently joined to the protein glycogenin via an acetal linkage to a tyrosine–OH group on the protein. Sugar units are added to the glycogen polymer by the action of glycogen synthase. The reaction involves transfer of a glucosyl unit from UDP-glucose to the C-4 hydroxyl group at a nonreducing end of a glycogen strand. The mechanism proceeds by cleavage of the COO bond between the glucose moiety and the -phosphate of UDP-glucose, leaving an oxonium ion intermediate, which is rapidly attacked by the C-4 hydroxyl oxygen of a terminal glucose unit on glycogen (Figure 23.19). The reaction is exergonic and has a G° of 13.3 kJ/mol.

									O
	CH2OH			O				HN
	HO				O	O
								O	N
	HO			OH O P O
						P O	CH2	O
					O–	O–	H		H
							H		H
Oxonium							OH		OH
							UDP-glucose
ion intermediate
						UDP
CH2OH	+
	.....
HO	O		CH2OH		O
	HO
HO
	OH		HO		CH2OH
					OH O	O
							CH2OH
					HO
						OH O			O
					Glycogen (n residues)		HO		OH O
CH2OH
HO	O
			CH2OH			H+
HO	OH O				O
		HO			CH2OH
					OH O	O
							CH2OH
					HO
						OH O			O
				Glycogen (n + 1 residues)			HO		OH O

FIGURE 23.19 ● The glycogen sy tion. Cleavage of the COO bond of cose yields an oxonium intermediat the hydroxyl oxygen of the termina a glycogen molecule completes the

FIGURE 23.20

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758 Chapter 23 ● Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway

(1 4)-terminal chains of glycogen

O

O

O

O

O

	O
O	O
	O

O

O

O O O

O

O

O

O

O

O

O

O

O

O

O

O

O

O O

O

O

O

O

O

O

O

O

O

O

Branching

O

O

O

enzyme

O

O

cuts here...

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

H

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

H

O

O

O

O

...and transfers

O

O

O

O

O

a seven residue

O

O

O

terminal segment

O

O

O

O

to a C(6)–OH

O

group

O

O

O

O

O

O

HO

O

O

O

● Formation of glycogen branches by the branching enzyme. Sixor seven-residue segments of a growing glycogen chain are transferred to the C-6 hydroxyl group of a glucose residue on the same or a nearby chain.

Glycogen Branching Occurs by Transfer of Terminal Chain Segments

Glycogen is a branched polymer of glucose units. The branches arise from-(1 n 6) linkages which occur every 8 to 12 residues. As noted in Chapter 7, the branches provide multiple sites for rapid degradation or elongation of the polymer and also increase its solubility. Glycogen branches are formed by amylo-(1,4 n 1,6)-transglycosylase, also known as branching enzyme. The reaction involves the transfer of a sixor seven-residue segment from the nonreducing end of a linear chain at least 11 residues in length to the C-6 hydroxyl of a glucose residue of the same chain or another chain (Figure 23.20). For each branching reaction, the resulting polymer has gained a new terminus at which growth can occur.

23.5 ● Control of Glycogen Metabolism

Glycogen Metabolism Is Highly Regulated

Synthesis and degradation of glycogen must be carefully controlled so that this important energy reservoir can properly serve the metabolic needs of the organism. Glucose is the principal metabolic fuel for the brain, and the concentration of glucose in circulating blood must be maintained at about 5 mM for this purpose. Glucose derived from glycogen breakdown is also a primary energy source for muscle contraction. Control of glycogen metabolism is effected via reciprocal regulation of glycogen phosphorylase and glycogen synthase. Thus, activation of glycogen phosphorylase is tightly linked to inhibition of glycogen synthase, and vice versa. Regulation involves both allosteric control and covalent modification, with the latter being under hormonal control. The regulation of glycogen phosphorylase is discussed in detail in Chapter 15.

Regulation of Glycogen Synthase by Covalent Modification

Glycogen synthase also exists in two distinct forms which can be interconverted by the action of specific enzymes: active, dephosphorylated glycogen synthase I (glucose-6-P-independent) and less active phosphorylated glycogen synthase D (glucose-6-P-dependent). The nature of phosphorylation is more complex with glycogen synthase. As many as nine serine residues on the enzyme appear to be subject to phosphorylation, each site’s phosphorylation having some effect on enzyme activity.

Dephosphorylation of both glycogen phosphorylase and glycogen synthase is carried out by phosphoprotein phosphatase 1. The action of phosphoprotein phosphatase 1 inactivates glycogen phosphorylase and activates glycogen synthase.

Hormones Regulate Glycogen Synthesis and Degradation

Storage and utilization of tissue glycogen, maintenance of blood glucose concentration, and other aspects of carbohydrate metabolism are meticulously regulated by hormones, including insulin, glucagon, epinephrine, and the glucocorticoids.

Insulin Is a Response to Increased Blood Glucose

The primary hormone responsible for conversion of glucose to glycogen is insulin (Figure 6.36). Insulin is secreted by special cells in the pancreas called the islets of Langerhans. Secretion of insulin is a response to increased glucose in the

(a and c adapted from Rhodes and Pflanzer, 1992. Human Physiology.

