REVIEW ARTICLE

Glycogen storage disease type Ib: role of glucose-6-

phosphate transporter in cell metabolism and function
Sang Wan Sim1, David A. Weinstein2, Young Mok Lee2 and Hyun Sik Jun1
1 Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong, Korea
2 Glycogen Storage Disease Program, University of Connecticut School of Medicine, Farmington, CT, USA

Correspondence Cellular metabolism generally refers to biochemical processes that produce or

H. S. Jun, Department of Biotechnology and
Bioinformatics, College of Science and
Technology, Korea University, Sejong 339-
700, Korea
Tel: +82-44-860-1411
E-mail: toddjun@korea.ac.kr
(Received 12 July 2019, revised 16 October
2019, accepted 25 October 2019, available
online 22 November 2019)
doi:10.1002/1873-3468.13666
Edited by Maria Papatriantafyllou
consume energy within the cell. Recent studies have established that aberrant
metabolic states caused by internal or external stresses and genetic mutations
are intertwined with several human pathologies. Gaining insight into these
metabolic alterations is, therefore, essential for understanding the pathophysi-
ology of various diseases. Glycogen storage disease type Ib (GSD-Ib) is an
autosomal recessive disorder characterized by hypoglycemia, excessive glyco-
gen accumulation in the liver and kidney, neutropenia, neutrophil dysfunction,
and inflammatory bowel disease. GSD-Ib is caused by a deficiency of glu-
cose-6-phosphate transporter (G6PT). Recently, it was reported that defi-
ciency of G6PT also leads to the aberrant proliferation and differentiation of
mesenchymal stem cells and impaired regulatory T-cell function. This review
describes the broad impact of altered cellular metabolism resulting from a
lack of G6PT activity on cellular function and considers the prospects of
developing novel approaches for GSD-Ib treatment.

Keywords: autoimmune disease; CD4+ T cell; function; glucose-6-

phosphate transporter; glycogen storage disease type Ib; macrophage;
mesenchymal stem cell; metabolism; monocyte; neutrophil

Introduction to glycogen storage

disease type I
Living organisms require a constant supply of energy
to support essential processes for life. In our body,
most cells acquire this energy from glucose, which
enters the cell through glucose transporters and is
immediately converted to glucose-6-phosphate (G6P)
by either hexokinase or glucokinase [1]. Glucose/G6P
is metabolized through four major pathways, glycoly-
sis, pentose phosphate pathway (PPP), tricarboxylic
acid (TCA) cycle, and fatty acid synthesis [1,2], which
produce different substrates that are utilized in two
main ways. Firstly, glycolysis and oxidative phospho-
rylation (OXPHOS) through the TCA cycle provide
substrates for adenosine triphosphate (ATP) produc-
tion to maintain various cellular activities in most cell
types [3]. Secondly, diverse substrates produced at var-
ious steps are utilized as building blocks for macro-
molecules, such as DNA, RNA, and proteins, which
are essential for the proliferation, differentiation, and
effector functions of cells [1,4].
Many studies have demonstrated that the repro-
gramming of cellular metabolism drives the differentia-
tion and effector functions of stem cells and immune
cells [1,5]. In this regard, cellular metabolism is a
dynamic biochemical process that adapts to the

Abbreviations
DC, dendritic cell; G6P, glucose-6-phosphate; G6PT, glucose-6-phosphate transporter; GSD-Ib, glycogen storage disease type Ib; HIF-1a,
hypoxia-inducible factor-1a; hMSC, human mesenchymal stem cell; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway;
Treg, regulatory T cell.

FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies 3
Role of G6PT in cell metabolism and function
bioenergetic demands of cells and its dysregulation
resulting from genetic mutations and internal or exter-
nal stresses can cause diseases in humans [6].
Glycogen storage disease type I (GSD-I), also
known as von Gierke disease, is an autosomal reces-
sive disorder due to altered cellular metabolism [7].
Type I GSD is divided into two subtypes, GSD-Ia and
glycogen storage disease type Ib (GSD-Ib), caused by
mutations in G6PC and G6PT (also known as
SLC37A4) genes, respectively [8–11]. Glucose-6-phos-
phate transporter (G6PT) is localized in the ER mem-
brane, where it facilitates the translocation of G6P
from the cytoplasm into the ER lumen and its subse-
quent hydrolysis into glucose and phosphate (Pi),
thereby controlling the cytoplasmic glucose/G6P con-
centration [12,13]. Hydrolysis of G6P is catalyzed by
glucose-6-phosphatase (G6Pase) located in the ER
membrane, and hydrolyzed glucose is released into the
cytoplasm [8,14]. This ER-mediated cycling of glucose
limits cytoplasmic glucose/G6P availability, in turn
regulating glycolysis and PPP, and ultimately glucose
homeostasis [7,15]. There are two enzymatically active
G6Pases: G6Pase-a, encoded by G6PC, is primarily
expressed in gluconeogenic organs, such as the liver,
kidney, and intestine [8], and ubiquitously expressed
G6Pase-b, encoded by G6PC3 [14]. Both GSD-Ia and
-Ib manifest as hypoglycemia, excessive glycogen accu-
mulation, growth retardation, hyperlipidemia, and lac-
tic acidemia [7], whereas immune disorders, including
neutropenia and myeloid dysfunctions, are unique to
GSD-Ib and lead to recurrent bacterial infections in
GSD-Ib patients [16–18]. Deficiency of G6Pase-b, also
called severe congenital neutropenia syndrome type 4
(SCN4), does not lead to GSD, even though it causes
neutropenia and myeloid dysfunctions observed in
GSD-Ib patients [19–24]. SCN4 also shows nonhema-
tological defects, such as a structural defect in the
heart and abnormalities in urogenital organs, suggest-
ing that G6Pase-b plays additional roles that have not
been fully identified yet [20].
Most recently, G6PT was found to play a critical
role in both CD4+ T-cell functions and the prolifera-
tion and differentiation of human mesenchymal stem
cells (hMSCs), suggesting that immune deficiencies in
GSD-Ib extend beyond neutropenia and neutrophil
dysfunction [25,26]. Multipotent hMSCs are character-
ized not only by their ability to differentiate into
mesodermal lineages, such as adipocytes, osteocytes,
and chondrocytes [27], but also by immunoregulatory
capacity on both innate and adaptive immune cells
[28–30]. The majority of research on GSD-Ib has been
focused on metabolic phenotypes of the liver and neu-
trophil-specific immune deficiencies. Although these
4 FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies
S. W. Sim et al.
are now well established, other aspects of immune dis-
orders observed in GSD-Ib patients are still poorly
understood. In this review, we will introduce the gen-
eral metabolic and functional phenotypes of immune
cells and will discuss the impact of altered cellular
metabolism, resulting from a lack of G6PT activity in
immune cells, including neutrophils, macrophages,
CD4+ T cells, and mesenchymal stem cells. Finally, the
limitations of current therapies and the development
of novel clinical approaches for the treatment of GSD-
Ib will be discussed [31–33].
Glucose-6-phosphate transporter
Glucose-6-phosphate transporter is encoded by the
solute carrier family 37 member 4 (SLC37A4) gene
and is localized in the ER membrane. In humans,
G6PT is a single-copy gene composed of nine exons
on chromosome 11q23 and its two spliced variants
contain 429 and 451 amino acids, respectively
[10,34,35]. The former transcript is expressed ubiqui-
tously (G6PT), while the latter one is exclusively
expressed in the brain, heart, and muscle (vG6PT)
[11,36]. The functional differences between these tran-
scripts are not understood because both proteins are
catalytically active, consist of 10 transmembrane
helices, and have their NH2 and COOH termini
located in the cytoplasm [36,37]. G6PT belongs to a
sugar-phosphate/phosphate antiporter that exchanges
cytoplasmic G6P for inorganic phosphate stored in the
lumen of the ER [12]. On the ER membrane, G6PT
transports G6P from the cytoplasm into the ER lumen
and delivers it to G6Pase-a or G6Pase-b for hydrolysis
into glucose and phosphate. Thus, G6PT plays a vital
role in maintaining glucose homeostasis in blood and
energy homeostasis in the cells [7,15] (Fig. 1A).
Deficiency of G6PT and Glycogen
storage disease type Ib
Glycogen storage disease type Ib is a rare inherited
disease that is caused by G6PT deficiency. GSD-Ib is
characterized by impaired glucose homeostasis and
immune disorders, including neutropenia and neu-
trophil dysfunction [7,15]. As a result of these immune
deficiencies, GSD-Ib patients suffer from recurrent
bacterial infections. The vast majority of GSD-Ib
patients who manifest neutropenia also develop inflam-
matory bowel disease, which is not distinguishable
from Crohn’s disease [16,38]. A study that examined
the hypothalamus–pituitary–thyroid axis in seven
GSD-Ib patients revealed that 57% of the patients
showed thyroid autoimmunity and hypothyroidism
S. W. Sim et al. Role of G6PT in cell metabolism and function

Fig. 1. Pathways for G6P metabolism in gluconeogenic organs and neutrophils. (A) Gluconeogenic organs, such as the liver, kidney, and
intestine, primarily express G6Pase-a. Interprandial glucose homeostasis is maintained by the G6PT/G6Pase-a, which is localized in the ER
membrane. G6PT transports G6P from the cytoplasm into the lumen of the ER, and then, G6Pase-a hydrolyzes G6P to glucose and
phosphate, which are ultimately released into the cytoplasm. In gluconeogenic organs, glucose can be generated from glycogenolysis and
gluconeogenesis. G6PT/G6Pase-a plays a critical role in the final step of these two pathways, regulating the blood glucose for use by
nongluconeogenic organs between meals. (B) Neutrophil glucose homeostasis is maintained by the G6PT/G6Pase-b. In contrast with
G6Pase-a, G6Pase-b is ubiquitously expressed, but functions in a similar manner as G6PT/G6Pase-a. In wild-type neutrophils, glucose is
metabolized into G6P, which can be further utilized in the PPP, glycolysis, glycogen synthesis, and ER cycling. Most recently, a new
substrate for G6Pase-b, 1,5-AG6P, was discovered. Even though the transporter on the plasma membrane for 1,5-AG is unknown, 1,5-AG is
phosphorylated into 1,5-AG6P by hexokinases or ADP-GK in the cytoplasm. G6PT can transport both G6P and 1,5-AG6P into the ER lumen,
and G6Pase-b hydrolyzes two phosphorylated forms to glucose/phosphate and 1,5-AG/phosphate, respectively. In wild-type neutrophils,
1,5-AG6P is continuously converted into 1,5-AG by ER cycling, maintaining the constant physiological concentration.

