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Articles in PresS. Am J Physiol Endocrinol Metab (February 14, 2006). doi:10.1152/ajpendo.00652.

2005

Glycogen Branches Out: New Perspectives on the Role of Glycogen


Metabolism in the Integration of Metabolic Pathways

Cynthia C. Greenberg, Michael J. Jurczak, Arpad M. Danos


and Matthew J. Brady*

From the Department of Medicine, Committee on Molecular Metabolism and


Nutrition, the University of Chicago, Chicago, Illinois

*Corresponding author. Mailing address: MC1027, 5841 S. Maryland Ave, Chicago, IL 60637
Phone: (773) 702-2346
Fax: (773) 834-0486
E-mail: mbrady@medicine.bsd.uchicago.edu

Copyright 2006 by the American Physiological Society.


ABSTRACT

Glycogen is the storage form of carbohydrate for virtually every organism from yeast to
primates. Most mammalian tissues store glucose as glycogen with the major depots located in
muscle and liver. The French physiologist Claude Bernard first identified a starch-like substance
in liver and muscle and coined the term glycogen, or sugar former, in the 1850s. During the
150 years since its identification, researchers in the field of glycogen metabolism have made
numerous discoveries that are now recognized as significant milestones in biochemistry and cell
signaling. Even so, more questions remain, and studies continue to demonstrate the complexity
of the regulation of glycogen metabolism. Under classical definitions, the functions of glycogen
seem clear: muscle glycogen is degraded to generate ATP during increased energy demand,
whereas hepatic glycogen is broken down for release of glucose to the bloodstream to supply
other tissues. However, recent findings demonstrate that the roles of glycogen metabolism in
energy sensing, integration of metabolic pathways, and coordination of cellular responses to
hormonal stimuli are far more complex.

INTRODUCTION
Glycogen Structure and Key Enzymes of Its Metabolism
Glycogen synthesis follows a simple but strictly ordered process, resulting in a complex
structure (37, 54). The initiation of glycogen synthesis is provided by self-glucosylation of
glycogenin (55). To this oligosaccharide primer, glycogen synthase utilizes UDP-glucose to add
glucose molecules by 1-4 linkages, which is the rate-controlling step of glycogen synthesis.
Glycogen synthase activity is controlled by covalent modification, allosteric activation, and
enzymatic translocation. The enzyme is phosphorylated on up to nine residues, resulting in its
progressive inactivation and decreased sensitivity to allosteric activators (31). Binding of
glucose-6-phosphate (G6P) to glycogen synthase causes unfolding of the enzyme, resulting in
allosteric activation that overrides inhibition by phosphorylation. In addition, G6P binding
promotes conformational changes that favor dephosphorylation of the enzyme. Translocation of
glycogen synthase to glycogen particles in response to stimuli such as insulin represents a third
mechanism by which enzymatic activity is regulated (13, 42, 49). When the elongating glycogen
chain consists of at least 11 residues, branching enzyme transfers a chain of seven molecules to
another chain by an 1-6 bond. Thus, glycogen synthase elongates the glycogen chain, and

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branching enzyme produces new branches, creating a molecule with a helical structure of 12
concentric tiers (37).
For glycogen degradation, the synchronous activities of glycogen phosphorylase and
debranching enzyme are required. Glycogen phosphorylase, which catalyzes the rate-limiting
step of glycogenolysis, cleaves 1-4 linkages to remove glucose molecules from the glycogen
chain. When four glucose units remain before a branch point, the transferase activity of
debranching enzyme catalyzes the transfer of three glucose residues to an adjacent branch of the
glycogen chain. Through a second enzymatic glucosidase component located in the same
protein, debranching enzyme next cleaves the 1-6 bond to release the glucose moiety from the
branch point. Glycogen phosphorylase is then able to continue removal of glucose residues from
the glycogen chain (37).
Glycogen phosphorylase is regulated by phosphorylation of a single serine residue at the
N-terminus and by allosteric binding of a number of molecules including AMP, ATP, G6P,
glucose, and caffeine (25). The enzyme exists as a dimer with each subunit linked by the
essential cofactor pyridoxal phosphate, which provides the phosphate as an electron donor for
release of glucose-1-phosphate. The covalent modification of glycogen phosphorylase in
response to changes in intracellular cAMP and calcium levels is mediated by the activation of
phosphorylase kinase, the sole enzyme that phosphorylates and activates glycogen phosphorylase
(5). Thus, both glycogen synthase and phosphorylase are regulated by multiple mechanisms that
enable glycogen metabolism to be acutely responsive to the varying metabolic demands in both
liver and skeletal muscle cells.

