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Medicinal mushrooms in prevention and control of diabetes mellitus

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Abstract

Fungal Diversity, 56 (1), 1-29 (2012). Diabetes mellitus is a life-threatening chronic metabolic disease caused by lack of insulin and/or insulin dysfunction, characterized by high levels of glucose in the blood (hyperglycemia). Millions worldwide suffer from diabetes and its complications. Significantly, it has been recognized that type 2 diabetes is an important preventable disease and can be avoided or delayed by lifestyle intervention. Presently, there are many chemical and biochemical hypoglycemic agents (synthetic drugs), that are used in treating diabetes and are effective in controlling hyperglycemia. However, as they may have harmful side-effects and fail to significantly alter the course of diabetic complications, natural anti-diabetic drugs from medicinal plants have attracted a great deal of attention. Medicinal mushrooms have been valued as a traditional source of natural bioactive compounds over many centuries and have been targeted as potential hypoglycemic and anti-diabetic agents. Bioactive metabolites including polysaccharides, proteins, dietary fibres, and many other biomolecules isolated from medicinal mushrooms and their cultured mycelia have been shown to be successful in diabetes treatment as biological antihyperglycemic agents. In this review we discuss the biological nature of diabetes and, in particular, explore some promising mushrooms that have experimental anti-diabetic properties, preventing or reducing the development of diabetes mellitus. The importance of medicinal mushrooms as agents of medical nutrition therapy and how their metabolites can be used as supportive candidates for prevention and control of diabetes is explored. Future prospects for this field of study and the difficulties and constraints that might affect the development of rational drug products from medicinal mushrooms are discussed.
Medicinal mushrooms in prevention and control
of diabetes mellitus
Dilani D. De Silva &Sylvie Rapior &Kevin D. Hyde &
Ali H. Bahkali
Received: 18 June 2012 /Accepted: 9 July 2012 / Published online: 4 September 2012
#Mushroom Research Foundation 2012
Abstract Diabetes mellitus is a life-threatening chronic
metabolic disease caused by lack of insulin and/or insulin
dysfunction, characterized by high levels of glucose in the
blood (hyperglycemia). Millions worldwide suffer from
diabetes and its complications. Significantly, it has been
recognized that type 2 diabetes is an important preventable
disease and can be avoided or delayed by lifestyle interven-
tion. Presently, there are many chemical and biochemical
hypoglycemic agents (synthetic drugs), that are used in
treating diabetes and are effective in controlling hypergly-
cemia. However, as they may have harmful side-effects and
fail to significantly alter the course of diabetic complica-
tions, natural anti-diabetic drugs from medicinal plants have
attracted a great deal of attention. Medicinal mushrooms
have been valued as a traditional source of natural bioactive
compounds over many centuries and have been targeted as
potential hypoglycemic and anti-diabetic agents. Bioactive
metabolites including polysaccharides, proteins, dietary
fibres, and many other biomolecules isolated from medici-
nal mushrooms and their cultured mycelia have been shown
to be successful in diabetes treatment as biological anti-
hyperglycemic agents. In this review we discuss the biolog-
ical nature of diabetes and, in particular, explore some
promising mushrooms that have experimental anti-diabetic
properties, preventing or reducing the development of dia-
betes mellitus. The importance of medicinal mushrooms as
agents of medical nutrition therapy and how their metabo-
lites can be used as supportive candidates for prevention and
control of diabetes is explored. Future prospects for this
field of study and the difficulties and constraints that might
affect the development of rational drug products from
medicinal mushrooms are discussed.
Keywords Medicinal mushrooms .Diabetes mellitus .
Anti-diabetic agents .Anti-hyperglycemic agents .
Bioactive metabolites .Mushroom supplementation .
Diabetes prevention
Introduction
Diabetes is a chronic disease causing several health prob-
lems to millions worldwide and has become a significant
ailment in many countries (Wild et al. 2004; WHO 2011;
Hagopian et al. 2011; Smith et al. 2012). Diabetes mellitus,
or simply, diabetes, is a group of metabolic diseases char-
acterized by high blood glucose levels that result from
insulin imbalances. In one way this can be considered as a
consequence of metabolic syndrome and gives rise to varied
complications including high morbidity and mortality rates
D. D. De Silva :K. D. Hyde (*)
Institute of Excellence in Fungal Research,
Mae Fah Luang University,
Chiang Rai 57100, Thailand
e-mail: kdhyde3@gmail.com
D. D. De Silva
e-mail: desilvadilani9@gmail.com
D. D. De Silva :K. D. Hyde
School of Science, Mae Fah Luang University,
Chiang Rai 57100, Thailand
D. D. De Silva
Department of Botany, Faculty of Science,
University of Peradeniya,
Peradeniya 20500, Sri Lanka
S. Rapior (*)
Faculty of Pharmacy, University Montpellier 1, UMR 5175 CEFE,
BP 14491, 15, avenue Charles Flahault,
34093 Montpellier Cedex 5, France
e-mail: sylvie.rapior@univ-montp1.fr
A. H. Bahkali
Botany and Microbiology Department, College of Science,
King Saud University,
Riyadh 11442, Saudi Arabia
Fungal Diversity (2012) 56:129
DOI 10.1007/s13225-012-0187-4
with increased risk of cardiovascular diseases and even
cancers (Zimmet et al. 1997; Kaur et al. 2002; Laaksonen
et al. 2004; Potenza and Mechanick 2009; Tourlouki et al.
2009; Cheng et al. 2012b; Dong et al. 2012; Hansen et al.
2012;Li2012). The disease also contributes to complica-
tions, such as retinopathy, neuropathy and renal dysfunction
through a series of pathological changes (Agardh et al.
2002; Thornalley 2002; Porta and Allione 2004; White et
al. 2008; Sobngwi et al. 2012; Winkley et al. 2012).
According to the WHO (2011), diabetes mellitus
accounts for 2.2 % of deaths in the world and is a one of
the main causes of death among humans. The most recent
data released by the Center for Disease Control and Preven-
tion (CDC) reports that diabetes is the seventh leading cause
of death in the United States; diabetes affects 25.8 million
(8.3 %) of the US population (CDC 2011). One major
tragedy of diabetes is that it can remain undiagnosed for
long periods without serious symptoms and ends up with
many untreatable complications such as coronary heart dis-
ease (Ved et al. 2010). Therefore early diagnosis and a
healthy lifestyle are crucial to reducing risk (Vinicor 1998;
Zhang and Ning 2011; Yates et al. 2012).
Epidemiological studies suggested that risk factors for
diabetes and its complications include hypercholesterolemia
and hyperglycemia, which are largely influenced by diet
(Kaur et al. 2002; Tourlouki et al. 2009; Igel et al. 2012).
It has been scientifically proven that a diet supplemented
with fruits and vegetables has beneficial effects on diabetes
and many cardiovascular diseases (Gallagher et al 2003;
Bazzano et al. 2008;Mirmiranetal.2009; Kanazawa
2011). A dietary pattern incorporating higher amounts of
low-fat dairy products may lower the risk of type 2 diabetes
and can be correlated with lessened hypertension, metabolic
syndrome and cognitive function in the middle-aged (Choi
et al. 2005; Liu et al. 2006; Crichton et al. 2012).
Medicinal mushrooms have been identified as remark-
able therapeutic agents in traditional folk medicines and
important as popular as culinary products all over the world
(Ying et al. 1987; Rapior et al. 2000; Halpern 2010; Deep-
alakshmi and Mirunalini 2011; Dotan et al. 2011; Muszyn-
ska et al. 2011; Abdullah et al. 2012). Species of medicinal
mushrooms have a long history of use for disease treatment
in folk medicines, especially in countries such as China,
India, Japan and Korea (Hobbs 1995,2000,2004,2005;
Chang 1999; Mizuno 1999a,b; Reshetnikov et al. 2001;
Ajith and Janardhanan 2007; De Silva et al. 2012; Lee et al.
2012). Medicinal mushrooms have shown therapeutic action
against the development of many diseases, primarily
because they contain a number of biologically active com-
pounds (Bao et al. 2001; Petrova et al. 2005; Moradali et al.
2007; Zhang et al. 2007; Lee and Hong 2011); they are also
used in cosmetics because of their medicinal properties
(Hyde et al. 2010). This includes mainly high molecular
weight compounds such as polysaccharides, proteins and
lipids as well as a number of low molecular weight metab-
olites such as lectins, lactones, terpenoids, alkaloids, sterols
and phenolic substances (Kidd 2000; Alexandre et al. 2007;
Zhong and Xiao 2009; Chung et al. 2010; Xiao et al. 2011).
The polysaccharide (β-glucans) contained in mushrooms, in
particular, can restore the functions of pancreatic tissues
causing an increase in insulin output by the functional
β-cells, thus lowering the blood glucose levels and has also
been shown to improve the sensitivity of peripheral cells to
circulating insulin (Misra et al. 2009; Qiang et al. 2009;
Xiao et al. 2011). Health conscious diets can incorporate
mushrooms as ideal low energy foods for diabetes patients
as they contain very low amounts, or are lacking in fats and
cholesterol, are low in carbohydrates, and high in proteins,
vitamins and minerals (Mattila et al. 2002; Guillamón et al.
2010; Phillips et al. 2011a,b; Ulziijargal and Mau 2011;
Smiderle et al. 2012).
The consumption of mushrooms markedly decreased the
lipid levels including as total cholesterol, total triglyceride,
and low-density lipoprotein cholesterol, and increased the
level of high-density lipoprotein cholesterol (Kim et al.
2001c; Alarcon et al. 2003; Jeong et al. 2010; Wani et al.
2010; Chen et al. 2011,2012). Besides containing macro-
nutrients in a well-balanced proportion, mushrooms also
have important micronutrients (vitamins) and non-nutrients
(phenolics) with bioactive properties such as anti-oxidants
(Ayaz et al. 2011; Reis et al. 2011; Wang et al. 2011a,b;
Beluhan and Ranogajec 2011; Abdullah et al. 2012; Pereira
et al. 2012; Liu et al. 2012). Mushrooms are also high in
water and fibre content (Mattila et al. 2001; Colak et al.