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23.5 ● Control of Glycogen Metabol

A D E E P E R L O O K

Carbohydrate Utilization in Exercise

Animals have a remarkable ability to “shift gears” metabolically during periods of strenuous exercise or activity. Metabolic adaptations allow the body to draw on different sources of energy (all of which produce ATP) for different types of activity. During periods of short-term, high-intensity exercise (e.g., a 100-m dash), most of the required energy is supplied directly by existing stores of ATP and creatine phosphate (Figure, part a). Long-term, lowintensity exercise (a 10-km run or a 42.2-km marathon) is fueled almost entirely by aerobic metabolism. Between these extremes is a variety of activities (an 800-m run, for example) that rely on anaerobic glycolysis—conversion of glucose to lactate in the muscles and utilization of the Cori cycle.

For all these activities, breakdown of muscle glycogen provides much of the needed glucose. The rate of glycogen con-

sumption depends upon the intensity of the exercise ( b). By contrast, glucose derived from gluconeogenesis small contributions to total glucose consumed duri During prolonged mild exercise, gluconeogenesis a only about 8% of the total glucose consumed. During cise, this percentage becomes even lower.

Choice of diet has a dramatic effect on glycogen lowing exhaustive exercise. A diet consisting mainl and fat results in very little recovery of muscle gly after 5 days (Figure, part c). On the other hand, a hi drate diet provides faster restoration of muscle glyco this case, however, complete recovery of glycogen about 2 days.

	(a)
	100	from phosphocreatine
energy	75
		from ATP			Aerobic
				metabolism
total	50
				Anaerobic
of				metabolism
%	25
	0
	0	30	60	90	120
		Duration of work (sec)

(b)

100

Light exercise

content	75			Moderate
				exercise
% glycogen	50
	25	Heavy
		exercise
	0
	0	30	60	90	120
		Exercise time (min)

		(c)
		24	2 hours of exercise
Muscle glycogen content	(grams/kg of muscle)	20
		16		High-carbohydrate diet
		12
		8	No food		Fat & protein diet
		4
		0
		0	10	20	30	40	50	5 days
			Hours of recovery

(a) Contributions of the various energy sources to muscle activity during mild exercise. (b) Consumption of glycogen stores in fast-twitch muscles during light, moderate, and heavy exercise. (c) Rate of glycogen replenishment following exhaustive exercise.

Philadelphia: Saunders College Publishing; b adapted from Horton and Terjung, 1988. Exercise, Nutrition and Energy Metabolism. New York: Macmillan.)

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760 Chapter 23 ● Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway

Liver

Spleen

Splenic vein

Portal vein

Pancreas

Pancreatic veins

blood. When blood glucose levels rise (after a meal, for example), insulin is secreted from the pancreas into the pancreatic vein, which empties into the portal vein system (Figure 23.21), so that insulin traverses the liver before it enters the systemic blood supply. Insulin acts to rapidly lower blood glucose concentration in several ways. Insulin stimulates glycogen synthesis and inhibits glycogen breakdown in liver and muscle.

Several other physiological effects of insulin also serve to lower blood and tissue glucose levels (Figure 23.22). Insulin stimulates the active transport of glucose (and amino acids) across the plasma membranes of muscle and adipose tissue. Insulin also increases cellular utilization of glucose by inducing the synthesis of several important glycolytic enzymes, namely, glucokinase, phosphofructokinase, and pyruvate kinase. In addition, insulin acts to inhibit several enzymes of gluconeogenesis. These various actions enable the organism to respond quickly to increases in blood glucose levels.

FIGURE 23.21 ● The portal vein system carries pancreatic secretions such as insulin and glucagon to the liver and then into the rest of the circulatory system.

Glucagon and Epinephrine Stimulate Glycogen Breakdown

Catabolism of tissue glycogen is triggered by the actions of the hormones epinephrine and glucagon (Figure 23.23). In response to decreased blood glucose, glucagon is released from the cells in pancreatic islets of Langerhans. This peptide hormone travels through the blood to specific receptors on liver cell membranes. (Glucagon is active in liver and adipose tissue, but not in other tissues.) Similarly, signals from the central nervous system cause release of epinephrine (Figure 23.24)—also known as adrenaline—from the adrenal glands into the bloodstream. Epinephrine acts on liver and muscles. When either hormone binds to its receptor on the outside surface of the cell membrane, a cascade is initiated that activates glycogen phosphorylase and inhibits glycogen synthase. The result of these actions is tightly coordinated stimulation of glycogen breakdown and inhibition of glycogen synthesis.

Insulin

Insulin receptor

Active transport	+	Protein phosphorylation	Gluconeogenesis
		and second messenger
		modulation
Glycolysis	+		+ Protein synthesis
	+	+
Glycogen		Lipid	Lipid
synthesis		synthesis	breakdown

FIGURE 23.22 ● The metabolic effects of insulin. As described in Chapter 34, binding of insulin to membrane receptors stimulates the protein kinase activity of the receptor. Subsequent phosphorylation of target proteins modulates the effects indicated.