SKELETAL MUSCLE GLYCOGEN


During rest, storage of glucose as glycogen is enhanced by insulin stimulation of glucose uptake
in muscle, which is mediated by the translocation of GLUT4 transporters to the plasma
membrane (62). Entering glucose is phosphorylated to G6P by hexokinase II, and may enter
glycolysis to produce ATP or be converted by phosphoglucomutase to glucose-1-phosphate,
which is further metabolized for glycogen synthesis. Additionally, insulin induces the
dephosphorylation of glycogen synthase via inhibition of upstream kinases and activation of
phosphatases (4). Thus, insulin synergistically stimulates glycogen synthesis in muscle by

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coordinately increasing intracellular concentrations of G6P and by dephosphorylation and
activation of glycogen synthase.
In humans, skeletal muscle is the primary site for glucose disposal, where up to 90% of
an oral glucose load is converted to glycogen (26). Skeletal muscle fibers differ in the amount of
glycogen they store, and are classified as Type I (fast switch) or Type II (slow twitch), based on
their contractile speed and metabolic properties. Type I fibers are responsible for slow speed
contractions and utilize oxidative pathways for ATP production, while Type II fibers are capable
of rapid contractions and rely primarily on glycolytic pathways for energy production. Type II
fibers are further classified as Type IIa and Type IIb, where IIa fibers make use of both oxidative
and glycolytic pathways for energy production, while IIb rely primarily on glycolysis. Thus
type I fibers rely more on FFA oxidation during contraction, while type II fibers are more
dependent on glucose uptake and glycolysis.
Muscle glycogen metabolism can be viewed simply as the major site of insulin-
stimulated glucose storage during times of energetic abundance, while conversely, glycogen is
broken down to provide ATP to the working muscle during exercise. However, recent work in
transgenic animals has challenged the notion that muscle glycogen levels are essential for
exercise, as modulation of muscle glycogen stores did not impact on exercise performance (45,
46). Further, since glycogen stores are finite, their depletion results in the switching of energy
utilization to extracellular glucose and FFA as exercise continues (21). A number of factors may
influence when and to what extent glycogen and other fuels are utilized to maintain ATP
homeostasis, including the intensity of the exercise, the dietary supply of carbohydrate or lipid,
and training status of the individual (21). In this section, we consider energy utilization in
muscle before, during and after a single bout of exercise in order to demonstrate that glycogen
metabolism is a key regulator that integrates multiple energetic pathways.

Glycogen Metabolism During Exercise


Immediate Fuel Utilization
At the beginning of a bout of exercise, contraction of skeletal muscle results in the
hydrolysis of ATP and a transient rise in ADP and Pi levels. Creatine phosphate/creatine kinase
acts as a cellular buffer for ATP levels by providing a source of Pi that can be added to ADP to
form ATP by creatine kinase. However, this system is quickly overwhelmed during sustained

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exercise, and increasing ADP levels stimulate the activity of adenylate kinase, which catalyzes
the conversion of two ADP molecules to one ATP and one AMP molecule. As the ATP from
this pathway is rapidly consumed, the AMP:ATP ratio rises, initiating a number of metabolic
events geared towards maintaining energy required for contraction.