2009). Moreover, they contain natural insulin-like com-
pounds and enzymes which help break down sugar or starch
in foods and improve insulin resistance (Kim et al. 2005,
2010a,b). Mushrooms are also known to contain certain
compounds which help proper functioning of the liver
(Wani et al. 2010), pancreas and other endocrinal glands,
thereby promoting formation of insulin and related hor-
mones which ensure healthy metabolic functioning (Wasser
and Weiss 1999; Zhang and Lin 2004; Chen et al. 2012).
Most medicinal mushrooms such as Agaricus bisporus,A.
subrufescens,Cordyceps sinensis, Coprinus comatus,
Ganoderma lucidum, Inonotus obliquus, Phellinus linteus,
Pleurotus spp, Poria cocos and Sparassis crispa have been
reported to have hypoglycemic effects on reducing blood
glucose levels and anti-diabetic effects (Cha et al. 2006;
Yang et al. 2008; Seto et al. 2009; Jeong et al. 2010; Kim
et al. 2010a,b; Lu et al. 2010; Yamamoto and Kimura 2010;
Lee et al. 2010; Li et al. 2011a,b).
Medicinal mushrooms and their constitutive active com-
pounds have been described to have beneficial effects in
reducing many diseases including cancer, hypertension,
metabolic syndrome and cardiovascular diseases (Poucheret
2 Fungal Diversity (2012) 56:129
et al. 2006; Chen and Seviour 2007; Francia et al. 2007;
Guillamón et al. 2011; Martin 2010; Jiangwei et al. 2011;
Mujićet al. 2011; Wasser 2011; De Silva et al. 2012; Rathee
et al. 2012). Many studies have focused on their immuno-
modulatory and anti-tumor effects because mushrooms may
contain a diverse array of biologically active metabolites
(β-D-glucans, immunomodulatory proteins, secondary
metabolites) with well-known immune enhancing capabili-
ties (Bao et al. 2001; Johnston 2005; Petrova et al. 2005;
Moradali et al. 2007; Zhang et al. 2007; Reis et al. 2011;
Wasser 2011; Wu et al. 2012).
Some chemical and biochemical hypoglycemic agents
(anti-diabetes agents), such as insulin, metformin (Andujar-
Plata et al. 2012;Greevyetal.2011), tolbutamide, gliclazide
(Avogaro 2012), phenformin, troglitazone and rosigitazone,
exenatide are the mainstay in the treatment of diabetes
and are effective in controlling hyperglycemia (Scheen
2011;Majithiaetal.2011;Liday2011; Avogaro 2012;
Colagiuri 2012). However, these anti-diabetes agents
may have harmful side-effects, fail to significantly alter
the course of diabetic complications and there is insuf-
ficient knowledge on the pharmacological management
of the disease (Eurich et al. 2007;Anon2008,2009;
Liday 2011; Seino et al. 2012). Therefore, natural anti-
diabetic drugs from medicinal plants have attracted a great
deal of attention (Yeh et al. 2003;Kirkhametal.2009;
Petersen et al. 2011; Poraj-Kobielska et al. 2011).
Admittedly, diabetes is a metabolic disorder which
should be controlled or prevented with appropriate lifestyle
adaptations including exercise, appropriate food and health-
relevant environments (Ianculov et al. 2010; Chaufan et al.
2011; Jenkins and Hagberg 2011; Smith et al. 2012). Indeed
healthy foods rich in various medicinal properties pro-
vide a means to good health (Milner 2000; de Mello et
al. 2011). Edible and medicinal mushrooms are func-
tional foods and thus a good solution to controlling
diabetes and a potent source of biologically active com-
pounds with anti-diabetic effects. Many mushroom spe-
cies appear to be effective for both the control of blood
glucose levels and the modification of the course of
diabetic complications. Several examples of medicinal
mushrooms and their putative anti-diabetic effects are
shown in Table 1.
In this review we discuss the biological nature of diabetes
and particularly explore some promising mushrooms that
have demonstrated clinical and/or experimental anti-diabetic
properties by preventing or lowering the development of
diabetes mellitus. Even though current scientific /clinical
evidence does not sufficiently demonstrate the direct hypo-
glycemic effects of mushrooms for use as commercial drugs
or nutraceuticals, identification of their potential ability in
preventing diabetes could be a useful investment in future
drug discoveries.
What is diabetes?
The pathogenesis of diabetes is mainly due either to the
pancreas not producing enough insulin or when the cells
cannot respond effectively to the insulin it produces
(Kuzuya et al. 2002; Kawasaki et al. 2004; Stadler et al.
2009; ADA 2011). Insulin is a hormone that is needed to
convert sugar, starches and other food into energy needed
for daily life and it is a hormone that regulates blood sugar.
Low insulin levels and/or insulin resistance prevents the
body from converting glucose into glycogen (mostly in the
liver), which in turn makes it difficult or impossible to
remove excess glucose from the blood (Chinner et al.
2005; ADA 2011). Hyperglycaemia, i.e., excessive levels
of blood sugar, is a common effect of uncontrolled diabetes.
This is generally a glucose level higher than 10 mmol/
l (180 mg/dl), but symptoms may not start to become
noticeable until even higher values such as 1520 mmol/
l (270360 mg/dl) and over time leads to serious damage to
many of the bodys systems, especially the nerves and
cardiovascular system (Capes et al. 2001; Anon 2011).
There are three main types of diabetes mellitus. Type 1
diabetes results from the bodys failure to produce insulin.
Type 1 diabetes mellitus is characterized by loss of the
insulin-producing β-cells of the islets of Langerhans in the
pancreas leading to insulin deficiency (also referred to as
insulin-dependent diabetes mellitus,IDDM) (Kobayashi
1994; Kuzuya et al. 2002; Pozzilli et al. 2011). Type 1
diabetes can affect children or adults but was traditionally
termed juvenile diabetesbecause it represents a majority
of the diabetes cases in children.
Being the most common type of diabetes, type 2 diabetes
results from a condition in which cells fail to use insulin
properly (insulin resistance), sometimes combined with an
absolute insulin deficiency (non-insulin-dependent diabetes
mellitus,NIDDM) (Kitagawa et al. 1994; Beck-Nielsen et al.
1995;Horton1995). The onset of type 2 diabetes has
become most common in middle aged or later life, although
it is being more frequently seen in adolescents and young
adults due to an increase in child obesity and inactivity
(Rosenbloom et al. 1999; Norris et al. 2002; Pozzilli and
Guglielmi 2009). The increase in the number of children and
young adolescents with a mixture of the two types of dia-
betes (i.e. persons who are obese and/or have basic features
of insulin resistance as well as having antibodies in the
blood which act against the insulin producing β-cells of
the pancreas causing a decrease in the bodys ability to
produce insulin) has recently become topical. Under the
current classification, it is difficult to define the type of
diabetes which has elements of both type 1 diabetes and
type 2 diabetes, and is referred to as double diabetes(or
hybrid diabetes) (Pozzilli and Buzzetti 2007; Pozzilli and
Guglielmi 2009). Prediabetes is a state in which the fasting
Fungal Diversity (2012) 56:129 3
Table 1 Medicinal mushroom species with reported anti-diabetic effects
Mushroom species Bioactive compound Anti-diabetic effect References
Agaricus bisporus Dehydrated fruiting body
extracts
Lowers blood glucose and cholesterol levels Jeong et al. 2010
Yamac et al. 2010
Agaricus campestris Aqueous fruiting body
extract
Anti-hyperglycemic, insulin-releasing and insulin like activity Gray and Flatt 1998
Agaricus subrufescens
(A. blazei Murril, A. brasiliensis)
β-glucans and enzymatically
produced oligosaccharides
Improved insulin resistance in type 2 diabetes mellitus through increase in
adiponectin concentrations
Kim et al. 2005
Niwa et al. 2011
Agaricus sylvaticus Aqueous fruiting body extract Strong anti-oxidative effects with reduced cholesterol and triglyceride levels Fortes and Carvalho
Garbi Novaes 2011
Orsine et al. 2012
Auricularia auricula-judae Dried mycelia powder Significant reduction of plasma glucose total cholesterol and triglyceride levels Kim et al. 2007
Cerrena unicolor Extracellular polysaccharide Significant decrease in serum glucose level Yamac et al. 2009
Coprinus comatus 4,5- Dihydroxy-2-methoxy-
benzaldehyde (comatin)
Inhibiters of the non-enzymatic glycosylation (NEG) reaction Ding et al. 2010
Decreases concentrations of fructosamine, triglycerides and total cholesterol.
Maintains a low level of blood glucose and improves glucose tolerance
Cordyceps militaris Polysaccharide-enriched
fraction of fruiting body
Insulin like and insulin release promoting activity Yun et al. 2003
Hypoglycemic effects with lower elevation rates of blood glucose levels Zhang et al. 2006
Ophiocordyceps sinensis
(Cordyceps sinensis)
Polysaccharide fraction CSP-1 Results in a significant drop in blood glucose levels. Increases blood insulin levels. Li et al. 2003,2006
Causes induced release of insulin from the residual pancreatic cells and/or reduced
insulin metabolism in the body
Vanadium enriched fermented
culture
Anti-depressant-like activity and hypoglycemic activities Guo et al. 2010,2011
Cordyceps takaomantana
(Paecilomyces tenuipes)
Fruiting body extract containing
4- β- acetoxyscirpendiol (ASD)
Lowering blood sugar in the circulatory system as specific inhibitors of Na+/ glucose
transporter-1 (SGLT-1)
Yoo and Lee 2006
Yoo et al. 2005
Ganoderma lucidum sensu lato (3β,24E)-lanosta-7,9(11),24-
trien-3,26-diol (ganoderol B)
Strong α-glucosidase inhibition Fatmawati et al. 2011
Water extracts of polysaccharides
from fruiting bodies
Dose-dependently increased nonenzymic and enzymic anti-oxidants, serum insulin
levels and reduced lipid peroxidation and blood glucose
Jia et al. 2009
Water extract of whole
fruit body
Lowering the serum glucose levels through the suppression of the hepatic
phosphoenolpyruvate carboxykinase (PEPCK) gene expression
Seto et al. 2009
Grifola frondosa Mushroom extracts rich
in vanadium
Decreases blood glucose HbA1c levels Cui et al. 2009
Glycoprotein extract
(SX-fraction)
Improved glucose tolerance despite no elevation of circulating insulin concentrations
and showed enhanced sensitivity to exogenous insulin.
