Phytochemistry xxx (2015) xxx–xxx

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Phytochemistry
journal homepage: www.elsevier.com/locate/phytochem

Anti-diabetic effects of Ganoderma lucidum

Haou-Tzong Ma a,1, Jung-Feng Hsieh b,1, Shui-Tein Chen a,c,⇑
a
Institute of Biological Chemistry and Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
b
Department of Food Science, Fu Jen Catholic University, Taipei 242, Taiwan
c
Institute of Biochemical Science, National Taiwan University, Taipei 10617, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Ganoderma lucidum is a white rot fungus widely used as a tonic for the promotion of longevity and health.
Available online xxxx Extracts of G. lucidum have been recognized as an alternative adjuvant treatment for diabetes. Among the
many biologically active constituents of G. lucidum, polysaccharides, proteoglycans, proteins and triter-
Keywords: penoids have been shown to have hypoglycemic effects. G. lucidum polysaccharides have been reported
Ganoderma lucidum to have hypoglycemic activity by increasing plasma insulin levels and decreasing plasma sugar levels in
Ganodermataceae mice. Protein tyrosine phosphatase 1B is a promising therapeutic target in diabetes, and G. lucidum pro-
Triterpenoids
teoglycan can inhibit this enzyme in vitro. Moreover, G. lucidum triterpenoids were shown to have
Polysaccharides
Diabetes
inhibitory activity on aldose reductase and a-glucosidase that can suppress postprandial hyperglycemia.
In addition, a protein Ling Zhi-8 extracted from G. lucidum significantly decreased lymphocyte infiltration
and increased the antibody detection of insulin in diabetic mice. This review summarizes most of the
research about the hypoglycemic action effects of polysaccharides, proteoglycans, proteins and tritr-
erpenoids from G. lucidum as a guide for future research.
Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction
Ganoderma lucidum called ‘Ling-Zhi’ in Chinese, ‘Reishi’ in
Japanese, and ‘Yeongji’ in Korean, is a basidiomycete white rot fun-
gus that has been used as a health-preserving and therapeutic
agent. Even today, G. lucidum is widely used in traditional
Chinese medicine and food products to increase human vitality
and longevity (Sliva, 2006). Over the past several decades, a consid-
erable amount of research has shown that numerous pharmaco-
logical compounds contained in G. lucidum have anti-cancer,
anti-diabetic, anti-hepatotoxic, and immunomodulatory properties
(Boh, 2013; Boh et al., 2007; Paterson, 2006). Moreover, G. lucidum
has diverse biological activities in animal and in in vitro models,
and results from scientific investigations in humans also suggest
potential health benefits and therapeutic applications (Cheuk
et al., 2007; Olaku and White, 2011; Wachtel-Galor et al., 2004).
G. lucidum contains various bioactive molecules, such as
triterpenoids, polysaccharides, nucleotides, fatty acids, glycopro-
teins, sterols, steroids, proteins and peptides (Batra et al., 2013;
Wachtel-Galor et al., 2011). Among these, triterpenoids,
polysaccharides, glycoproteins, and proteins have hypoglycemic
⇑ Corresponding author at: Institute of Biological Chemistry, Academia Sinica,
Nankang, Taipei 115, Taiwan. Tel.: +886 2 27886230; fax: +886 2 27883473.
E-mail address: bcchen@gate.sinica.edu.tw (S.-T. Chen).
1
These authors contributed equally to this work.
effects (Fatmawati et al., 2009; Hikino et al., 1985, 1989; Kino
et al., 1990; Teng et al., 2012). Polysaccharides inhibit hyper-
glycemia by regulating the expression of several key enzymes in
the glucose metabolism pathway, such as hepatic glucokinase,
phosphofructokinase, glucose-6-phosphate dehydrogenase,
hepatic glycogen phosphorylase (hepatic GP), fructose-1,6-
bisphosphatase (FBPase), phosphoenolpyruvate carboxykinase
(PEPCK) and glucose-6-phosphatase (G6Pase) respectively (Agius,
2007; McCormack et al., 2001; Xiao et al., 2012). Over 140
triterpenoids have been isolated from Ganoderma, and fifteen
triterpenoids have been identified in G. lucidum (Wu et al., 2013).
Recently, many investigations have sought to analyze relationships
between the structure and biological function of these triter-
penoids (Fatmawati et al., 2011b; Li et al., 2013; Liu et al.,
2006a,b; Shiao, 2003) and glycans (Pan et al., 2014).
Triterpenoids show aldose reductase and a-glucosidase inhibitory
activities, which were correlated with glucose metabolism and
diabetic complications (Bhatnagar and Srivastava, 1992;
Fatmawati et al., 2010a,b, 2011a,b, 2013; Gabbay, 1975; Martin
and Montgomery, 1996; Schemmel et al., 2010). Protein extracted
from G. lucidum reduced plasma glucose concentrations resulting
in the promotion of anti-type I diabetes activity (Kino et al.,
1989, 1990). The aim of the current review is to summarize the
anti-diabetic effects of G. lucidum.