Regulation of Glycolysis by Glycogen Levels


As the above immediate energy sources are depleted, the muscle cell must then rely on
the glycolytic pathway to provide ATP for continued contraction. Glycolysis is initially
activated by the increases in AMP and Pi, which stimulate the rate-limiting enzyme in glycolysis,
phosphofructokinase. Glycolysis is stimulated as well by an increase in provision of G6P to this
pathway, which occurs at the onset of exercise initially due to augmented rates of
glycogenolysis, and as exercise continues, through an increase in glucose uptake via the
contraction-induced, insulin-independent translocation of GLUT4 vesicles to the plasma
membrane (24). The metabolism of G6P by the glycolytic pathway results in the generation of
fructose-2,6-bisphosphate, which is a potent allosteric activator of phosphofructokinase, and thus
a key metabolic regulator of glycolytic rates and ATP production (53).
A variety of stimuli are integrated in the regulation of glycogen phosphorylase activity,
allowing glycogen breakdown to change in parallel with the energy demands of the exercising
muscle. The onset of contraction results in the release of calcium stores from the sarcoplasmic
reticulum, causing the activation of phosphorylase kinase and subsequent phosphorylation and
activation of glycogen phosphorylase. The majority of glycogen phosphorylase and
phosphorylase kinase in the cell is found at the sarcoplasmic reticulum bound to glycogen (32,
38, 63), allowing for the coupling of contraction, calcium release, and glycogen breakdown.
Glycogen phosphorylase is also allosterically activated by increased [Pi] within the cell, which
rises as ATP levels fall reflecting an energy deficit. As activity continues, glycogen
phosphorylase may also be activated in response to increased extracellular epinephrine levels,
which result in activation of PKA that in turn phosphorylates and activates phosphorylase kinase.
Tight metabolic coupling exists between glycogen mobilization and ATP production via
glycolysis. In fact, studies indicate that the G6P arising from muscle glycogen breakdown is
more efficiently coupled to glycolysis than that arising from GLUT4 and hexokinase,
particularly during high intensity exercise when 80% of the glucose consumed by glycolysis

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arises from glycogenolysis (56). Additionally, at moderate intensity exercise, the rate of
glycogenolysis greatly exceeded the rate of glucose transport, suggesting a greater contribution
of glycogen breakdown to maintenance of ATP levels. Thus, at the onset of exercise, the
provision of G6P to the glycolytic pathway from glycogen breakdown would inhibit extracellular
glucose transport by both allosteric inhibition of hexokinase II and via diminishment of the
glucose concentration gradient across the plasma membrane.

Glucose Transport during Exercise


Due to the finite nature of glycogen stores, as contraction continues, glycogen
phosphorylase activity decreases to prevent complete depletion of cellular glycogen levels (7).
The release of glycogen phosphorylase from glycogen partially accounts for the observed
reversal in glycogenolysis (21). As glycogen breakdown diminishes during continued
contraction, the unfavorable conditions for extracellular glucose uptake and utilization are
dissipated. Glucose transport into the muscle is increased, correlated acutely with enhanced
GLUT4 translocation to the plasma membrane (24, 52), and in trained individuals, upregulation
of GLUT4 mRNA and protein levels (20, 30). Several studies indicate that muscular glycogen
content prior to exercise also affects the regulation of glucose transport (2, 12), although others
report no effect (1, 18). The differential effects on glucose uptake seen in these studies could be
due to differences in the exercise intensity of the protocols. In the studies where moderate
intensity exercise without fatigue is used, the observed increases in fat oxidation may
compensate for the reduction in muscle glycogenolysis in the low starting glycogen groups, such
that glucose transport into the muscle was not elevated. However, at higher intensities when
glycogen stores are significantly depleted and lipid metabolism becomes limiting, an increase in
glucose uptake would become necessary to fuel continued muscular contraction.

Regulation of Fuel Partitioning by Glycogen Metabolism


In addition to increasing glucose transport as glycogen stores become depleted, skeletal
muscle can also oxidize FFA to produce ATP in order to preserve glycogen levels. Support for
the role of glycogen levels in regulating the switch in fuel utilization by muscle during exercise
comes from studies where glycogen content was manipulated prior to exercise (1, 2, 9, 18, 65).
In each of these studies, increased muscle glycogen storage prior to exercise led to increased

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carbohydrate oxidation during exercise compared to controls. Conversely, decreasing muscle
glycogen stores prior to exercise decreased carbohydrate oxidation and increased lipid oxidation.
Studies also found that subjects with low glycogen prior to exercise displayed increased
norepinephrine and FFA levels during exercise (65). These findings are similar to observations
made in McArdles patients, who lack functional muscle glycogen phosphorylase and cannot
breakdown glycogen stores (33). Substantial evidence suggests that the inability to mobilize
muscle glycogen in McArdles patients can be directly communicated to the central nervous
system, in turn promoting lipid utilization (64, 65). Further evidence supporting a role for
glycogen in the regulation of substrate utilization during exercise comes from a recently
described transgenic mouse model, which lacks the muscle isoform of glycogen synthase and
thus muscle glycogen stores (44). The authors observed no change in exercise capacity vs. wild
type animals (46), but there was an increase in type I fiber content in the gastrocnemius muscle,
indicative of a compensatory enhancement in lipid oxidative capacity. So although the exercise
capacity of the transgenic mice was unaffected by the loss of muscle glycogen stores, the
adaptive differentiation of oxidative type I fibers indicate that physiologically muscle glycogen
stores serve as an important energy source during exercise.
Cumulatively, these observations reveal that the metabolic changes resulting from
glycogen depletion during exercise promotes the utilization of FFA for ATP generation. Further,
repeated or sustained loss of skeletal muscle glycogen, through exercise training or in transgenic
animals, results in adaptive responses at the levels of gene transcription and muscle fiber type
differentiation, to increase lipid oxidative capacity. These adaptive changes in substrate
utilization are geared towards the preservation of finite muscle glycogen stores (47).