[39]. Numerous mutations have been identified in
SLC37A4; however, all GSD-Ib patients do not show
neutropenia even though they display metabolic phe-
notypes of the disease, suggesting that other factors
could modify gene activity [15]. To date, 91 mutations
in the G6PT gene have been described, including 39
missense, 11 nonsense, 21 insertion/deletion, and 19
splicing mutations. These mutations are distributed
throughout the coding region and exon–intron junc-
tions [40]. Among these genetic changes, site-directed
mutagenesis and transient expression assays have con-
firmed the pathogenicity of 31 missense mutations and
two deletions. Of note, these pathogenic mutations
abolish or greatly reduce the microsomal uptake activ-
ity of G6P [10,41–43].
Cellular metabolism and function of
neutrophils
In humans, neutrophils account for about 50–70% of
circulating leukocytes and serve as the first line of
defense against foreign antigens, such as bacteria and
fungi [44]. Once terminally differentiated, neutrophils
are relatively short-lived and about 1011 new neu-
trophils are produced daily [45]. Neutrophils respond
to immunological challenges, migrating to injured or
infected tissues where the oxygen is limited [46]. At the
infected sites, they destroy invading pathogens through
phagocytosis, respiratory burst activity, the release of
granule contents, and extracellular traps [47]. These
microenvironmental and functional changes are
accompanied by metabolic changes that have a direct
role in regulating neutrophil function [48,49].
It has been known that neutrophils primarily rely
on glycolysis and exhibit significant low levels of
OXPHOS [49–51]. To fuel their effector functions,
including the respiratory burst activity and the forma-
tion of neutrophil extracellular traps, neutrophils heav-
ily utilize glucose and glycolysis [49,50,52]. Consistent
with this notion, inhibition of glycolysis by 2-
deoxyglucose, a glucose molecule that is taken up by
glucose transporters but cannot undergo further gly-
colysis, severely reduced cellular ATP concentration
and impaired the phagocytic response of neutrophils
[49,53]. Activated neutrophils synthesize NADPH to
support their respiratory burst activity [54]. A shunt
into the PPP, which generates ribose for nucleotide
synthesis, forms the NADPH cofactor required for
reactive oxygen species (ROS) production via the
NADPH oxidase 2 activity [55]. In addition, neu-
trophils exploit glutaminolysis, which uses several steps
from the TCA cycle and produces NADPH from the
oxidation of glutamine-derived malate to pyruvate [1]
(Fig. 1B).
Compared with most other mammalian cell types,
neutrophils contain very few mitochondria [51]. This

FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies 5
Role of G6PT in cell metabolism and function
observation has led to the impression that mitochon-
dria would lack the capacity for mitochondrial respira-
tion in neutrophils. However, a few studies have
revealed the unrecognized importance of mitochondria
in the function of neutrophils during infection and
inflammation, besides their well-established role in
apoptosis [50,56]. Fossati et al. [50] suggested that
some effector functions of neutrophils require intact
mitochondrial functionality. Bao et al. [56] revealed
that stimulation with f-Met-Leu-Phe (fMLP) rapidly
increases the mitochondrial membrane potential and
ATP synthesis, using a method that can observe ATP
release from living cells in real time. The released ATP
is produced by mitochondria and is essential for the
activation of neutrophils. In addition, the initial burst
of ATP release is followed by a metabolic switch to
glycolysis for further ATP production that contributes
to sustained intracellular Ca2+ levels and maintenance
of functional cell responses [56]. Taken together, mito-
chondria appear to have an unexpected role in the
function of neutrophils.
Neutrophils and G6PT
The mechanism of immune deficiency in GSD-Ib and
its relationship with G6P metabolism has long been
unclear. In 2003, Kuijpers et al. [57] suggested a rela-
tionship between apoptosis and neutropenia, showing
that the neutrophils of GSD-Ib patients exhibit
enhanced apoptosis, but the underlying mechanism
remained uncertain. In this regard, the discovery of
G6Pase-b and its expression in neutrophils have led to
a better understanding of the role of the G6PT/
G6Pase-b complex in neutrophil homeostasis and func-
tion [19].
Neutrophils from G6pt / mice show enhanced ER
stress, as identified by the increased expression of the
molecular chaperones GRP78 and GRP170, and pro-
tein disulfide isomerase [58]. Similarly, neutrophils
from G6pc3 / mice also exhibit increased ER stress
and apoptosis [19]. Consistent with these results, char-
acterization of neutrophils from GSD-Ib and SCN4
patients demonstrated that defects in G6PT or
G6Pase-b cause ER stress, leading to an increased rate
of apoptosis [20,21,23,58]. Furthermore, additional evi-
dence proved that mitochondrial oxidative stress partly
contributes to the apoptosis of neutrophils in both
G6pt / and G6pc3 / mice [58,59].
In addition to neutropenia, both GSD-Ib and SCN4
patients also exhibited neutrophil dysfunctions, such as
impaired respiratory burst activity, chemotaxis, cal-
cium mobilization, phagocytic activities, and migration
[17,19]. Neutrophils cannot produce glucose via
6 FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies
S. W. Sim et al.
gluconeogenesis; thus, they are highly dependent on
the continuous supply of glucose from the blood to
function and survive [49]. Intracellular glucose/G6P in
neutrophils is metabolized via three primary pathways:
glycolysis, PPP, and ER cycling [21]. The latter path-
way regulates the other two cytoplasmic pathways by
controlling the availability of cytoplasmic glucose/G6P
[21]. In GSD-Ib patients, neutrophils showed reduced
glucose uptake [13]. In keeping with this finding,
impaired energy homeostasis, including decreased
levels of G6P, lactate, and ATP, is also observed in
G6PT / neutrophils. In addition, this study also
demonstrated that both ER and the mitochondrial
stress-induced hypoxia-inducible factor-1a (HIF-1a)/
peroxisome proliferator-activated receptor-c (PPAR-c)
pathway downregulate respiratory burst, chemotaxis,
and calcium mobilization activities, leading to neu-
trophil dysfunction [13]. Neutrophils of SCN4 patients
also showed reduced glucose uptake and decreased
levels of energy homeostasis which lead to neutrophil
dysfunction [21]. However, whether the HIF-1a/
PPAR-c pathway is involved in neutrophil dysfunction
in SCN4 patients or mice remains to be further exam-
ined.
Most recently, Veiga-da-Cunha et al. [60] proposed
the interesting underlying mechanism for neutropenia
and neutrophil dysfunction observed in GSD-Ib and
SCN4 patients. To investigate the exact role of G6PT
and G6Pase-b, they compared the substrate prefer-
ences and kinetic properties of G6Pase-a and G6Pase-
b. As a result, they found that the G6Pase-b acts much
more efficiently on 1,5-anhydroglucitol-6-phosphate
(1,5-AG6P) than on G6P, whereas G6Pase-a prefers
G6P to 1,5-AG6P [60]. The 1,5-AG6P is a G6P struc-
tural analog produced by the phosphorylation of 1,5-
anhydroglucitol (1,5-AG). 1,5-AG is a glucose analog
present in the blood and food-derived polyol, although
some of the 1,5-AG in our body is produced from glu-
cose [61,62]. The 1,5-AG has been used as a bioche-
mical marker for diabetes mellitus because its
concentration in the plasma is constant under the nor-
moglycemic condition, while its reabsorption and the
plasma level dramatically decrease under the hyper-
glycemic conditions [63–65]. Although the metabolic
pathway and the function of 1,5-AG are not fully
understood, the structural similarity between glucose
and 1,5-AG raised the possibility that 1,5-AG could be
taken up into the cells through the glucose trans-
porters [66].
Once glucose and 1,5-AG enter the cell, they are
phosphorylated by glucose-phosphorylating enzymes,
such as hexokinase. It is well known that glucose is
phosphorylated into G6P by hexokinase in most cells
S. W. Sim et al. Role of G6PT in cell metabolism and function

or glucokinase in certain cells, including liver cells [15].
In the case of 1,5-AG, it has been proposed that it
would be phosphorylated by at least two distinct
enzymes [62]. Vegia-da-Cunha et al. [60]also described
that 1,5-AG is accidentally phosphorylated by glucose-
phosphorylating enzymes, such as hexokinases and
ADP-glucokinase (ADP-GK). 1,5-AG6P is then trans-
ported into the ER lumen by G6PT and dephosphory-
lated by G6Pase-b, maintaining the physiological
intracellular level of 1,5-AG6P [60]. When 1,5-AG
administered to control, G6pt / , and G6pc3 / mice,
1,5-AG6P accumulated massively in the knockout neu-
trophils compared with the control ones. The accumu-
lation of 1,5-AG6P was shown to inhibit the
enzymatic activities of hexokinases, resulting in
decreased glucose phosphorylation and reduced glu-
cose metabolism. These results suggest that regulation
of 1,5-AG6P by G6PT/G6Pase-b is a critical factor for
the function and survival of neutrophils (Fig. 2).
Cellular metabolism and function of
monocytes and macrophages
Monocytes are members of the mononuclear phago-
cytes, which comprise monocytes and two other major
subtypes: dendritic cells (DCs) and macrophages [67].
They are characterized by a unilobular nucleus and
have an important role in the innate immune system,
like the neutrophils [68]. Monocytes and neutrophils
share some similar physiological roles, but marrow
and blood monocytes can also proliferate and differen-
tiate into macrophages [69]. Once released from the
bone marrow into the blood, monocytes circulate in
the blood to survey the body for sites of inflammation
[70]. When they encounter inflammatory stress signals
including chemokines, complement components, and
the products of tissue matrix degradation, monocytes
differentiate into the proinflammatory (M1) or anti-in-
flammatory (M2) macrophages [67].
Macrophages are found in almost every tissue in
our body and show great functional diversity, from
immune responses to pathogens to development,
homeostasis, and repair [68]. Tissue homeostasis is reg-
ulated by resident macrophages, which act as sentinels
and respond to changes in physiology as well as exter-
nal challenges, such as injury or infection [68]. As a
response to environmental challenges, monocytes from
blood, spleen, and bone marrow can be also recruited
and differentiated into macrophages in injured or
infected tissues [71].
Interestingly, recent studies have shown that innate
immune cells, such as monocytes and macrophages,
can remember a previous encounter with foreign anti-
gens and contribute to the immunological memory of
our immune system whereby it mounts a faster and
greater response when rechallenged by the same anti-
gens. These adaptive characteristics of the innate
immune system have been called trained immunity [72]
because it enables innate immune cells to respond
more effectively to secondary stimuli after they are
stimulated with a pathogen [73,74]. This requires that
monocytes and macrophages undergo intracellular
metabolic and epigenetic changes, the latter involving
histone modifications [75].