Preuss et al. 2007
Hericium erinaceus Methanol extract of the
mushroom
Hypoglycemic effects with significantly lower elevation rates of blood glucose levels Wang et al. 2005
Inonotus obliquus Culture broth Significant anti-hyperglycemic, anti-lipid peroxidative and antioxidant effects in
alloxan-induced diabetic mice
Sun et al. 2008
Xu et al. 2011
Ethyl acetate fraction Anti-hyperglycemic and anti-lipidperoxidative effects through decrease in blood
glucose level.
Lu et al. 2010
Terpenoid and sterol
compounds
Decreased the total cholesterol level in serum, increased glutathione peroxidase activity.
Decreased the levels of triglycerides and malondialdehyde, and increased the HDL
cholesterol level in serum and the hepatic glycogen level
4 Fungal Diversity (2012) 56:129
Table 1 (continued)
Mushroom species Bioactive compound Anti-diabetic effect References
Laetiporus sulphureus
var. miniatus
Crude extracellular
polysaccharides (EPS)
Increased the insulin antigenesity via proliferation or regeneration of diabetic
islet β-cells
Hwang and Yun 2010
Lentinula edodes Exo-polymer Hypoglycemic effects with lower levels of blood glucose, decreased the levels
of triglycerides and cholesterol.
Yang et al. 2002
Increased insulin levels
Lentinus strigosus Exopolysaccharides (EPS)
from mycelial culture
Decreased plasma glucose level up to 21.1 % at the dose of 150 mg/kg bw. Yamac et al. 2008
Induces regeneration of pancreatic islets and remediates destruction of microvascular
pancreatic islets
Phellinus baumii Exopolysaccharides
(heteropolysaccharides and
proteoglycans)
Reduced fasting blood glucose levels by 52.3 % compare to control Hwang et al. 2005
Amelioration of liver functions
Exopolysaccharides (EPS) by
submerged mycelial culture
Reduced fasting blood glucose levels, improved glucose tolerance, and systemic
insulin sensitivity
Cho et al. 2007
Regulates through peroxisome profilerator-activated receptor (PPAR-γ) mediated
lipid metabolism
Phellinus linteus Polysaccharides Inhibits the development of autoimmune diabetes by regulating cytokine expression Kim et al. 2010a,b
Submerged mycelial culture Decreased the concentrations of triglycerides and blood glucose levels Kim et al. 2001a,b
Hispidin Anti-diabetic property through preventing β-cells damage via hydrogen
peroxide-induced apoptosis and increased insulin secretion
Jang et al. 2010
Hispidin class of derivatives Act as natural aldose reductase inhibitors, in preventing diabetic complications Lee et al. 2008a,b
Phellinus merrillii Ethanol extracts Strong α-glucosidase and aldose reductase inhibitory activities Huang et al. 2011
Phellinus ribis (Phylloporia ribis) Polychlorinated compounds Therapeutic effects through the enhance PPAR-γagonistic activity Lee et al. 2008a,b
Pleurotus eryngii Diet rich with mushroom Improved insulin sensitivity and exerts anti-hyperglycemic and anti-hyperlipidemic
effects
Kim et al. 2010a,b
Pleurotus pulmonarius Aqueous extract of the
mushroom
Reduced the serum glucose level in alloxan-treated diabetic mice and increased
glucose tolerance
Badole et al. 2006
Sparassis crispa β-glucan component An effective promoter of wound healing in patients with diabetes. Increase in the
migration of macrophages and fibroblasts, and directly increases the synthesis
of type I collagen
Kwon et al. 2008
Freeze dried fruiting body
samples
Increased plasma levels of adiponectine Yamamoto and Kimura 2010
Decreases the concentrations of blood glucose levels, serum triglycerides and
total cholesterol levels
Tremella fuciformis Exopolysaccharides (EPS) by
submerged mycelial culture
Reduced fasting blood glucose levels, improved glucose tolerance, and systemic
insulin sensitivity
Cho et al. 2007
Regulates through peroxisome profilerator-activated receptor (PPAR-γ) mediated
lipid metabolism
Tremella mesenterica Fruiting body extract Reduced fasting blood glucose levels in streptozocin-induced type 1 diabetic
rats and pre-diabetic impaired glucose tolerant rats
Lo et al. 2006a
Tremella aurantia Acidic polysaccharide Reduced the serum glucose levels, total-cholesterol and triglyceride levels Kiho et al. 2001
Significant decrease in plasma lipoperoxide level
Wolfiporia extensa Crude extract and triterpenes Reduced postprandial blood glucose levels in db/db mice via enhanced insulin
sensitivity irrespective of PPAR-γ
Li et al. 2011a,b
Fungal Diversity (2012) 56:129 5
blood glucose level is elevated to above what is considered
normal levels, but is not high enough to be classified as
diabetes mellitus (Moutzouri et al. 2011). While in this
range, patients are at risk for not only developing type 2
diabetes, but may be prone to increased risk of microvascu-
lar and macrovascular complications including cardiovascu-
lar diseases (Gossain and Aldasouqi 2010). Prediabetes has
been reported as Americas largest healthcare epidemic,
affecting more than 57 million Americans (ADA 2008).
Prediabetes is also commonly termed as borderline diabetes,
impaired glucose tolerance (IGT), and/or impaired fasting
glucose (IFG) (Nichols et al. 2007; Moutzouri et al. 2011).
The third type, gestational diabetes develops in pregnant
women who have never had diabetes before, and have a
high blood glucose level during pregnancy (King 1998;
Ben-Haroush et al. 2004; Zhang and Ning 2011). It may
more similar to type 2 diabetes mellitus, and is fully treat-
able but requires careful medical supervision throughout the
pregnancy.
The most recent research discussing the pathophysiology
of type 2 diabetes correlates with the concept of activation
of the innate immune system and is directly linked with
insulin resistance and development of atherosclerosis (Fer-
nández-Real and Pickup 2012). The human innate immune
system is the bodys first-line of defense against several
foreign stimulations including microbial, chemical, physical
and even psychological injuries, which ensures the homeo-
stasis inside the body. When there is an imbalance between
the response to the stimulus, or when the threat is frequent
(e.g. continued over nutrition or inactivity), there is disease
instead of repair (Stumvoll et al. 2003). Recent evidence
indicates that innate immunity is closely linked to insulin
resistance and this link may involve genetic and cellular
factors that trigger the responses leading to diabetes and its
complications (Pickup et al. 1997; Fernández-Real and
Ricart 1999; Xie and Du 2011).
Although there may be a multiple causes for developing
diabetes, factors can be broadly categorized as environmental
and inherited (Prokopenko et al. 2008; Gupta et al. 2012).
Type 1 diabetes mainly occurs due to inherited factors and
type 2 diabetes is due primarily to lifestyle factors and genet-
ics. Epidemiological studies reported a bi-directional relation-
ship between diabetes and other disease types and their effects
on incidence of diabetes. Metabolic disorders such as over-
weight, obesity and stress related disorders such as depression
(Stuart and Baune 2012) are indirectly attributed to this and
are also reported as risk indicators of cardiovascular disease
(Lange and Piette 2005; Schneider et al 2011;Thyagarajan-
Sahu et al. 2011;Osanaietal.2012; Stuart and Baune 2012).
Diabetes, is a chronic disease which cannot be fully cured,
however, type 2 diabetes may be prevented or delayed by
proper food intake (de Mello et al. 2011;Doddetal.2011;
Wolden-Kirk et al. 2011) and several changes in lifestyle
(Vinicor 1998;Huetal.2001;Goldberg2006;Shawahnaet
al. 2012). Basically intake of food which is low in fat and high
in fibre content, avoidance of excessive weight gain, regular
physical exercise, and avoidance of aggravating factors such
as smoking and a stressful lifestyle could be beneficial
(Morrato et al. 2007;Kerretal.2011; Jenkins and Hagberg
2011; Wolden-Kirk et al. 2011;Brunetal.2009,2012;
Smith et al. 2012).
It is interesting to note that diabetes care has improved
with many technological advances in the field. From
improvements in insulin pumps to the implementation of
continuous glucose monitors, technology is helping deal
with diabetes better than ever before (Cobelli et al. 2011;
Farret et al 2012; Riveline et al. 2012).
Mushrooms as potent anti-diabetic agents
Agaricus bisporus (White button mushroom)
Agaricus bisporus is a popular edible mushroom worldwide.
The mushroom has potential anti-inflammatory, hypoglyce-
mic and hypocholesterolemic effects due to presence of high
amounts of acidic polysaccharides, dietary fibre, and anti-
oxidants, such as vitamins C, B
12
, and D; folate, ergothio-
neine; and polyphenol (Fukushima et al. 2000; Mattila et al.
2001; Koyyalamudi et al. 2009a,b; Geosel et al. 2011).
Literature also suggests that increased intake of white button
mushrooms may promote innate immunity against tumors
and viruses (Wu et al. 2007: Adotey et al. 2011; De Silva et
al. 2012). High concentrations of blood cholesterol levels,
hypercholesterolemia, can lead to a progression of hyper-
glycemia/type 2 diabetes in humans and animals (Mathe
1995; Kuller 2006). Cholesterol directly effects β-cell
metabolism and opens a novel set of mechanisms that may
contribute to β-cell dysfunction and the onset of diabetes
(Hao et al. 2007). Epidemiological studies suggest that
higher levels of dietary fibre intake play a significant pro-
tective role with respect to diabetes, in lowering the dietary
glycemic load and shows potent hypocholesterolemic
effects (Anderson et al. 2009).
Diabetic rats fed A. bisporus fruiting bodies exhibited
significant anti-glycemic and anti-hypercholesterolemic
effects (Jeong et al. 2010; Volman et al. 2010). Moreover,
the mushrooms had a positive influence on lipid metabolism
and liver function. Although soluble dietary fibre is the most
likely candidate in lowering blood glucose levels and cho-
lesterol levels, other constituents, such as anti-oxidants (pol-
yphenols, vitamin C, and ergothioneine), proteins, and
polysaccharides may also play an important role. Extracts
from A. bisporus may result in decreased severity of
streptozotocin-induced diabetes in rats with considerable
protective effects on the pancreas and apparent repopulation
6 Fungal Diversity (2012) 56:129
of β-cells (Yamac et al. 2010). Serum glucose levels de-
creased by 29.68 % and insulin levels increased to 78.5 %
with an oral administration of extract dose of 400 mg/kg
body weight per day.