http://dx.doi.org/10.1016/j.phytochem.2015.02.017
0031-9422/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Ma, H.-T., et al. Anti-diabetic effects of Ganoderma lucidum. Phytochemistry (2015), http://dx.doi.org/10.1016/
j.phytochem.2015.02.017
2 H.-T. Ma et al. / Phytochemistry xxx (2015) xxx–xxx
2. Anti-diabetic agents from G. lucidum
2.1. Polysaccharides
Polysaccharides extracted from G. lucidum are reported to have
hypoglycemic effects by increasing plasma insulin levels and
decreasing plasma sugar levels in mice (Hikino et al., 1985,
1989). Furthermore, G. lucidum polysaccharides have been shown
to enhance the activities of hepatic glucokinase, phosphofruc-
tokinase, and glucose-6-phosphate dehydrogenase. G. lucidum
polysaccharides also inhibits glycogen synthetase activity, thereby
decreasing hepatic glucose production, which can in-turn prevent
hyperglycemia (Agius, 2007; McCormack et al., 2001). G. lucidum
polysaccharides (50 and 100 mg/kg/d) can decrease the mRNA
level of key enzymes involved in glycogenolysis and/or
gluconeogenesis, such as hepatic glycogenphosphorylase, fruc-
tose-1,6-bisphosphatase, phosphoenolpyruvate carboxykinase
and glucose-6-phosphatase (Xiao et al., 2012). G. lucidum
polysaccharides can also increase body weight, blood glucose
levels and serum insulin levels and decrease blood lipid levels
(Li et al., 2011). Additionally, G. lucidum polysaccharides decreased
serum glucose levels and abnormal serum insulin levels in
STZ/high fat diet-induced type II diabetic mice (Xiao et al., 2012).
G. lucidum polysaccharides with low molecular weights can cause
hypoglycemic effects, protect pancreatic cells from cell death,
and promote b-cell regeneration by up-regulating Bcl-2 (an anti-
apoptosis protein) and PDX-1 (which encourages development of
pancreas b-cells (Oliver-Krasinski et al., 2009). Zheng et al.
(2012) further reported that inducible nitric oxide synthases and
caspase-3 were down-regulated in STZ-induced diabetic rats,
which induced apoptosis. Zhang et al. (2003) found that G. lucidum
polysaccharides protect pancreatic cell against alloxan-induced
damage by inhibiting NF-rB activity. Endothelial cell apoptosis is
associated with cardiovascular complications, the main cause of
mortality and morbidity in patient with diabetes (He et al.,
2005). Hyperglycemia is an inducer of endothelial cell apoptosis
in diabetic mice (Du et al., 1998; Recchioni et al., 2002).
Wound healing in diabetic patients is slowed by multiple
mechanisms, such as dysregulated growth factor production,
angiogenesis and inappropriate ECM remodeling (Brem and
Tomic-Canic, 2007). Slower wound healing in patients increases
the risk for amputations. Tie et al. (2012) investigated whether
G. lucidum polysaccharides can stimulate wound healing in
STZ-induced diabetic mice. In this respect, G. lucidum polysaccha-
rides increased approximately 21 percent of wound closures in