Fig. 2. Proposed explanation for neutropenia and neutrophil dysfunction in GSD-Ib. In the G6PT / neutrophils, glucose and 1,5-AG that
have entered the cell are metabolized by hexokinase and hexokinase or ADP-GK, respectively. Loss of G6PT causes the massive
accumulation of cytosolic 1,5-AG6P, which inhibits the hexose-phosphorylating enzymes, such as hexokinases or ADP-GK. Even though
which hexose-phosphorylating enzymes are inhibited is unknown, this inhibition results in the reduction of further glucose utilization. This is
likely responsible for impaired energy homeostasis and functionality, as well as increased ER and oxidative stress.

FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies 7
Role of G6PT in cell metabolism and function
M1 and M2 macrophages have
different metabolic phenotypes
In the M1 inflammatory phenotype, activated macro-
phages have high microbicidal activity, as well as
enhanced production of proinflammatory cytokines
and ROS [76]. These macrophages exhibit a metabolic
shift from OXPHOS to glycolysis and PPP, enabling
them to generate enough ATP and biosynthetic materi-
als, which include amino acids for protein synthesis,
ribose for nucleotides, and NADPH for the produc-
tion of ROS by NADPH oxidase [77,78]. Pharmaco-
logical inhibition of glycolysis blunted many effector
functions of the M1 inflammatory phenotypes, includ-
ing phagocytosis, secretion of proinflammatory cytoki-
nes, and the generation of ROS [79,80]. As with
glycolysis, some intermediates of the TCA cycle serve
as key biosynthetic materials for the effector functions
of M1 macrophages [81,82]. The upregulation of gly-
colytic metabolism also generates pyruvate to fuel the
TCA cycle, even though the M1 inflammatory macro-
phages show impaired mitochondrial OXPHOS which
is disrupted in two places, after citrate and succinate,
respectively [83]. The citrate synthesis is increased to
produce fatty acids, lipids, and prostaglandins which
act as a proinflammatory mediator [82]. In addition to
the accumulation of citrate, the M1 macrophages exhi-
bit increased accumulation of succinate, which results
in the stabilization of HIF-1a, thereby promoting
expression of LPS-induced IL-1b [84].
In contrast with the functional characteristics of the
M1 macrophages, alternatively activated M2 macro-
phages are associated with tissue remodeling, resolution
of inflammation, anti-inflammatory responses, and anti-
gen presentation [77,78]. These M2 macrophages utilize
an intact TCA cycle and enhanced mitochondrial
OXPHOS to generate ATP [77]. They are involved in
time-consuming tissue repair and defense against extra-
cellular parasites, suggesting that OXPHOS could be
more suitable for the role of M2 macrophage [85]. M2
macrophages also exhibit upregulation of the entire pro-
gram for fatty acid metabolism, including fatty acid
uptake, fatty acid oxidation, and mitochondrial biogen-
esis [86,87]. These metabolic changes are regulated by
PPAR-c co-activator-1b, which is a transcriptional co-
activator that upregulates expression of genes involved
in fatty acid oxidation [86].
Role of G6PT in monocytes and
macrophages
Glycogen storage disease type Ib patients show mono-
cyte dysfunction, even if signs are not clearly
8 FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies
S. W. Sim et al.
recognized [17,18]. GSD-Ib monocytes exhibit
decreased PPP activities and respiratory burst, which
includes oxygen consumption, production of superox-
ide anion, and calcium mobilization when they are
stimulated by fMLP or phorbol 12-myristate 13-ac-
etate [17]. However, the magnitude of impairment of
respiratory burst in monocytes is not as severe as that
observed in G6PT-deficient neutrophils. Kilpatrick
et al. described these differences as being due to the
different metabolic capabilities of neutrophils and
monocytes; neutrophils are highly dependent on gly-
colysis, while monocytes use mitochondria more than
neutrophils to produce ATP via OXPHOS [17].
There has been no reported case of GSD-Ib macro-
phage dysfunction. However, G6pc3 / macrophages
exhibit impaired respiratory burst, chemotaxis, calcium
mobilization, and phagocytosis activities which result
from impaired energy homeostasis [22]. This suggests
that G6PT deficiency can also cause macrophage dys-
function, although further research is required to clar-
ify this point.
Metabolism and function of CD4+ T
cells
CD4+ T cells organize diverse aspects of adaptive
immunity, including responses to pathogens, allergens,
and tumors, and it is accepted that establishment and
maintenance of immune responses, homeostasis, mem-
ory, and self-tolerance rely on them [88]. T-cell pro-
genitors in the thymus are derived from common
lymphoid progenitor present in the bone marrow [89].
T-cell progenitors undergo several changes during T-
cell maturation: generation of CD4+CD8+ double-posi-
tive thymocytes, positive and negative selection of dou-
ble-positive thymocytes, interaction of positively
selected thymocytes with medullary thymic epithelial
cells to complete T-cell development, and the export of
na€ıve mature T cells from the thymus [90]. Upon
recognition of a cognate antigen presented by compe-
tent antigen-presenting cells, na€ıve CD4+ T cells differ-
entiate into distinct CD4+ effector T cells (Th1, Th2,
and Th17 cells), CD4+ regulatory T cells (Tregs), and
memory T cells [91].
Na€ıve T cells have little energy demands and require
only basal biosynthesis for immune surveillance of sec-
ondary lymphoid tissues prior to activation [92]. To
meet this need, they rely on the fatty acid b-oxidation,
and pyruvate and glutamine oxidation through the
TCA cycle, which yield high energy [93]. Upon activa-
tion, more energy and various substrates are necessary
for cellular proliferation, which requires biosynthesis
of DNA, RNA, and protein [94]. These energy
S. W. Sim et al. Role of G6PT in cell metabolism and function