Agaricus campestris (Field mushroom or meadow
mushroom)
Biologically active extracts of A. campestris have been
considered as a traditional treatment for diabetes. Anti-
hyperglycemic effects in administration of A. campestris in
the diet or drinking water of streptozocin-induced diabetic
mice have been demonstrated (Gray and Flatt 1998). In
particular, 1 mg/ml of aqueous extract, significantly stimu-
lated 2-deoxyglucose transport, glucose oxidation, and the
incorporation of glucose into glycogen in the abdominal
muscle of the mouse. In acute 20 minute tests, 0.25
1.0 mg/ml aqueous extract of A. campestris evoked a step-
wise 3.5 to 4.6 fold stimulation of insulin secretion from the
pancreatic β-cell line (Gray and Flatt 1998).
Activity of A. campestris extract was found to be heat
stable, acetone soluble, and unaltered by exposure to alkali,
but decreased with exposure to acid. The presence of both
low and high molecular weight substances in A. campestris
are responsible for the anti-hypertriglyceridemic, insulin
releasing, and insulin like activities (Gray and Flatt 1998).
A study conducted to assess the possible effects of plant
products on glucose diffusion across the gastrointestinal
tract showed the aqueous extracts of A. campestris and
various other plants extracts significantly decreased the
glucose movement, but were less effective than agrimony
and avocado (Gallagher et al. 2003)
Agaricus subrufescens (Almond mushroom)
Agaricus subrufescens (also known as Agaricus blazei or
Agaricus brasiliensis) is an edible mushroom, with a some-
what sweet taste and taste, and fragrance of almonds
(Kerrigan 2005). Agaricus subrufescens has been valued
as a medicinal mushroom having several biologically active
metabolites including polyphenols, polysaccharides and
glycoproteins which are thought to be responsible for its
immunostimulatory and anti-tumor properties (Firenzuoli et
al. 2008; Geosel et al. 2011; Lima et al. 2011; De Silva et al.
2012; Wisitrassameewong et al. 2012). Agaricus subrufes-
cens is a common mushroom in South America and in Asia,
and has been widely used in traditional medicine as a
remedy for certain types of cancers and diabetes (Sorimachi
and Koge 2008; Ishii et al. 2011).
β-Glucans and oligosaccharides of A. subrufescens
showed anti-hyperglycemic, anti-hypertriglyceridemic,
anti-hypercholesterolemic, and anti-arteriosclerotic activity
indicating overall anti-diabetic activity in diabetic rats (Kim
et al. 2005). Another study suggests that soluble β-glucan
from the mushroom has glucose reducing properties and
improves pancreatic β-cells in chemical-induced diabetic
rats through the inhibition of intestinal α-glucosidase and
enhancement of insulin secretion (Higaki et al. 2005).
A randomized, double-blinded, and placebo-controlled
clinical trial conducted with A. subrufescens fruiting body
extract in combination with metformin and gliclazide
showed improved insulin resistance in type 2 diabetes
patients. The increased adiponectin concentrations after tak-
ing fruiting body extract might be the mechanism that was
responsible for the beneficial effects (Hsu et al. 2007). Apart
from the hypoglycemic effect of β-glucans in A. subrufes-
cens, recent studies were carried out to explore other possi-
ble constituents. A hot-water extract of the submerged-
culture broth of A. subrufescens showed it to have potent
hypoglycemic action, which could be useful in the treatment
of diabetes mellitus. The hypoglycemic action might be
attributed to isoflavonoids including genistein, genistin,
daidzein, and daidzin and other substance derived from the
culture media of soybean flakes of the extract (Oh et al.
2010).
There has been much recent attention given to the rela-
tionship between diabetes and oxidative stress, which sug-
gests that oxidative stress is a mainstream effect of the
metabolic mechanisms by which overfeeding leads to insu-
lin resistance (Bisbal et al. 2010; Zhai et al. 2011). One
study suggested that the anti-diabetic effects of A. subrufes-
cens result from the suppression of oxidative stress and
proinflammatory cytokine, TNF-α, and improvement in β-
cells mass (Niwa et al. 2011). Diabetic patients with im-
paired metabolic control are more susceptible for pulmonary
complications with micro- and macro vascular disorders
(Davis et al. 2000; Kaparianos et al. 2008). A study dem-
onstrated the beneficial effect of A. subrufescens aqueous
extract on oxidative stress variables and pulmonary mor-
phopathology in streptozotocin-induced diabetes (Cangeri
Di Naso et al. 2010).
Agaricus sylvaticus (Sun Mushroom)
Agaricus sylvaticus, is a popular Brazilian mushroom spe-
cies of major importance as a food product and contains
substances with pharmacological and nutritional potential
(Taveira et al. 2008; Fortes and Carvalho Garbi Novaes
2011; Orsine et al. 2012). Pharmacologically active substan-
ces present in the mushroom such as phenolic compounds,
polyketides, terpenes and steroids are recognized as excel-
lent anti-oxidants and have attracted considerable attention
in clinical studies on immunosuppressed patients due to
their potential in acting as adjuvantsin cancer therapy
(Taveira et al. 2008; Fortes and Carvalho Garbi Novaes
2011). The ability of these extracts in manipulating the
Fungal Diversity (2012) 56:129 7
metabolic parameters could be equally beneficial in diabetic
treatments.
A randomized, double-blinded, placebo-controlled clini-
cal trial was conducted to evaluate the metabolic and blood
pressure effects on 56 patients with colorectal cancer who
supplemented with A. sylvaticus (Fortes et al. 2008). The A.
sylvaticus group presented a significant reduction of fasting
plasma glucose (p00.02), total cholesterol (p00.01), creat-
inine (p00.05), aspartate aminotransferase (p00.05), ala-
nine aminotransferase (p00.04), systolic blood pressure
(p00.0001) and diastolic blood pressure (p00.0001), while
these alterations were not observed in the placebo group
(Fortes et al. 2008,2009; Fortes and Carvalho Garbi Novaes
2011). Higher levels of cholesterol and triglyceride lead to
higher risk factors for diabetes, and a higher risk of devel-
oping cardiovascular disease (Schneider et al 2011;
Thyagarajan-Sahu et al. 2011). Prevention of onset of ath-
eroma plaques in hypercholesterolemic rabbits by water
extracts of the mushroom A. sylvaticus containing strong
anti-oxidants was also noted (Percario et al. 2008). Con-
trolled levels of all these metabolic parameters may reduce
the development of diabetes and related metabolic diseases.
Auricularia auricula-judae (Jews Ear, Jelly Ear mushroom)
Auricularia auricula-judae, an edible mushroom which
belongs to the family Auriculariaceae is widespread in
China and many parts of the world. Modern pharmacolog-
ical research indicates that this genus including A. auricula-
judae and A. polytricha has several medicinal properties
including antioxidant, antitumor, hypolipidemic and immu-
nomodulatory activities (Luo et al. 2008; Song and Du
2010; Chen et al. 2011).
The hypoglycemic effect of water-soluble polysacchar-
ides from fruiting bodies of A. auricula-judae was investi-
gated on genetically diabetic mice and showed that
mushroom supplementation had a significant effect in low-
ering plasma glucose, insulin, urinary glucose, and food
intake. Most interestingly the study showed that reduced
food consumption was not a major factor contributing to
the hypoglycemic action of extract (Yuan et al. 1998). A
further study also showed that hot-water extracts from A.
auricula-judae had a reductive effect on food intake and
blood glucose concentrations (Takeujchi et al. 2004).
Administration of dried powder of A. auricula mycelia
(AAM) (0.5 g/kg bw and 1.0 g/kg bw) caused a statistically
significant reduction of plasma glucose (35 % and 39 %,
respectively), total cholesterol (18 % and 22 %, respective-
ly) and triglyceride (12 % and 13 %, respectively) levels
with potential anti-diabetic effects (Kim et al. 2007). Ano-
ther study indicated that polyphenolic compounds and poly-
saccharides found in A. auricula, prevented hypercholester-
olemia with improving antioxidant status, decreasing the
level of total cholesterol and the atherosclerosis index, and
increasing the level of high-density lipoprotein cholesterol
(Chen et al. 2011).
Coprinus comatus (Shaggy ink cap)
Another delicious and nutritious edible mushroom, Copri-
nus comatus, is highly valued for its medicinal properties. It
has been reported to possess anti-diabetes, anti-oxidative,
antitumor, and anti-mutagen properties, and to protect the
liver from damage (Lee et al. 1999; Zaidman et al. 2008;Yu
et al. 2009; Popovićet al. 2010; Dotan et al. 2011).
Taking advantage of the ability of mushrooms to absorb
trace elements, several studies were designed to evaluate the
hypoglycemic effect of C. comatus enriched with vanadium.
Vanadium compounds have the ability to imitate insulin and
have shown anti-diabetic effects in several studies (Shechter
1990; Goldfine et al. 1995; Ma and Fu 2009). C. comatus
enriched with vanadium had significant anti-hyperglycemic
effects on mouse model tests and was confirmed as a hypo-
glycemic food or medicine (Han et al. 2006b; Han and Liu
2009; Lv et al. 2009; Yamac et al. 2009). Fermented C.
comatus rich in vanadium (CCRV) produced signifi-
cant decreases in blood glucose level, insulin secretion
(p<0.05, p<0.01) and inhibited levels gluconeogenesis in
hyperglycemic mice (p<0.01) (Zhou and Han 2008).
Despite previous anti-diabetes research on C. comatus,
there are only few reports concerning anti-diabetic activity
of 4,5-dihydroxy-2-methoxy-benzaldehyde (called comatin)
found in C. comatus. Comatin is an inhibitor of the non-
enzymatic glycosylation (NEG) reaction. It was revealed
that the blood glucose concentration of normal rats treated
with comatin at 80 mg/kg body weight was reduced from
5.14 mM to 4.28 mM in 3 h. Also, the concentrations of
fructosamine, triglycerides and total cholesterol in induced-
diabetic rats were significantly decreased. These results
indicate that comatin could maintain a low level of blood
glucose and improve glucose tolerance (Ding et al. 2010).
Recently extracellular polysaccharides from C. comatus
were produced using the submerged fermentation system
(Ding et al. 2012) and these had high inhibitory effects on
non-enzymatic glycosylation. These findings can be applied
to improve the performance of C. comatus cultures in the
production of bioactive metabolites on a bioreactor scale
and provide the foundation for further investigation into
medicinally active compounds derived from C. comatus.