Role of AMPK in Fuel Utilization


Recent work has suggested that the enzyme AMP-activated protein kinase (AMPK) may
be the molecular link between alterations in glycogen levels and the timing of the shift from
carbohydrate to lipid metabolism during exercise (66). AMPK is a key regulator of cellular
energy metabolism due to its activation by increases in the AMP:ATP ratio (17), and its effects
on increasing energy production and inhibition of energy storage, particularly as glycogen.
AMPK regulates numerous cellular processes, including increased oxidation of lipids, enhanced
glucose transport and several of the long term adaptations associated with exercise, such as

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upregulation of GLUT4 expression and increased mitochondrial content (6, 67). AMPK
inactivates glycogen synthase (68), inhibiting glycogen synthesis in an effort to shunt glucose
delivery from storage to glycolysis.
Several lines of evidence suggest that changes in intracellular glycogen stores may
regulate AMPK activation. First, an inverse relationship between high glycogen levels and
AMPK activity is logical and has been observed in rat and human skeletal muscle (11, 68, 69).
Conversely, low muscular glycogen levels at the onset of exercise enhanced AMPK activation
when compared to high muscle glycogen controls (11, 68, 69). Finally, the loss of glycogen
stores in the muscle glycogen synthase knockout mouse model correlated with a robust increase
in AMPK phosphorylation state (44). AMPK has been shown to directly bind glycogen (48), but
since glycogen addition did not affect AMPK activity in vitro (48), the significance of this
interaction may be at the level of subcellular localization of the kinase rather than a direct
modulation of enzymatic activity. Thus, during sustained exercise, as glycogen stores are
exhausted, activation of AMPK enables muscle fibers to switch over to energy utilization from
extracellular glucose (via increased GLUT4 translocation) and FFA oxidation (via inhibition of
acetyl-CoA carboxylase, the rate limiting enzyme for FA synthesis).

Glycogen Metabolism During Recovery


Regulation of Cellular Responses to Hormonal Input
Following a strenuous bout of exercise, skeletal muscle is geared towards increased
energy uptake and metabolism to produce ATP, and subsequently, repletion of glycogen stores.
Two of the hallmark features of recovery from glycogen-depleting exercise are the increased
response and sensitivity to insulin, resulting in enhanced GLUT4 translocation and glucose
uptake (29), and activation of glycogen synthase following refeeding. In exercised rats, glucose
uptake was significantly greater in muscle with low glycogen compared to high glycogen muscle
when perfused at the same insulin concentration (12). Furthermore, the authors found that the
rate of glycogen synthesis limited the rate of glucose transport, as opposed to the availability of
intracellular substrate, indicating that transport itself was not limiting.
The elevation in glycogen synthase activity after glycogen depletion may be regulated at
the level of protein translocation. As is the case with glycogen phosphorylase, glycogen
synthase binds directly to glycogen (38), yet basal and insulin-stimulated glycogen synthase

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activity is negatively correlated to glycogen levels (3, 10, 42). Using a subcellular fractionation
technique, Nielsen et al. demonstrated that in glycogen-replete muscle from rat, glycogen
synthase is primarily located in a glycogen-rich membrane fraction whereas in glycogen-
depleted muscle, glycogen synthase is found in a cytoskeleton fraction. Furthermore, enzymatic
activity was enhanced to a greater extent in the low glycogen versus high glycogen rats in
response to both insulin and muscle contraction, suggesting that glycogen stores dictated the
subcellular localization of glycogen synthase, which in turn correlated with alterations in
modulation of glycogen synthase activity (42). In a recent study, Prats et al. demonstrated the
redistribution of glycogen synthase in a phosphorylation-dependent manner to an intracellular
compartment where glycogen resynthesis occurred following depletion of glycogen stores (49).
However, the enzymatic mechanisms underlying alterations in glycogen synthase subcellular
distribution and degree of enzymatic activation remain poorly understood.