requirements are fulfilled with a metabolic change
toward aerobic glycolysis and glutamine oxidation that
fuels mitochondrial OXPHOS through the TCA cycle
[95,96]. Hereafter, T cells differentiate into various
subsets, which includes effector, memory, and Treg
[93]. Effector T cells maintain their metabolic pheno-
types in response to various cytokines, while the mem-
ory and Treg undergo metabolic changes [97]. Tregs
switch their metabolism toward fatty acid oxidation to
promote their growth and regulatory functions [98]. At
the end of an immune response, memory T cells are
produced and they showed similar cellular metabolism
with na€ıve T cells [99] (Fig. 3A).
Role of G6PT in CD4+ T cells
In addition to neutropenia and neutrophil dysfunction,
GSD-Ib patients also show an increased risk for developing
autoimmune disorders, including chronic inflammatory
bowel disease, Crohn’s disease, thyroid autoimmunity,
and myasthenia gravis [16,38,39,100,101].
Recently, Melis et al. [25] found that lymphopenia
in GSD-Ib patients results from the aberrant glycolysis
in CD4+CD25 conventional T cells (Tconvs). It has
been reported that chronic lymphopenia might affect
the proliferation of immune cells, which react with
self-antigens thereby promoting autoimmune diseases
[102]. This is supported by other studies describing the
relationship between autoimmune diseases and
immune deficiencies such as lymphopenia [103,104]. In
lymphopenia conditions, T cells undergo peripheral
proliferation even in the absence of foreign-antigen
stimulation [104]. This compensatory homeostatic pro-
liferation of T cells is known as lymphopenia-induced
proliferation (LIP), causing the restoration of the
peripheral T-cell pool without the thymic output of
na€ıve T cells [105,106]. Although the mechanism
underlying LIP is not fully understood, it has been
suggested that chronic lymphopenia might lead to the
proliferation of highly self-reactive T cells, conse-
quently causing autoimmunity [107,108].
The higher frequency of autoimmune diseases in
GSD-Ib can also be attributed to the reduced suppres-
sive capacity of CD4+CD25+FOXP3+ Tregs and
abnormal induction of FOXP3 in CD4+CD25
Tconvs, which are caused by impaired glycolysis [25].
Tregs can be broadly classified into two groups: thy-
mic Tregs, also known as natural Tregs, which develop

Fig. 3. Cellular metabolism of various CD4+ T-cell subsets and G6PT / T cells. (A) Na€ıve or memory T cells use glucose-derived pyruvate to
fuel the OXPHOS pathway, along with fatty acids and glutamine. This metabolic program facilitates their survival and migration through the
lymphatic system for immune surveillance. Upon activation, glycolysis and glutaminolysis are increased to generate biosynthetic materials,
which are required for rapid proliferation, while fatty acid oxidation is decreased. Following the activation of T cells, CD4+ T cells
differentiate into the effector subsets (Th1, Th2, and Th17 cells) and FOXP3+ Treg. FOXP3+ Tregs preferentially utilize exogenously derived
fatty acids through fatty acid oxidation to fuel their regulatory function. (B) In the G6PT / T cells, reduced glycolysis upon TCR stimulation
of CD4+CD25 conventional T cells (Tconvs) and lymphopenia were observed. These phenotypes are associated with decreased expression
of transcription factor FOXP3 in CD4+CD25 Tconvs and reduced suppressive function of CD4+CD25+FOXP3+ Treg, which can explain an
increased risk of autoimmune disorders in GSD-Ib patients.

FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies 9
Role of G6PT in cell metabolism and function
in the thymus, and induced Tregs (iTregs) generated
from conventional CD4+ T cells in the periphery after
antigen encounter [109]. Transcription factor FOXP3
is key for the development, and suppressive functions
of both Tregs and mutations in this gene are strongly
linked to immune dysregulation, autoimmune polyen-
docrinopathy, and enteropathy [110–112]. Further-
more, it was reported that the induction of FOXP3
splicing variants containing exon 2 (FOXP3-E2) in
human iTreg cells depends on glycolysis leading to the
development of iTregs from Tconvs following subopti-
mal stimulation via the TCR [113]. Collectively, the
hyperactivity of autoreactive T cells and the failure of
local regulatory mechanisms by Tregs could be
involved in the immunopathogenesis of autoimmune
diseases that are found in GSD-Ib patients. This
strongly suggests that G6PT plays a vital role in the
energy homeostasis and the function of lymphocytes,
as shown in myeloid cells [25,114,115] (Fig. 3B).
Potential impact of G6PT /
mesenchymal stem cells on immune
cells
Mesenchymal stem cells are a type of adult stem cells,
characterized by fibroblast-like multipotency and the
ability to differentiate into mesodermal tissues, such as
adipocytes, osteoblasts, and chondrocytes [27]. They
can be isolated from several tissues including bone
marrow and adipose tissue [116]. Throughout our
body, MSCs home to sites of tissue injury and repair
the tissue by either two processes: differentiation into
tissue-specific cell types, or creation of microenviron-
ment that enhances tissue repair of the endogenous
cells and modulates the immune responses
[30,117,118]. Therefore, cell-based regenerative thera-
pies that exploit MSCs are considered as a promising
approach in a variety of diseases [119].
Mesenchymal stem cells reside in hypoxic environ-
ments in vivo, such as the bone marrow and other
niches [120]. Compared to differentiated osteoblasts,
MSCs exhibit more glycolytic and lower levels of
OXPHOS metabolism, indicating that MSCs depend
more on glycolysis than do osteoblasts [121]. This
metabolic state may minimize ROS production to pre-
vent oxidative stress-induced senescence and enable
MSCs to preserve long-term self-renewal [122]. During
adipogenesis and osteogenesis, MSCs require increased
mitochondrial biogenesis and OXPHOS, while glycoly-
sis is upregulated during chondrogenesis [5]. We previ-
ously reported that a G6PT / hMSC line exhibits
increased proliferation and decreased differentiation
into adipocytes and osteoblasts [26]. These aberrant
10 FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies
S. W. Sim et al.
characteristics were supported by a metabolic shift
toward glycolysis rather than OXPHOS, along with
the differential expressions of the glycolytic enzyme
hexokinase 2 (HK2) and the mitochondrial anion car-
rier uncoupling protein 2 (UCP2) [26]. Furthermore,
G6PT deficiency in hMSC induced ER stress and
mitochondrial oxidative stress, which in turn led to
cyclooxygenase-2 (COX-2)-induced prostaglandin E2
(PGE2) production [26]. Considering that PGE2 pro-
duction by MSCs increases cell proliferation through
E-prostanoid 2 receptor in an autocrine manner as
well as its immunoregulatory function [123], it is rea-
sonable to suggest that increased PGE2 production
results in increased proliferation of G6PT / hMSC.
Taken together, G6PT plays an important role in regu-
lating the proliferation and differentiation of hMSC
by regulating glucose homeostasis.
In addition to their differentiation capacity, the
immunomodulatory potential of MSCs has been
reported to regulate the immune reaction in various
diseases [30,124]. For example, MSCs inhibit the prolif-
eration and cytotoxic activity of the natural killer (NK)
cells, as well as cytokine production [125,126]. They
also block the differentiation of monocytes into DCs,
alter mature DCs into immature DC states, and induce
interleukin-10 (IL-10) production by plasmacytoid DCs
(pDCs) [127–129]. In addition, they can inhibit the dif-
ferentiation of Treg [130,131]. Considering that these
effects are mainly mediated by PGE2 and its secretion
is upregulated in G6PT / hMSCs, the inactivation of
G6PT might affect not only immune deficiencies but
also the regulation of the immune responses including
autoimmune diseases by MSCs (Fig. 4).
Clinical therapies for immune
deficiencies in GSD-Ib patients
The current treatment for GSD-Ib patients involves
dietary therapy involving frequent oral administration
of uncooked cornstarch (a slow-releasing glucose
preparation) [132]. In addition to this, administration
of granulocyte colony-stimulating factor (G-CSF) is
commonly used to increase absolute neutrophil counts
and to alleviate the severity of recurrent bacterial
infections in GSD-Ib and SCN4 patients [31,38,133].
The combined dietary and G-CSF therapy significantly
improves the abnormal metabolic state and neutrope-
nia of GSD-Ib patients [132,133]. Above the ameliora-
tion of neutropenia, numerous studies have examined
whether G-CSF can also rescue neutrophil function
with contrasting outcomes [32,134–136]. Furthermore,
the toxicity of G-CSF therapy must also be considered
because it has been reported that long-term treatment
S. W. Sim et al. Role of G6PT in cell metabolism and function

Fig. 4. The effect of G6PT deficiency on hMSC metabolism and immunomodulation capacities of MSCs by PGE2 secretion. (A) G6PT
deficiency in hMSCs caused increased proliferation and impaired differentiation into adipocytes and osteocytes. These phenotypes were
associated with a metabolic shift toward glycolysis and stress-induced PGE2 secretion. Metabolic changes encompass increased glycolysis
and decreased OXPHOS, which was explained with increased expression of HK2 including Akt/GSK-3b signaling pathway and decreased
expression of UCP2. Furthermore, disruption of G6PT triggers an ER and mitochondrial oxidative stress that lead to COX-2-induced PGE2
production. (B) PGE2 secretion by normal MSCs can modulate various functions of some immune cells. MSCs can suppress the
proliferation, cytotoxicity, and cytokine production of resting NK cells. MSCs can also inhibit the differentiation into DC from monocytes, and
maturation and tumor necrosis factor (TNF) production of DCs s and upregulate the expression of interleukin-10 (IL-10) by pDCs. Finally, the
effect of MSC-derived PGE2 secretion includes defective activation of CD4+ T cells.