Glucose lowering activities of five extracts (ethanol
extract, water-soluble polysaccharide, alkali-soluble poly-
saccharide, protein and crude fibre) were prepared from
the stipe and cap of C. comatus. The water-soluble polysac-
charide of the cap powder (300 mg/kg p.o. daily) fed for
28 days to diabetic mice gave the best glucose lowering
activity of the five extracts and almost decreased the blood
8 Fungal Diversity (2012) 56:129
glucose levels to that of normal mice. Thus, C. comatus can
be developed as a potential oral hypoglycemic agent or
functional food in the control of diabetes mellitus (Li et al.
2010).
Cordyceps spp
Cordyceps are ascomycetes and are one of the most valued
fungi in traditional Chinese medicines. The medicine con-
sists of the dried fungus growing on caterpillar larva (Chen
and Jin 1992; Zhu et al. 1998a,b; Won and Park 2005;Yoo
et al. 2005; Leung et al. 2009; Das et al. 2010). According to
ancient descriptions, Cordyceps is believed to have impor-
tant pharmacological activities in protecting lung and kid-
ney functions and in promoting the essence and vital energy
(Ying et al. 1987; Zhu et al. 1998a). Recent scientific evi-
dence have shown that Cordyceps is capable of modulating
immune responses, and inhibiting tumor growth (Zhang
et al. 2006; Khan et al. 2010; Lee et al. 2011; Wong et al.
2010; De Silva et al. 2012;Yuetal.2012), improving
hyperlipidemia, and hyperglycemia, and sexual function
(Kiho et al. 1996,1999; Holliday et al. 2005; Shi et al.
2009).
Cordyceps militaris
Cordyceps militaris has traditionally been used as a tonic in
folk medicine and its activity has been corroborated in
recent research findings (Zhao-Long et al. 2000; Yu et al.
2004,2007; Won and Park 2005; Das et al. 2010; Yu et al.
2012). Oral administration of hot water extracts of C. mili-
taris fractionated by molecular weight showed mild hypo-
glycemic activity in streptozocin-induced diabetic rats (Yun
et al. (2003).The anti-diabetic effect of various fractions of
C. militaris was evaluated in streptozocin-induced diabetic
mice. Results showed that seven-day administration of the
ethanol soluble supernatant, cordycepin and acarbose, dra-
matically reduced blood glucose levels by 46.9, 48.4, and
37.5 %, respectively.
Wat er ex tra cts o f C. militaris (0.5 g/kg) ameliorated
insulin resistance and improved insulin secretion in type 2
diabetic rats. Impaired intracellular insulin action of rats was
induced by removal of 90 % of the pancreas and by feeding
a high fat diet (10 g/kg). This study implicated significant
reduction of fasting serum glucose levels, increased whole-
body glucose disposal rates and glucose utilization in skel-
etal muscles in rats and it was concluded that C. militaris
water extract contains a compound that acts as an insulin
sensitizer.
Prior to the streptozocin treatment, oral administration of
polysaccharide-enriched fractions significantly reduced glu-
cose levels by 6070 % in diabetic rats and suggests that C.
militaris polysaccharides may be promising as a polyphyletic
as it has protective action against streptozocin-induced diabe-
tes. It is evident that C. militaris has both insulin-like and
insulin release promoting activity and potential anti-diabetic
activity (Zhang et al. 2006). Cordycepin isolated from C.
militaris suppressed the diabetes regulating genes by acti-
vation in LPS-activated macrophages and inactivation of
NF-kB dependent inflammatory responses and suggests
that C. militaris will provide potential use as an immuno-
modulatory agent for treating diabetes (Shin et al. 2009).
A recent study concerned the hypoglycemic mechanism of
aqueous extracts of C. militaris tested with injection of
atropine and hemicholinium-3 (HC-3) to normal Wistar
rats, and a western blot was used to investigate insulin
signaling. Research findings indicate that C. militaris
can lower plasma glucose via the stimulation of insulin
secretion and cholinergic activation and the extracts
decreased the plasma glucose by 21 % and induced
additional insulin secretion by 54.5 % after 30 minutes
(Cheng et al. 2012a).
Cordyceps sinensis (Caterpillar fungus)
Fruiting bodies of Cordyceps attenuated diabetes induced
weight loss, polydipsia and hyperglycemia, and these
improvements suggest that the fruiting body of Cordyceps
has a potential to be a functional food for diabetes patients
(Lo et al. 2004,2006b; Misra et al. 2009). Free-radical-
induced lipid peroxidation is a common phenomenon which
has been associated with several diseases, including diabetes
mellitus (Feillet-Coudray et al. 1999). In type 1 diabetes
islet cells may be damaged selectively due to the insufficient
amounts of pancreatic anti-oxidant enzymes (superoxide
dismutase, catalase and glutathione peroxidase) (Kakkar et
al. 1998) and this can be prevented by use of an anti-oxidant
which reduces the cell damage (Prasad 2000).
In one randomized trial, 95 % of patients treated with 3 g/
day of C. sinensis showed a decrease in their blood sugar
levels, while the control group showed only 54 % improve-
ment with treatment by other methods (Guo and Zhang
1995). CSP-1, a polysaccharide with strong anti-oxidant
activity was isolated from cultured Cordyceps mycelia with
potent hypoglycemic effects. Administration of a CSP-1
dose of higher than 200 mg/kg body wt. daily for seven
days, produced a significant drop in blood glucose levels
and increased serum insulin levels in diabetic animals which
suggests that CSP-1 may stimulate pancreatic release of
insulin and/or reduce insulin metabolism (Li et al. 2003,
2006). The immunoregulatory activity of extracts of C.
sinensis can be beneficially used to inhibit and regulate
diabetes which is an autoimmune disease. Oral admin-
istration of C. sinensis resulted in reduction in the
overall incidence of diabetes due to an increase in the
Fungal Diversity (2012) 56:129 9
ratio of Treg cells to Th17 in the spleen and pancreatic
lymph nodes (Shi et al. 2009).
A new area of research focused on the prevalence of
depression in diabetic patients. Diabetes mellitus is accom-
panied by hormonal and neurochemical changes that can be
associated with anxiety and depression (Lustman et al.
1983; Musselman et al. 2003; Talbot and Nouwen 2000).
Recent studies suggest a potential strategy for contemporary
treatment of depression and diabetes through the co-effect of
C. sinensis enriched with vanadium. Cordyceps sinensis has
both anti-depressant-like activity and hypoglycemic activi-
ties (Nishizawa et al. 2007; Li et al. 2006); studies have also
shown the hypoglycemic functions of vanadium by insulin
mimicry (Shechter 1990; Goldfine et al. 1995). Co-effective
interactions of both C. sinensis and vanadium together may
provide a possible treatment strategy to depression associ-
ated with diabetes (Guo et al. 2010,2011). CordyMax is a
standardized mycelial fermentation product of C. sinensis
which has been produced from a strain Cs-4. Much research
has been conducted to evaluate the efficacy of the strain and
it was found that CordyMax improves glucose metabolism
and increases insulin sensitivity in normal rats (Zhu et al.
1998a,b). Another study concluded that CordyMax Cs-4
may have potentially beneficial effects on maintaining
whole-body glucose disposal with a less pronounced effect
on insulin secretion in carbohydrate metabolism (Balon et
al. 2002). A recent study investigated the potential hypogly-
cemic and renoprotective effects of an extract from the
solid-state fermented mycelium of C. sinensis. Extracts pro-
mote β-cell survival, increases renal NKA activity and
decreases collagen deposition, and mesangial matrix accu-
mulation suggests that C. sinensis might be a potential drug
candidate for preserving β-cell function and offer renopro-
tection, which may afford a promising therapy for diabetes
mellitus (Kan et al. 2012).
Ganoderma lucidum sensu lato (Lingzhi)
Ganoderma lucidum has been utilized for centuries in East
Asia to prevent or treat various diseases and used in tradi-
tional Chinese medicine as a tonic in promoting good
health, perpetual youth, vitality, and longevity (Ying et al.
1987; Hobbs 1995; Chang and Mshigeni 2000; Sanodiya et
al. 2009; Deepalakshmi and Mirunalini 2011). In China, G.
lucidum is called Lingzhi. The Japanese name for the
Ganoderma family is Reishi(Wachtel-Galor et al. 2004).
Scientific investigations have repeatedly confirmed the ben-
eficial effects of G. lucidum to health and it is now frequent-
ly promoted as an effective agent against cancers due to its
intrinsic immunomodulatory and anti-tumor properties (Liu
et al. 2009; Shang et al. 2011; Ye et al. 2011). The primary
bioactive compounds are commonly considered to be
polysaccharides and triterpenoids (Hung et al. 2008;
Cheng et al. 2010). Recent studies on G. lucidum have
shown many interesting biological activities, including
anti-tumor, anti-inflammatory, anti-oxidant and anti-
diabetic effects (Paterson 2006;Mengetal.2011;Ye
et al. 2011;DeSilvaetal.2012).
Anti-hyperglycemic and anti-hypercholestromic effects
of G. lucidum have been extensively studied and have
shown potential therapeutic activities. Hypoglycemic effects
of G. lucidum-polysaccharides (G. lucidum-PS) are related
to facilitation of Ca
2+
influx into the pancreatic β-cells and
thus insulin release (Zhang and Lin 2004; Bastami et al.
2007). Prevention of the progression of diabetic renal
complications as well as a lowering of the increased
serum glucose and triglyceride levels was reported in
streptozotocin-induced diabetic mice (Zhang et al. 2003).
It was found that G. lucidum-polysaccharides reversed the
alloxan-induced viability loss of islets via an inhibition of
NF-κB activation and the suppression of free radical
formation.
The liver is an important organ in determining glucose
homeostasis and cholesterol levels in blood and phospho-
enolpyruvate carboxykinase is a hepatic enzyme which is
involved in the regulation of gluconeogenesis (Saltiel and
Kahn 2001). G.lucidum consumption can provide beneficial
effects in treating type 2 diabetes mellitus by lowering the
serum glucose levels through the suppression of the hepa-
tic phosphoenolpyruvate carboxykinase gene expression
(Seto et al. 2009).