Glycogen Supercompensation
The phenomenon of glycogen supercompensation provides further evidence for the role
of glycogen levels in dictating muscle energy metabolism and hormonal sensitivity. Glycogen
supercompensation occurs following exercise and carbohydrate refeeding, when muscle
glycogen stores are replenished to levels above the normal fed store. Glycogen
supercompensation results in transient insulin resistance that is corrected upon return of cellular
glycogen levels to their physiological set point. Studies showed that both insulin-stimulated and
contraction-induced translocation of GLUT4 to the plasma membrane were reduced in glycogen
supercompensated muscle of rats, resulting in decreased glucose uptake (28). Furthermore, the
reduction masked the adaptive increases in GLUT4 expression resulting from exercise training
(22, 27, 28).
Conversely, Garcia-Roves and colleagues examined the effects of preventing glycogen
repletion on the post-exercise GLUT4 increase (15). Rats were subjected to bouts of swimming
exercise, then either fasted or fed normal or carbohydrate-free chow. In rats fed normal chow
following exercise, elevated GLUT4 levels and insulin sensitivity returned to baseline levels
within 42 hours post-exercise, after glycogen levels were restored. In contrast, in the rats fed
carbohydrate-free food to prevent glycogen restoration, the increases in GLUT4 expression and
insulin sensitivity were retained for at least 66 hours. At this point, when fed carbohydrate-

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containing chow, the rats accumulated glycogen to a similar extent as rats fed normal chow
immediately following exercise. In parallel, GLUT4 protein levels returned to baseline
concentrations (15). Thus, these data show that the adaptations to increase glucose transport
after exercise will persist until glycogen levels are restored, underscoring the importance of
glycogen stores in the physiological responses of skeletal muscle. However, the molecular
mechanisms by which alteration of glycogen levels, and presumably modulation of metabolic
fluxes into and out of glycogen stores, are translated into adaptive changes in muscle gene
expression are not currently understood.

LIVER GLYCOGEN
Overview
Although the majority of postprandial plasma glucose is stored in skeletal muscle, hepatic
glycogen makes up 10% of total liver weight when fully replete, reflecting the importance of
glycogen metabolism in liver function. When plasma glucose levels rise after a meal, the liver
clears glucose and stores it as glycogen. Conversely when blood glucose concentrations fall
during fasting or exercise, hepatic glycolytic rates drop due to decreased levels of the key
glycolytic regulator fructose-2,6-biphosphatase. The liver produces glucose in response to an
increase in the circulating glucagon:insulin ratio via mobilization of hepatic glycogen stores, and
increased expression of key gluconeogenic enzymes resulting in de novo synthesis of glucose
from 3-carbon precursors. Thus, hepatic glycogen metabolism plays a central role in
maintaining circulating blood glucose levels around the physiological set point of 5 mM.
The differential functions for liver vs. muscle glycogen metabolism are highlighted by
the tissue-specific enzymatic isoforms regulating glucose and glycogen metabolism. Muscle and
liver express different isoforms of glycogen synthase and phosphorylase. Although their
regulation by covalent modification is similar, each enzyme is differentially sensitive to
allosteric regulators, reflecting the metabolic demands of liver and muscle. Additionally, the
major glucose transporter in liver is GLUT2, which unlike GLUT4, is constitutively localized in
the plasma membrane and possesses a relatively low affinity for glucose. Hepatocytes also
express a specialized hexokinase, termed glucokinase, which is not subject to feedback inhibition
by G6P. Similar to their function in the pancreatic -cell, the kinetic properties of GLUT2 and
glucokinase together act as a glucose sensor in which glucose uptake fluctuates in synchrony

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with changes in plasma glucose concentrations, enabling the regulated uptake and production of
glucose as needed.