with G-CSF can induce myelodysplasia or acute mye-
loid leukemia [137–140]. Concerning the improvement
of the neutrophil functions, Jun et al. [13] showed that
the addition of the PPAR-c antagonist GW9662 signif-
icantly enhanced fMLP-mediated chemotaxis, calcium
mobilization, and superoxide production. Therefore,
the combinational use of both G-CSF and GW9662
could be considered to improve neutropenia and neu-
trophil dysfunctions of GSD-Ib patients.
As a viable therapeutic option, the potential of gene
therapy for GSD-Ib has been evaluated [141]. This
study revealed that an adenoviral vector carrying a
human G6PT infusion transiently corrects both abnor-
mal metabolism and myeloid abnormalities in G6pt /
mice. Although studies on the long-term efficacy and
safety of this therapy are still necessary, genetic correc-
tion seems to be a promising treatment option for GSD-
Ib patients. Most recent gene therapy development
using adeno-associated virus vectors (AAV-hG6PT) on
G6pt / mice showed improved survival rate and glu-
cose homeostasis profiles. However, AAV-hG6PT was
not sufficient to correct the immune deficiency (neu-
tropenia and neutrophil dysfunction) and further inves-
tigation is needed to achieve effective viral vector-
mediated delivery of therapeutic genes into cell types
other than hepatocytes [142]. The deficiency of ubiqui-
tously expressed G6PT may need a multidirectional
approach [143]. Stem cell transplantation is emerging as
an attractive option for inheritable genetic deficiencies
[144,145], and there are documented cases of successful
hematopoietic stem cell transplantations in GSD-Ib
patients [146,147]. Although studies on the long-term
efficacy, safety, and accessibility to donor cells are
underway, this would be one of the most promising
options for future treatments for GSD-Ib patients.
Summary and perspectives
Glycogen storage disease type Ib is an autosomal
genetic disorder that leads to metabolic and myeloid
abnormalities. G6PT is a ubiquitously expressed ER-
resident G6P transporter that transfers cytoplasmic
G6P into the lumen of the ER. In immune cells, G6PT
and G6Pase-b are essential for the hydrolysis of G6P
into glucose, regulating endogenous glucose produc-
tion. This metabolic regulatory role of G6PT/G6Pase-
b becomes more important as the unrecognized role of
G6Pase-b is uncovered. G6PT / neutrophils exhibit
increased ER-induced apoptosis, mitochondrial oxida-
tive stress, and decreased energy metabolism, which
drives functional impairment through the HIF-1a/
PPAR-c pathway. In addition, G6PT / monocytes
show impaired respiratory burst, suggesting that the
function of G6PT in glucose homeostasis can influence
other immune cell types. In concordance with this
observation, it was reported that G6PT plays a critical
role in regulating the suppressive activity of Treg, pro-
viding evidence for an increased autoimmune risk in
GSD-Ib. In addition to immune cells, G6PT deficiency
in hMSCs leads to a metabolic shift toward glycolysis
and defects in differentiation capacities into adipocytes
and osteoblasts, upregulating COX-2-induced PGE2

FEBS Letters 594 (2020) 3–18 ª 2019 Federation of European Biochemical Societies 11
Role of G6PT in cell metabolism and function
secretion. With an immunomodulatory activity, G6PT-
deficient hMSCs might also have an impact on
immune regulation.
The biological role of G6PT in diverse cell types is
being elucidated; G6PT-mediated metabolism and
intermediate metabolic products are critical for cell
proliferation, differentiation, functions, and cell death.
However, molecular mechanisms underlying the com-
plex phenotypes observed in cells of GSD-Ib remain to
be investigated. Moreover, considering that cells from
different tissues or organs are confronted with a large
variety of microenvironments and diverse metabolic
fuels, it is possible that the role of G6PT may be sensi-
tive to different microenvironments. G6PT-deficient
mouse model and cell lines are available, and their
phenotypes should be characterized in detail, focusing
particularly on metabolism and metabolic products.
These studies may give valuable insights as to the
development of novel therapies for metabolic and
functional correction of cells, such as neutrophils and
macrophages in GSD-Ib.
Acknowledgements
This work was supported by Basic Science Research
Program through the National Research Foundation
of Korea (NRF) funded by the Ministry of Education,
Science and Technology (2016R1D1A3B03931840).
Additional support was provided by Cooperative
Research Program for Agriculture Science & Technol-
ogy Development (Project No. PJ01323004) and the
Global Center for GSD for grant support along with
the following GSD-Ib philanthropy funds managed by
the University of Connecticut Foundation: the Jonah
Pournazarian fund and the McMillan GSD-Ib research
fund.
Declaration of financial disclosure
The authors have no financial interest to disclose.
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