Cellular oxidative damage is a well-established general
mechanism for cell and tissue injury and is primarily caused
by reactive oxygen species (ROS) (Agarwal and Sohal
1993; Adachi et al. 1998; Aksenova et al. 1998). An imbal-
ance between the formation of active oxygen metabolites
and the rate at which they are destroyed by enzymic and
nonenzymic anti-oxidants is referred to as oxidative stress
(Papas 1996). It has been suggested that cellular oxidative
damage and oxidative stress plays an important role in some
physiological conditions and in many diseases, including
diabetes mellitus (DM) (Feillet-Coudray et al. 1999). Natu-
ral protective anti-oxidative enzymes found in cells (glu-
cose-6- phosphate dehydrogenase, superoxide dismutase
(SOD), catalase (CAT), glutathione-S-transferase (GST)
and reduced glutathione) are important in both preventing
the production of free radicals and repairing oxidative dam-
age (Chandra et al. 1994; Kakkar et al. 1998). In a random-
ized, placebo-controlled clinical study, Ganopoly
(polysaccharide fractions extracted from G. lucidum by a
patented technique) was given to 71 patients with confirmed
type 2 diabetes mellitus and it showed efficacious and safe
lowering of blood glucose concentrations (Gao et al. 2004).
A recent study demonstrated that polysaccharides isolat-
ed from G. lucidum significantly increased nonenzymic and
enzymic anti-oxidants, and serum insulin levels, and
10 Fungal Diversity (2012) 56:129
reduced lipid peroxidation and blood glucose levels in
streptozocin-diabetic rats (Jia et al. 2009; Rubel et al. 2011).
Suffering from diabetes for a long time may cause myo-
cardial fibrosis, gradually leading to the development of a
risk factor for cardiovascular disease (Asbun and Villarreal
2006). G. lucidum-polysccharides were used in the treat-
ment of myocardial fibrosis found in diabetes (Meng et al.
2011). It was also shown that polysaccharides attenuated
myocardial collagen cross-linking in diabetic rats, which
was related to the decreased level of advanced glycation
end products and augmented activities of antioxidant
enzymes. Gl-PS accelerates refractory wound healing and
improved wound angiogenesis in streptozotocin-induced
type 1 diabetic mice, by suppression of cutaneous
MnSOD nitration, p66Shc and mitochondrial oxidative
stress (Tie et al. 2012).
Apart from the polysaccharide fraction, G. lucidum has
terpenoid constituents which possess many biological activ-
ities (Sliva 2003; Cheng et al. 2010; Weng and Yen 2010;
Grienke et al. 2011).Lanostane triterpenoid isolated from G.
lucidum, namely ganoderol B[(3β,24E)-lanosta-7,9(11),24-
trien-3,26-diol], had strong inhibitory activity on α-
glucosidase (Fatmawati et al. 2011). Alpha-glucosidase, an
enzyme located in the small intestine epithelium, catalyzes
the cleavage of disaccharides and oligosaccharides to glu-
cose. Any compound that inhibits the activity of α-
glucosidase can be proposed as a treatment for diabetes
mellitus type 2, since it works by preventing the digestion
of carbohydrates. Ganoderol B shows high α-glucosidase
inhibition with an IC
50
of 48.5 μg/ml (119.8 μM) effect in in
vitro studies.
Resistance to the hormones insulin and leptin are com-
mon metabolic conditions prevailing in type 2 diabetes
mellitus patients and it is mainly associated with increased
activity and expression of protein tyrosine phosphatase
(PTP)1B. Therefore, inhibition of (PTP)1B activity or its
expression should compensate the insulin and leptin resis-
tance by providing a therapeutic approach to type 2 diabetes
mellitus and obese patients (Popov 2011). Recently, a novel
(PTP)1B activity inhibitor, named Fudan-Yueyang- G. luci-
dum, was identified from the fruiting bodies of G. lucidum
and showed an efficient (PTP)1B inhibitory potency. Orally
administered proteoglycan extract, Fudan-Yueyang- G. luci-
dum to streptozotocin-induced diabetic rats showed a sig-
nificant decrease (IC
50
05.12± 0.05 μg/mL) in plasma
glucose levels (Teng et al. 2011) and the underlying mech-
anisms responsible for the anti-diabetic effect of G. lucidum
were identified. It was suggested that the hypoglycemic
effect of Fudan-Yueyang- G. lucidum is caused by inhibition
of the (PTP)1B expression and activity. Further, regulation
of the tyrosine phosphorylation level of the IR 13-subunit is
also promising as an insulin sensitizer for the therapy of type
2 diabetes and accompanied dyslipidaemia (Teng et al.
2012; Wang et al. 2012). Furthermore, Fudan-Yueyang- G.
lucidum significantly decreased the levels of free fatty acid,
triglyceride, total cholesterol and low density lipoprotein-
cholesterol as well as increased the level of high density
lipoprotein-cholesterol accompanied with other metabolic
disorders (Teng et al. 2011,2012).
Grifola frondosa (Maitake)
Grifola frondosa is very popular in Korea, China and Japan
and is thought to have many varied medicinal properties
(Mori et al. 2008; Misra et al. 2009). Several experiments
have found many beneficial activities attributable to G.
frondosa and/or its extracts. Maitake lowers blood sugar
because the mushroom naturally contains an α-glucosidase
inhibitor. Alpha-glucosidase inhibitors are presently known to
occur in aqueous methanol extracts of the seeds of Momordica
charantia and the fruit bodies of G. frondosa (Matsuur et al.
2002). Researchers evaluated the anti-diabetic effect of an
α-glucan (MT-α-glucan) from the fruit body of Maitake
mushrooms on KK-Ay mice. Data suggest that MT-α-glucan
has an anti-diabetic effect on KK-Ay mice, which might be
related to its effect on insulin receptors (i.e., increasing insulin
sensitivity and ameliorating insulin resistance of peripheral
target tissues) (Hong et al. 2007).
Fermented G. frondosa rich in vanadium (GFRV) signif-
icantly induced decreases of the blood glucose levels in
hyperglycemic mice (Cui et al. 2009). In addition, sub-
merged culture mycelium and broth of G. frondosa
improved glycemic responses in diabetic rats with signifi-
cant decreases in postprandial blood glucose levels and
serum triglyceride, fructosamine levels (Lo et al. 2008).
Further studies with a few human trials have also shown
that the anti-diabetic activity is present in the fruit body of
G. frondosa (Horio and Ohtsuru 2001; Konno 2001;
Manohar et al. 2002).
Hericium erinaceus (Lions Mane Mushroom)
Hericium erinaceus is an edible mushroom in the tooth
fungus group, native to North America which possesses
significant medicinal properties. H.erinaceus is a rare food
which contains components promoting NGF (nerve growth
factor) synthesis and can be regarded as a useful food for the
prevention of dementia and improving mild cognitive im-
pairment without any adverse effects (Kawagishi et al.
1996; Mori et al. 2009). Recent studies have determined
that Hericium spp may have important physiological func-
tions in humans, including anti-oxidant activities, anti-
tumor promoting activities and the regulation of blood lipid
levels and blood glucose levels (Wang et al. 2005; Wong et
al. 2009; Kim et al. 2011).
Fungal Diversity (2012) 56:129 11
An extract of the mushroom has been demonstrated to be
effective at lowering blood sugar and lipid levels in diabetic
rats. The blood sugar levels of the rats fed with the extract
decreased by 1926 % and the serum lipids decreased by
20 % compared to that of the control diabetic rats (Wang et
al. 2005). The biotransformation of Ginkgo biloba leaf
extract by H. erinaceus showed regulated blood glucose
effects through the increase of the serum superoxide dismu-
tase activity (Zhang et al. 2008).
Inonotus obliquus (White rot fungus/ Chaga)
Inonotus obliquus belongs to the family Hymenochaetaceae
of the basidiomycetes and is used as a folk health remedy in
Russia and western Siberia (Mizuno et al. 1999; Dai 2010;
Lee and Yun 2011). Many biologically active metabolites
such as polyphenolic compounds, triterpenoids, and steroids
have been identified from this mushroom, and these have
shown various biological activities, including anti-viral
(Ichimura et al. 1999), anti-fungal (Kahlos 1994), hepato-
protective (Wasser and Weiss 1999) anti-tumor (Mizuno et
al. 1999; Kim et al. 2006) and hypoglycemic (Mizuno et al.
1999) effects. A study conducted to investigate the protec-
tive effects of Chaga mushroom supplement against diabe-
tes, via the mitigation of oxidative stress and reduction of
blood glucose in streptozotocin-induced diabetic rats,
showed that the extracts may initially act on protecting
endogenous DNA damage in the short-term by triggering
high levels of total radical-trapping antioxidant potential
(Cha et al. 2006; Park et al. 2009).
Alloxan-induced diabetic mice treated with dry matter
culture broth of I. obliquus had significantly decreased
serum contents of free fatty acids (FFA), total cholesterol
(TC), triglyceride (TG) and low density lipoprotein-
cholesterol (LDL-C) levels. Whereas I. obliquus culture
broth demonstrate a significant anti-hyperglycemic and
anti-lipidperoxidative effects by increased levels of high
density lipoprotein-cholesterol (HDL-C), insulin and hepatic
glycogen (Sun et al. 2008). An extracted polysaccharide frac-
tion of I. obliquus administered to mice with diabetes mellitus
resulted in significant increased concentrations of anti-oxidant
enzymes which restored damaged pancreatic tissues (Xu et al.
2011). Crude polysaccharides from dry matter of culture broth
of I. obliquus demonstrated a similar anti-oxidative effect with
a significant anti-hyperglycemic activity and anti-
lipidperoxidative properties (Xu et al. 2010a,b). Func-
tional polysaccharides from I. obliquus showed anti-
hyperglycemic effects and regulated lipid metabolism
(Joo et al. 2010;Xinetal.2010;Huetal.2012).
Another study conducted to evaluate the photochemical
and hypoglycemic characteristics of the mushroom demon-
strated that the ethyl acetate fraction from I. obliquus
produced significant anti-hyperglycemic and anti-
lipidperoxidative effects in alloxan-induced diabetic mice
(Lu et al. 2010). Terpenoid and sterol compounds were the
major active constituents including lanosterol (1), 3β-
hydroxy-lanosta-8,24-diene-21-al (2), inotodiol (3), ergos-
terol peroxide (4) and trametenolic acid (5). Moreover,
inotodiol and trametenolic acid showed an inhibitory effect
on α-amylase activity and a scavenging effect on 1,1-
diphenyl-2-picrylhydrazyl radicals.