Hepatic Glycogen Metabolism in the Fasted State


Two Models of Hepatic Glucose Output
The liver provides glucose to the bloodstream during times of fast or increased energy
demand through gluconeogenesis and the mobilization of intracellular glycogen stores. These
pathways have been considered separate entities, each providing glucose-6-phosphate that is
dephosphorylated and secreted from hepatocytes (Fig. 1A). However, recent work in several
areas has suggested that gluconeogenesis and glycogen metabolism comprise a single
interconnected metabolic circuit rather than two discrete arms (Fig. 1B). These results suggest
that as in muscle, hepatic glycogen metabolism occupies a key role in the coordination of cellular
responses with nutrient status under a variety of physiological conditions.
Evidence for the interrelation of gluconeogenesis and glycogenolysis came from studies
where human volunteers were infused with gluconeogenic precursors under insulin and glucagon
clamps. It was hypothesized that an increased supply of gluconeogenic precursors would result
in enhanced hepatic glucose output. Instead, researchers found that hepatic glucose production
and plasma glucose concentrations were not significantly altered, suggesting that glycogen
breakdown was downregulated when gluconeogenic precursor supply was increased (23).
Similarly, inhibition of gluconeogenesis did not correct hyperglycemia in Type 2 diabetic
patients, again because glycogen breakdown was increased to maintain hepatic glucose output
(50). The results of these studies suggested the hypothesis of hepatic interregulation, in which
modulation of one arm of glucose production would be compensated for by changes in the other,
thus maintaining hepatic glucose output at the same level. However, in 1998, Martin et al.
demonstrated that glycogenolysis could be reduced in vivo in a mouse model of diabetes by
administration of a glycogen phosphorylase inhibitor, CP-91149 (34). Unlike studies in which
gluconeogenesis was inhibited, reduction of glycogenolysis resulted in decreased hepatic glucose
output and improvement of hyperglycemia (34). Fosgerau and colleagues reported similar
results using another glycogen phosphorylase inhibitor, DAB, in a canine model (14). These
studies demonstrated that changes in gluconeogenesis may result in alterations in glycogenolysis,
but that the converse does not occur.

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Under the classical model (Fig. 1A) where gluconeogenesis and glycogenolysis are
considered two separate entities, the mechanism for interregulation is unclear. The view of two
discrete pathways also makes it difficult to hypothesize why alterations of gluconeogenesis affect
glycogenolysis but not the converse. Instead, the results of these studies suggest a model in
which gluconeogenesis and glycogen metabolism are a continuous pathway (Fig. 1B). In this
model, gluconeogenic precursors are metabolized to G6P, which would then be used for
glycogen synthesis. Glycogenolysis would proceed, and the pool of G6P arising from glycogen
breakdown would be dephosphorylated and extruded to the bloodstream. This model helps
predict multiple layers of regulation and explains how inhibition of glycogen phosphorylase
would result in reduction of hepatic glucose production and plasma glucose levels.

Hepatic Glycogen Metabolism in the Fed State


Glucose and Gluconeogenic Precursor Disposal in the Liver
Further evidence in support of a continuous pathway for gluconeogenesis and glycogen
metabolism comes from studies of nutrient disposal in the fed state. Glycogen may be
synthesized from extracellular glucose (direct pathway) or from glucose derived from
gluconeogenic substrates (indirect pathway). Although studies dating back to the 1930s showed
that administration of labeled glucose through a single bolus resulted in the majority of hepatic
glycogen synthesized via the direct pathway, a growing body of evidence in the 1970s indicated
that G6P from glucose was inefficiently used as the immediate precursor of liver glycogen. This
apparent inconsistency was termed the glucose paradox (reviewed in (36).
To address the different outcomes of these studies, Newgard and colleagues compared
results from different experimental designs and evaluated which more closely approximated
physiological conditions. In the older experiments, administration of the large intragastric bolus
resulted in a nonphysiological hyperglycemia that presumably allowed glucose to enter the
hepatocyte via GLUT2 and glucokinase at higher than normal rates. In the later studies, labeled
glucose was infused intragastrically at a constant rate to achieve circulating glucose levels
similar to rats refed following a fast. Under these conditions, less than a third of liver glycogen
was synthesized via the direct pathway (41). Additional evidence came from studies in humans
by Shulman and colleagues, which indicated that gluconeogenic compounds are the major
carbon source for hepatic glycogen (8, 58, 60). Finally, ODoherty et al. demonstrated that