Fig. 1. Schematic diagram of Ganoderma lucidum polysaccharides anti-diabetes properties. (?: indicates activation or upregulation;
downregulation).
Please cite this article in press as: Ma, H.-T., et al. Anti-diabetic effects of Ganoderma lucidum. Phytochemistry (2015), http://dx.doi.org/10.1016/
j.phytochem.2015.02.017
diabetic mice and elevated wound angiogenesis in part by decreas-
ing mitochondria oxidative stress by inhibiting activity and nitra-
tion of manganese superoxide dismutase (MnSOD), suppressing
glutathione peroxidase (GPx) activity, decreasing redox enzyme
p66Shc expression and phosphorylation. Cheng et al. (2013) also
demonstrated that G. lucidum polysaccharides have the same
wound-healing effects in STZ-induced diabetic mice. All of the
mechanisms were shown in Fig. 1.
2.2. Proteoglycans
Protein tyrosine phosphatase 1B (PTP1B) is a promising
therapeutic target in diabetes, and it plays an important role in
the negative regulation of insulin receptor signaling and decreas-
es expression of insulin receptor b subunit (Combs, 2010;
Feldhammer et al., 2013). Teng et al. (2011) first reported that
proteoglycan extracted from G. lucidum can inhibit PTP1B in vitro.
Extractions of G. lucidum were divided into seven fractions. The
fifth fraction, called FYGL (Fudan-Yueyang-G. lucidum), had the
lowest IC50 to inhibit PTP1B activity (5.12 ± 0.05 lg/mL) in vitro.
FYGL has dose-dependent hypoglycemic and hypolipidemic
effects and increases blood insulin levels, inhibits PTP1B activity
and decreases PTP1B protein expression in skeletal muscle cells
(Teng et al., 2012). Diabetic (db/db) mice have point mutation
of leptin receptor which cause obesity and diabetes. In db/db
mice, glucose transporter 4 (GLUT4) protein expression was
induced by FYGL in skeletal muscle cells and adipocyte cells
(Pan et al., 2013). Hepatic GLUT2 expression was inhibited by
FYGL and correlated with hepatic glucose output (Oka et al.,
1990). These properties of FYGL increase the use of glucose in
muscle cells and adipocytes and lower hepatic glucose output
into the blood to decrease blood glucose levels. Furthermore,
FYGL also exerts effects on pancreatic islet regeneration and
antioxidant activity in db/db mice (Pan et al., 2013). The glycan
structure of FYGL was analyzed by periodate oxidation, Smith
degradation, methylation analysis, 1H & 13C 1D NMR and 2D
NMR respectively. FYGL is a homogeneous and acidic proteogly-
can (85 ± 2% polysaccharides and 15 ± 2% proteins) that contains
O-linkage type polysaccharides (repeat unit: 1,6-linked glucose,
1,2,4-linked galactose, 1,2-linked rhamnose and 1-linked glucose
as terminal), and its molecular weight is 100.2 kDa (Pan et al.,
2014). Because FYGL is sensitive to glycosidase, the researchers
hypothesized that FYGL glycan is removed in the stomach or
small intestine, with the glycan-dissociated protein motifs enter
into circulation to interact with PTP1B.
: indicates inhibition or
 H.-T. Ma et al. / Phytochemistry xxx (2015) xxx–xxx 3