Postprandial hyperglycemia is a key event in the devel-
opment of type 2 diabetes mellitus and complications
associated with the disease. An acid protein-bound polysac-
charide IOPS, isolated from I. obliquus with a molecular
weight of 1.7×10
4
Da exhibited an inhibitory activity
against α-glucosidase with the IC
50
value of 93.3 μg/ml.
In addition, it produced inhibitory activity on hydroxyl
radicalsandonformationofthiobarbituric acid-reactive
substances in Fe
2+
/ascorbate-induced lipid peroxidation in
rat liver tissues (Chen et al. 2010). The authors claimed that
these research findings will benefit the investigation of
effective and safe α-glucosidase inhibitors from natural
materials and could be a good candidate for development
as functional foods or lead compounds for use in anti-
diabetes treatments (Chen et al. 2010).
Comparison of hypoglycemic activity of fermented I.
obliquus rich in vanadium and wild-growing I. obliquus
showed that mushrooms enriched with vanadium had high
bioavailability and low toxicity to animals, and could be
used as a means of vanadium supplementation, with an
expectation of obtaining anti-hyperglycemic activity (Zhang
et al. 2011b).
Lentinula edodes (Shiitake)
Lentinula edodes is widely consumed as a nutritional health
food worldwide, and contains proteins, lipids, carbohy-
drates, fibre, minerals, vitamins B1, B2 and C, ergosterol,
lectins and lentinan. It was the first medicinal mushroom to
enter the realm of modern biotechnology and used in the
treatment of several diseases (Cheung 2008; Zhang et al.
2011a). An exopolymer (200 mg/kg of the body weight)
produced from submerged mycelia cultures of L. edodes
reduced plasma glucose level by 21.5 % and increased
plasma insulin by 22.1 % in streptozocin-induced diabetic
rats as compared to normal rats. It also lowered plasma total
cholesterol levels and triglyceride by 25.1 and 44.5 %
respectively (Yang et al. 2002). A glycoprotein with a mo-
lecular weight of 52 kDa and containing 83.5 % carbohy-
drate and 16.5 % protein was the candidate bioactive
compound. It is evident that L. edodes could alleviate the
damage of pancreatic β-cells to some extent, promoting
insulin synthesis and thus lower the plasma glucose levels
(Yang et al. 2002). Supplementation of Shiitake mushroom
with other potential medicinal plant extracts showed
12 Fungal Diversity (2012) 56:129
significant effects on plasma blood glucose levels and im-
proved immunity (Guo et al. 2003).
Phellinus spp.
Phellinus is one of the largest of basidiomycete genera
with many species recognized as having medicinal prop-
erties. Polysaccharides, proteoglycans and derivatives of
polyphenols are the most cited medicinal metabolites
from Phellinus species being reported to have promising
anti-tumor activities (Han et al. 1999;2006a; Dai et al.
2010; Lee et al. 2010). These metabolites have also
been recognized as having anti-oxidant properties, and
in treating diabetes as well as its complications.
The hypoglycemic effect of Phellinus linteus proved
to have efficacy in lowering substantially the plasma
glucose and total trilgyceride level in streptozotocin-
induced diabetic rats (Kim et al. 2001a,b). Extracellular
polysaccharides extracted from mycelia grown in sub-
merged culture of Phellinus linteus showed hypoglyce-
mic effects with decreased plasma glucose, total
cholesterol and triacylglycerol concentrations by 49 %,
32 %, and 28 %, respectively (Kim et al. 2001b). More-
over, polysaccharides inhibit the development of autoim-
mune diabetes by regulating cytokine expression (Kim et
al. 2010a,b). Hispidin from P. l i n t e u s exhibited quench-
ing effects against reactive radicals in a dose-dependent
manner. In addition, hispidin was shown to inhibit hy-
drogen peroxide-induced apoptosis and increased insulin
secretion in hydrogen peroxide-treated cells. These com-
bined results indicate that hispidin may act as an anti-
diabetic through protecting β-cells from the toxic action
of reactive oxygen species in diabetes (Jang et al. 2010).
Hispidin also acts as natural aldose reductase inhibitors,
in preventing diabetic complications (Lee et al. 2010)
Crude exopolysaccharides produced from submerged
mycelial cultures of Phellinus baumii exhibited considerable
hypoglycemic effect with substantially reduced plasma glu-
cose levels (52.3 %) when fed to rats. The activities of
alanine aminotransferase (ALT) and asparate aminotransfer-
ase (AST) were significantly decreased by administration
of P. baumii exopolysaccharides, thereby exhibiting a
remedial role in liver function (Hwang et al. 2005). The
ethanol extracts of Phellinus merrillii (EPM) showed strong
α-glucosidase and aldose reductase activities. Alpha-
glucosidase and aldose reductase inhibitors were identified
as hispidin, hispolon and inotilone (Huang et al. 2011).
Unique polychlorinated compounds, named chlorophellins
A-C, have been isolated from the methanolic extract of the
fruiting body of the fungus Phellinus ribis and chlorophellin
C exhibited the most potent PPAR-gamma agonistic effect
for the therapy of type 2 diabetes compared to the other
compounds (Lee et al. 2008a,b).
Pleurotus spp. (Oyster mushrooms)
Pleurotus species have been used by different cultures
worldwide because of their nutritional value, medicinal
properties and other beneficial effects. Oyster mushrooms
are a good source of dietary fibre and other valuable
nutrients. They also contain a number of biologically active
compounds with therapeutic activities. Pleurotus species
have been proven to be a good source of essential amino acids
that have several medicinal properties and anti-oxidant activ-
ities (Mattila et al. 2001; Jayakumar et al. 2006; Badole et al
2006). Interestingly, Lovestatin, a cholesterol-lowering drug
isolated from Pleurotus species and its derivatives were
reported to be the best therapeutic agents for ameliorating
hypercholesterolemia (GundeCimerman and Plemenitas
2001; Mattila et al. 2001; Jayakumar et al. 2006).
Hypoglycemic activity of an aqueous extract of P. pul-
monarius in alloxan-induced diabetic mice has been
reported. Acute oral toxicity data showed no mortality in
the normal mice up to 5,000 mg/kg, while oral administra-
tion of extracts reduced the serum glucose level in alloxan-
treated diabetic mice at all the doses tested. The extract also
showed increased glucose tolerance in both normal and
diabetic mice (Badole et al. 2006). In a subsequent study,
the interaction of an aqueous extract of P. pulmonarius with
acarbose on serum glucose levels, and on an oral glucose-
tolerance test in alloxan induced diabetic mice was studied.
The anti-hyperglycemic effects of aqueous extract and acar-
bose alone were similar, but a combined treatment of P.
pulmonarius extract with acarbose produced a greater syn-
ergistic anti-hyperglycemic effect than either agent alone
(Badole and Bodhankar 2007).
Pleurotus species possess bioactive compounds, such as
polysaccharides, mevinolin and other statins, with hypocho-
lesterolemic activities (Gunde-Cimerman et al. 1993; Mattila
et al. 2001; Jayakumar et al. 2006). It has recently been
reported that P. citrinopileatus fruiting body extracts exerted
anti-hyperlipidemic effects. Serum triglyceride and total cho-
lesterol levels were lowered in hyperlipidemic rats supple-
mented with the extracts, while high-density lipoprotein
levels were significantly increased (Hu et al. 2006a). Similar
effects were noted when powdered P. ostreatus fruiting bodies
or a water-soluble polysaccharide extracted from P. citrinopi-
leatus fermentation broth were fed to hypercholesterolemic or
diabetic rats, respectively (Hossain et al. 2003; Hu et al.
2006b). The fasting blood glucose levels of diabetic rats fed
with polysaccharide extract were 44 % lower than the negative
controls with minimum damage to the islets of Langerhans. A
diet containing 4 % of P. ostreatus mushroom fed to rats with
insulin-dependent diabetes (streptozotocin 45 mg/kg) for two
months, had a significantly lower basal and postprandial gly-
caemia, with more than 40 % decrease in cholesterol concen-
trations (Chorváthová et al. 1993).
Fungal Diversity (2012) 56:129 13
Another important species, the king oyster mushroom
(Pleurotus eryngii) has been tested for insulin resistance,
anti-hyperglycemic and anti-hyperlipidemic effects in mice.
Dietary polysaccharides from the mushroom significantly
reduced the total cholesterol, triglyceride levels, and in-
creased high density lipoprotein cholesterol levels with
improved insulin sensitivity (Kim et al. 2010a,b). The
potential of Pleurotus eous in decreasing the hyperglycemic
levels in alloxan induced diabetic male albino rats were also
investigated (Raji et al. 2009). A novel polysaccharide-
peptide complex with hypoglycemic activities was isolated
and identified from the abalone mushroom P. abalones (Li
et al. 2011a,b;Wangetal.2011a). Diabetes mediated
oxidative stress is responsible for damaging the nuclear
component of the host cells and is known to be a vital cause
for the mutation related somatic and germinal cell dis-
orders (El-Rahim et al. 2010; Otton et al. 2004). A
novel antioxidant polysaccharide-peptide complex LB-
1b from the fruiting bodies of the edible abalone mush-
room exhibited a high antioxidant activity with a signifi-
cant hypoglycemic effect in drug-induced diabetic mice
(Li et al. 2012).
Pleurotus ostreatus extracts (especially high level) were
more effective in decreasing the genetic alterations and
sperm abnormalities in diabetes conditions and could reduce
the high blood glucose level in hyperglycemic rats (Ghaly et
al. 2011). Recently a clinical study was conducted with
participation of 120 diabetic patients to evaluate the efficacy
of oyster mushroom (Pleurotus spp.) on glycemic control.
The results included a significant association between mush-
room supplementation and gradual reduction in hyperglyce-
mia in type 2 diabetic subjects and demonstrate the potential
use of oyster mushroom for better glycemic control, positive
effects on lipid profiles and a better quality of life (Agrawal
et al. 2010).