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hepatic glycogen synthesis was increased in rats overexpressing PTG, a glycogen-targeting
subunit of protein phosphatase-1. Although glucose incorporation into glycogen (direct
pathway) was increased, the major mechanism for enhancement of glycogen synthesis was
through increased incorporation of gluconeogenic precursors into glycogen (indirect pathway)
(43).
It is now accepted that the major source of glucose for hepatic glycogen stores is derived
from 3-carbon compounds such as lactate, glycerol, and alanine and other gluconeogenic amino
acids rather than directly from extracellular glucose. The synthesis of these compounds into
glycogen comprises a system where gluconeogenesis and glycogen metabolism form a highly
interconnected pathway, even in the fed state (Fig. 1B). Although these data represent a fairly
recent paradigm shift, studies dating from the 1940s demonstrated that labeled carbon from
gluconeogenic compounds could be tracked to glycogen (61, 70). To confirm these initial
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observations, the laboratory of Radziuk administered C- and 3H-glucose tracers orally or
intravenously to human subjects in order to quantitate glycogen synthesis from glucose versus
gluconeogenic precursors. Data demonstrated 150% more deposition of labeled carbon from
gluconeogenic precursors over that from glucose (51). Studies also suggest that in addition to
providing substrate for glycogen synthesis, gluconeogenic compounds help regulate glycogen
metabolism (reviewed in (71). For example, several groups demonstrated that incubation of
isolated hepatocytes with gluconeogenic amino acids resulted in increased activation of glycogen
synthase (39, 40). Studies demonstrating feed-forward regulation of gluconeogenic compounds
on glycogen synthesis provide additional evidence for the proposed model of a continuous
metabolic pathway.

Glycogen Cycling as a Key Regulator of Hepatic Function


Under the proposed model, the funneling of gluconeogenic precursors and glucose
through glycogen appears to generate a futile cycle, in which glycogen synthesis and breakdown
occur simultaneously. However, numerous studies demonstrate that glycogen cycling is a
sensitively regulated circuit that allows the hepatocyte to be highly responsive to multiple
stimuli. In a study of humans fasted for 60 hours, as expected hepatic glycogen levels were low,
and gluconeogenesis accounted for the vast majority of hepatic glucose output (19). Subjects
were then infused for 10 hours with 13C-glycerol, followed by a pulse of glucagon, and glycogen

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stores allowed to recover. 78% of the post-glucagon glycogen was derived from the
gluconeogenic precursor (19). These data indicate that glucose cycles through glycogen even
when cellular stores are extremely low, which may prevent the complete depletion of cellular
glycogen stores during prolonged fast.
Pharmacological inhibitors of glycogen phosphorylase have provided another critical tool
to study the contribution of aberrant hepatic glucose output to hyperglycemia in diabetic patients,
but also glucose cycling through glycogen (34). In primary hepatocytes from fasted rat, no net
glycogen synthesis was detectable (35). However, both glycogen synthase and phosphorylase
were in an activated state, and addition of a phosphorylase inhibitor promoted glycogen
synthesis. Additionally, in a study of fasted dogs, addition of phosphorylase inhibitor resulted in
accumulation of glucose derived from gluconeogenic precursors into glycogen (57). These
studies provided further support to the notion that newly synthesized glucose cycles through
glycogen routinely in the fasted state. Finally, treatment of primary hepatocytes with a
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phosphorylase inhibitor blocked conversion of C-lactate to C-glucose by over 50% and
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resulted in a 3-fold increase in C-lactate incorporation into glycogen (34). This unexpected
result suggests that not only does glucose derived from gluconeogenesis cycle through glycogen,
this step may be required for efficient dephosphorylation and secretion of newly synthesized
glucose into the bloodstream (Fig. 1B).
Glucose cycling through glycogen also occurs in the fed state. Using perfused rat livers
under conditions favoring glycogen synthesis, tissues were pulsed with 13C-labeled glucose and
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chased with C-glucose or C-glucose as a control (59). In the continued presence of C-
glucose, there was an increase in NMR peak height in glycogen over time. However, during a
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C-glucose chase perfusion, there was a rapid decline in 13C-label content in glycogen, implying
continual turnover in liver glycogen even under conditions favoring glycogen accumulation,
since the 13C-label was briskly being lost from glycogen during a chase with 12C-glucose (59).
These data also indicate a role for glycogen turnover to prevent over-accumulation of hepatic
glycogen stores, which may be physiologically important due to expression of GLUT2 and GK
isoforms resulting in a continual flux of G6P into hepatocytes during prolonged hyperglycemia.
Finally, several studies have provided evidence that under certain experimental
conditions, glucose cycling through glycogen is negligible. In cells that had high glycogen stores
and then were treated with a high ratio of glucagon/insulin, glycogen turnover was undetectable

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due to low synthetic rates (16). Additionally, in glycogen-depleted cells that were then
stimulated with high glucose and insulin, glycogen degradation was markedly suppressed,
enabling maximal rates of glycogen repletion (14). These results indicate that glucose cycling
through glycogen is not constitutive, but adapts to the metabolic requirements of hepatocytes.