2.3. Triterpenoids essential in aldose reductase inhibitory activity (Fatmawati et al.,

G. lucidum triterpenoids are inhibitors of aldose reductase and
a-glucosidase (Fatmawati et al., 2010a,b, 2011a,b, 2013). Of these,
aldose reductase is the first enzyme in the polyol pathway, which
processes glucose into sorbitol. The accumulation of sorbitol can
leads to diabetic complications, such as neuropathy, nephropathy,
cataracts, and retinopathy (Bhatnagar and Srivastava, 1992;
Gabbay, 1975; Schemmel et al., 2010). Fatmawati et al. (2009)
found that methanol extracts of G. lucidum have the highest aldose
reductase inhibitory activity among 17 edible and medicinal mush-
rooms. In 50% of galactose-fed rats, the blood galactitol level was
reduced by ethanol extracts from G. lucidum compared to the con-
trol group. They identified ganoderic acid C2 (1), ganoderenic acid
A (2) and ganoderic acid Df (3) in a CHCl3 extracts that had aldose
reductase inhibitory activity, as shown in Fig. 2. 3 had the highest
aldose reductase inhibitory activity of these three compounds. The
only structural difference between 3 and ganoderic acid C1 (4) is
the hydroxyl group at C-11. The aldose reductase inhibitory IC50
of 3 and 4 is 22.8 and >194.4 lM respectively, indicating that
C-11 is important for aldose reductase inhibition via 3. The
hydroxyl groups of 1 at C-3, C-7, and C-15 are also crucial to aldose
reductase inhibitory activity of 3. Conversely, the C-20 and C-22
double bonds play important roles in the aldose reductase inhibi-
tion of 2. Furthermore, free carboxyl groups in 1 and 2 are also
2010b, 2011b).
a-Glucosidase converts disaccharides and oligosaccharides to
glucose located in the small intestine epithelium. Therefore, inhibi-
tion of a-glucosidase is a common strategy to relieve hyper-
glycemia. Ganoderol B (5) was identified in a CHCl3 extract as
having higher a-glucosidase inhibitory activity than acarbose, an
inhibitor of a-glucosidase that suppresses blood glucose level after
meals (119.8 and 521.5 lM, respectively) (Fatmawati et al., 2011a;
Martin and Montgomery, 1996). They validated the relationship
between structure and activity from 19 triterpenoids, including
ganoderic acid Df and ganoderol B, as shown in Fig. 2. They also
determined that in hydroxyl groups at C-3 and C-11, carboxylic
groups in the side-chain, the D24(25) and D20(22) were important
for a-glucosidase inhibitory activity (Fatmawati et al., 2013).
2.4. Proteins
Ling Zhi-8 (LZ-8), a protein extracted from G. lucidum, exhibits
immunomodulatory and anti-type I diabetes activities (Kino
et al., 1989, 1990). LZ-8 has mitogen activity and can lower plasma
glucose concentration. In NOD mice, LZ-8 significantly decreased
lymphocyte infiltration and increased antibody detection of insulin
in beta cells. They also found that LZ-8 can stimulate the
generation of suppressor T-cells to inhibit pokeweed-induced

Fig. 2. Structure of triterpenoids from Ganoderma lucidum which have aldose reductase or a-glucosidase inhibitory activity.

Please cite this article in press as: Ma, H.-T., et al. Anti-diabetic effects of Ganoderma lucidum. Phytochemistry (2015), http://dx.doi.org/10.1016/
j.phytochem.2015.02.017
4 H.-T. Ma et al. / Phytochemistry xxx (2015) xxx–xxx
mitogens that were produced by human peripheral blood lympho-
cytes. Therefore, they hypothesized that LZ-8 displays
immunomodulatory activity to inhibit diabetes by adjusting sub-
sets of immune cells. This hypothesis was supported by Hsu
et al. (2013) who demonstrated that LZ-8 can stimulate expansion
of FOXP3+ regulatory T-cells (FOXP3+ Treg). LZ-8 increased
CD18-dependent IL-2 production and CD45-mediated downstream
signals to stimulate the expansion of Treg cells.
3. Conclusion
In conclusion, a variety of G. lucidum molecules, such as
polysaccharides, triterpenoids, proteoglycans, and proteins, exhi-
bits anti-diabetic effects. Not only do those molecules possess
anti-hyperglycemia properties, they regulate lipid profiles and
immune responses. G. lucidum polysaccharides and FYGL decrease
the levels of total cholesterol, triglycerides, and low density
lipoprotein cholesterols in the body, which may help prevent
diabetic complications, such as atherosclerosis and hyperlipi-
demia. However, G. lucidum polysaccharides and FYGL contain
amino acids; therefore, it is very difficult to determine whether
the hyperglycemic effects are exerted by polypeptides or by
polysaccharides. Additional evidence is required to provide a com-
prehensive explanation of the mechanisms underlying the anti-
diabetic effects of G. lucidum polysaccharides and FYGL. Despite
previous research on the relationships between structure and
activity in triterpenoids, the mechanisms involved in these rela-
tionships have yet to be elucidated. Most studies of LZ-8 have
focused on immunomodulatory activities. Only a few reports have
suggested that LZ-8 has anti-diabetic properties. An attempt to
define what types of proteins or molecules are able interact with
LZ-8 could yield interesting results.
Acknowledgement
This study was supported by National Science Council Taiwan,
R.O.C. for financially supporting this research under Contract No.
(NSC100-2113-M-001-025-MY3).
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Teng, B.S., Wang, C.D., Zhang, D., Wu, J.S., Pan, D., Pan, L.F., Yang, H.J., Zhou, P., 2012. Jung-Feng Hsieh obtained his Ph.D. in the Department
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lucidum on streptozotocin-induced type 2 diabetic rats. Eur. Rev. Med. in 2003. He is currently holding an Associate
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Tie, L., Yang, H.Q., An, Y., Liu, S.Q., Han, J., Xu, Y., Hu, M., Li, W.D., Chen, A.F., Lin, Z.B., Catholic University, Taiwan. His research is mainly in
Li, X.J., 2012. Ganoderma lucidum polysaccharide accelerates refractory wound the field of isolation and characterization of phyto-
healing by inhibition of mitochondrial oxidative stress in type 1 diabetes. Cell. chemicals from traditional Chinese medicine. He has
Physiol. Biochem. 29, 583–594. published more than 30 peer-reviewed and review
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effects of Ganoderma lucidum polysaccharides in type 2 diabetic mice. Arch. 1989. Since then he has served in the Institute of
Pharm. Res. 35, 1793–1801. Biological Chemistry at Academia Sinica, Taiwan as
Zhang, H.N., He, J.H., Yuan, L., Lin, Z.B., 2003. In vitro and in vivo protective effect of associate researcher, assistant researcher and then as
Ganoderma lucidum polysaccharides on alloxan-induced pancreatic islets research fellow. He was also an invited research scholar
damage. Life Sci. 73, 2307–2319.
in the Department of Chemistry, Texas A&M University,
Zheng, J., Yang, B., Yu, Y., Chen, Q., Huang, T., Li, D., 2012. Ganoderma lucidum
USA from 1988 to 1989. His research mainly focused on
polysaccharides exert anti-hyperglycemic effect on streptozotocin-induced
the systems biology to connect genomic DNA, mRNA,
diabetic rats through affecting beta-cells. Comb. Chem. High Throughput
Screen. 15, 542–550. proteins interaction networks and related pathways,
development of new enzymatic procedures for organic
synthesis, protein engineering by chemical approach as
well as drug delivery and targeting.
Haou-Tzong Ma received his bachelor degree from the
Department of Life Science, Tunghai University, Taiwan.
He is currently pursuing his Ph.D. in cancer biology and
drug discovery at China Medicine University and
Academia Sinica under guidance of Dr. Shui-Tein Chen
to develop screening small molecules for anti-cancer
drug. His current research involves the studying on the
cell biology and anti-cancer drug screening.

Please cite this article in press as: Ma, H.-T., et al. Anti-diabetic effects of Ganoderma lucidum. Phytochemistry (2015), http://dx.doi.org/10.1016/
j.phytochem.2015.02.017