A Model to Predict Glucose Flux through Glycogen


The work on the interplay between hepatic glucose output, gluconeogenesis and glycogen
metabolism leads us to propose the model in Fig. 2, where rates of glucose cycling through
glycogen are dependent on intracellular glycogen stores and extracellular signals. Three to four
hours after a meal, as blood glucose levels start to fall, insulin secretion drops, leading to a
decrease in the insulin/glucagon ratio and an increase in [cAMP]c (Fig. 2, x-axis, left side). An
initial burst of glycogen mobilization occurs to provide glucose for release into the bloodstream
(Fig. 2, upper left), and glucose cycling would be low due to high glycogen stores and low
hepatic glucose production. As glycogen stores fall, the gluconeogenic component of hepatic
glucose output would increase (Fig. 2, bottom left) as lactate and pyruvate are synthesized into
G6P. Glucose cycling through glycogen would commence, in part to preserve glycogen stores.
Potentially, the linkage of these pathways into one circuit would also provide a metabolic
mechanism for the liver to keep track of total glucose production, and enable the liver to balance
energy demand by the body with its capacity to provide glucose from gluconeogenesis and
glycogenolysis. When the fast is broken by a meal, insulin and glucose levels would rise, and
[cAMP]c would fall (Fig. 2, x-axis, right side), and glucose storage as glycogen would be
favored. Initially, resynthesis of glycogen chains would be strongly favored, preventing glucose
cycling (Fig. 2, lower right). However, as glycogen levels grow, glycogen degradation and
glucose cycling would commence to prevent over-accumulation of glycogen (Fig. 2, upper
right).

Conclusion
Classical studies of glycogen metabolism have figured prominently in the progress of
biochemistry and signal transduction due to seminal discoveries in the areas of protein
phosphorylation, intracellular second messengers, and phosphatase targeting subunits.
Following in that tradition, current research has highlighted additional roles for glycogen in

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cellular physiology beyond its simple function as an energy depot. In muscle, where a variety of
energy sources are utilized during contraction, rates of glycogen metabolism help orchestrate the
changing integration of cellular fuel utilization pathways during exercise. In liver, glycogen
turnover links gluconeogenesis into a single circuit in order to coordinately modulate hepatic
glucose output. These findings also generate new questions regarding glycogen metabolic
function and regulation, insuring that the study of glycogen will continue to be a dynamic,
expanding field.

GRANTS
This work was supported in part by Grant R01-DK-0647722 from the National Institute of
Diabetes and Digestive and Kidney Diseases, and by a Career Development Award from the
American Diabetes Association.

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FIGURE LEGENDS

Figure 1. Schematic models of hepatic glucose output (HGO).


A. Classical model of de novo glucose synthesis (gluconeogenesis) and glycogen breakdown
(glycogenolysis) independently contributing to HGO. B. Diagram of cycling of newly
synthesized glucose through glycogen prior to secretion from hepatocytes.
G6Pase, glucose-6-phosphatase; GP, glycogen phosphorylase; GS, glycogen synthase; G,
glucose; P, phosphate; UDP, uridine diphospho.

Figure 2. A model predicting glycogen cycling in hepatocytes.


The rate of glucose flux through glycogen is dependent on intracellular levels of glycogen, and
extracellular levels of hormones and glucose. Please see text for details.
[cAMP]c, cytosolic cAMP levels.

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FIGURE 1

A. Hepatic Glucose Output

Glucose

Glucose
G6Pase
Pyruvate G -6 -P
PEPCK
GP
G -1 -P Glycogen

Gluconeogenesis Glycogenolysis

B. Hepatic Glucose Output II

Glucose

Glucose G6Pase
G -6-P
Pyruvate G - 6 -P
PEPCK G -1-P GP
GS
UDPG Glycogen

Gluconeogenesis Glycogen cycling

23
FIGURE 2

Very low cycling


Glycogen
degradation >>
Glycogen levels

synthesis
Glucose cycling
through glycogen
Very low cycling
Glycogen
synthesis >>
degradation
Insulin/glucagon ratio, extracellular glucose levels

[cAMP]c

24

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