Tremella fuciformis (Snow fungus or Silver ear fungus)
Tremella fuciformis is a commonly found mushroom which
is valued for its gelatinous texture as well as its supposed
medicinal benefits (Guo et al. 2003). Glucuronoxylomannan
(AC) from the fruiting bodies of T. fu cif orm is exhibited
significant dose-dependent hypoglycemic activity in nor-
mal mice, and also showed a significant activity in
streptozotocin-induced diabetic mice, when administered
by intraperitoneal administration (administration into
the peritoneal cavity) (Kiho et al. 1994). Anti-diabetic
activities of exopolysaccharides produced in submerged
T. fuciformis mycelial culture were investigated in mice
(Cho et al. 2007). The exopolysaccharides exhibited
considerable hypoglycemic effects and improved insulin
sensitivity possibly through regulating PPAR-gamma-
mediated lipid metabolism (Cho et al. 2007). These
results indicate that T. fuciformis has potential oral
hypoglycemic effects as a functional food for the man-
agement of diabetes mellitus.
Tremella mesenterica (Yellow brain mushroom)
The medicinal effects of the mushroom T. mesenterica is
mainly brought about by their acidic heteropolysaccharide
and several sugars including glucose contained in the fruit
bodies (Reshetnikov et al. 2001). In a study using
streptozocin-induced type 1 diabetic rats and nicotinamide
and streptozocin-induced prediabetic impared glucose toler-
ant rats, it was demonstrated that fruiting bodies of T.
mesenterica significantly reduced the elevated blood glu-
cose levels (Lo et al. 2006a).
Wolfiporia extensa (Poria cocos) (Pine-tree rotting
mushroom)
Poria cocos has long been used as Traditional Chinese
Medicine and food (Jia et al. 2003; Li et al. 2004). Poria
cocos, alone or in combination with other herbs is often used
to treat diabetes as well as other disorders (Jia et al. 2003;Li
et al. 2004). A mechanistic study on streptozocin treated
mice showed that the crude extract dehydrotumulosic acid,
dehydrotrametenolic acid and pachymic acid from P. cocos
exhibited different levels of insulin sensitizer activity (Sato
et al. 2002). The data suggested that the P. cocos extract and
its triterpenes reduced postprandial blood glucose levels in
db/db mice via enhanced insulin sensitivity irrespective of
PPAR-γ(Li et al. 2011a,b).
Medicine, nutrition and supplementation in preventing
diabetes
Diabetes is one of the worlds most important causes of
health expenditure, mortality, disability and lost economic
growth. World treatment costs are growing rapidly with the
larger costs of diabetes arising from disability and loss of
life caused by its complications, including heart diseases,
kidney, eye and foot disease (Wang et al. 2009a,b; Zhang et
al. 2010a; Thyagarajan-Sahu et al. 2011). Therefore the
disease imposes an increasing economic burden on national
health care systems worldwide. According to the Interna-
tional Diabetes Federation, the global health expenditure on
diabetes is expected to total at least USD $376 billion in
2010 and USD $490 billion in 2030. Globally, 12 % of the
health expenditures and USD $1330 per person are antici-
pated to be spent on diabetes treatments in 2010 (Shaw et al.
2010; Zhang et al. 2010a). Finding cures for this disease has
been a great challenge for scientists throughout this and the
previous century.
14 Fungal Diversity (2012) 56:129
Recent advances in medicine and developments in un-
derstanding the disease characteristics have given rise to
novel therapies to fight diabetes and related complications
(Lo and Wasser 2011; Sobngwi et al. 2012). However, few
clinical drugs are available for diabetes, and those that are
available usually have adverse side effects such as decreased
efficacy over time and low cost-effectiveness (Howlett and
Bailey 1999; Purnell 2008; Cheng and Fantus 2005). Thus,
more efficacious and safer anti-hyperglycemic agents are
needed. Therefore, research and development into novel
drugs for diabetes has been in great demand (Krentz and
Bailey 2005; Choi et al. 2011; Liday 2011; Scheen 2011;
Avogaro 2012; Barra et al. 2012). Many therapeutic strate-
gies from natural products with plant origins have been
developed as supportive methods for preventing and con-
trolling diabetes (Goyal et al. 2008; Karou et al. 2011;
Ranjbar et al. 2011;Ghoshetal.2012; Huseini et al.
2012). Currently, there is renewed interest in the plant based
medicines and functional foods for modulating physiologi-
cal effects and in the prevention and cure of diabetes. Today
mushrooms are considered as a type of functional food
which can ameliorate and prevent diabetes and its compli-
cations (Milner 2000; Perera and Li 2011).
Many of the curative and health promoting properties that
have been attributed to mushrooms by traditional folk med-
icine have been validated by recent scientific research (Jia et
al. 2009; Yamac et al. 2010; Lo and Wasser 2011; Huang et
al. 2011). Extensive research, mostly in Japan, China, and
Korea, where traditional medicines are still practiced and
also in several European countries, led to the isolation of
bioactive substances found in the fruiting bodies and the
mycelium of fungi. This, in turn, resulted in the develop-
ment of fungi-derived drugs and supplements effective
against human ailments. Significantly, several novel inves-
tigations on active constituents isolated from mushrooms
have been approved in several countries. Maitake-
D-fraction (Maitake Products, Inc. of New Jersey), an
over-the-counter immunostimulator compound derived
from Maitakesβ-(13)-D-glucans and β-(16)-D-glu-
cans, was approved in 1998 by the Food and Drug Admin-
istration (FDA) for the application for Investigational New
Drug (IND). This company also developed a new medicinal
mushroom preparation from Maitake (SF-Fraction-Glyco-
protein), which helps maintain healthy cardiovascular func-
tions and a healthy circulatory system. It was patented in the
USA (U.S. Patent # 5,773,426) (Shavit 2009). Some other
examples of patented mushroom extracts investigated in
recent years are shown in Table 2.
Examples of the available drug products and supplemen-
tary foods developed from medicinal mushrooms that claim
to provide beneficial effects on reducing blood glucose
levels and help in diabetes prevention are shown in Table 3
and Plate 1. There is growing evidence for the effectiveness
of using medical nutrition therapy in preventing and man-
aging chronic diseases such as diabetes (Pastors 2003; Anon
2010;Igeletal.2012). Intake of foods enriched with
medicinal properties is a cost effective means to achieve
significant health benefits by preventing or altering the
course of disease occurrence.
Furthermore, their intake may prevent or manage chronic
disease by increasing medication effectiveness, maintaining
nutritional status and preventing adverse complications
(Milner 2000; Curll et al. 2010; Thielen et al. 2010; Arathu-
zik and Goebel-Fabbri 2011). It has also been accepted that
medical nutrition therapy applications can be expanded and
integrated with pharmacotherapy and can increase the effec-
tiveness (Anon 2010).
As a general rule, prevention strategies are more efficient
than treatments, and always more cost effective (Pastors et
al 2002; Reimann et al. 2009; Costa et al. 2011; Andujar-
Plata et al. 2012; Romain et al. 2011,2012). What makes
mushrooms most valuable as a medicinal/therapeutic food
for curing diabetes is the fact that mushrooms can produce
several bioactive metabolites that can directly act upon
glucose metabolism and related biochemical pathways. On
the other hand they are important as nutritional foods to
provide complete defense against external, internal stressors
and inflammatory processes, and indirectly help in preven-
tion and amelioration of diabetes (Poucheret et al. 2006; Cui
et al. 2009; Guo et al. 2011; Lo and Wasser 2011; Da Silva
et al. 2012). Thus, incorporation of mushrooms as a daily
food or as a supplement, containing many nutrients such as
vanadium (Poucheret et al. 1998) and bioactive substances,
can assist in maintaining more normal cellular and immune
function which helps in normalizing blood glucose levels
(Wachtel-Galor et al. 2004; Han et al. 2006a,b; Zhou and
Han 2008; Han and Liu 2009; Cui et al. 2009; Guo et al.
2010,2011; Zhang et al. 2011a; Brennan et al. 2012).
Conclusions and future prospective
Diabetes mellitus is a life-threatening chronic metabolic
disease caused by lack of insulin and/or insulin dysfunction
characterized by hyperglycemia. Over 220 million people
worldwide suffer from diabetes and its complications, and
this number is predicted to increase in future years (Morrato
et al. 2007; Hagopian et al. 2011; Qi et al. 2011; Sattar
2012).
The growing impact of type 2 diabetes in the majority of
the population requires the introduction of better and more
secure treatments, but also requires the development of new
prevention strategies to reduce the incidence and prevalence
of the disease (Wang et al. 2009b; Narayan and Williamson
2010; Andujar-Plata et al. 2012). Significantly, type 2 dia-
betes is an important preventable disease and can be
Fungal Diversity (2012) 56:129 15
prevented or delayed by lifestyle intervention (Monnier et
al. 2004). Many studies have been published on the efficacy
of new preventive treatments for diabetes or its complica-
tions; however, there is still little information on its
applicability.
Medicinal mushrooms present an exciting opportunity
for the development of new types of therapeutics and have
been valued for their potential healing properties for centu-
ries. Mushrooms have been valued as remedies for disease
and as natural health foods for thousands of years, and they
are incredibly popular foods in numerous countries through-
out the world (Lindequist et al. 2005; Ferreira et al. 2010;
Guillamón et al. 2010; Pereira et al. 2012; Liu et al. 2012).
Biologically active metabolites and components derived
from medicinal mushrooms have been demonstrated to have
controlling effects on diabetes through the regulation of
several pathophysiological pathways related to the onset of
diabetes (Kim et al. 2005; Ding et al. 2010; Huang et al.
2011; Li et al. 2011a,b; Xiao et al. 2011). Some of the anti-
hyperglycemic mechanisms of medicinal mushrooms have
Table 2 Examples of patented products of mushroom extracts with claimed anti-diabetic properties (Source: http://www.freepatentsonline.com)
Claimed product/extract name Patent No Inventers
Agent for preventing/ameliorating diabetes and functional food for
preventing/ameliorating diabetes (Agrocybe aegerita (Brig.) Sing)
US 20070166320A1 Yamazaki K Nakagawa E (2007)
Crude exopolysaccharides produced from Phellinus baumii mycelium
having hypoglycemic activity and preparation method thereof
US 20060270626A1 Hwang HJ, Kim W, Yun JW, Choi JW (2006)
Health Promoting Dairy and Food Products Containing Mushroom
Glucan Produced Through Fermentation of Grifola frondosa
US 20080171104 Zhu Y, Sonnenberg ASM, Van Loo EN (2008)
Glycoprotein with antidiabetic, antihypertensive, antiobesity and
antihyperlipidemic effects from Grifola frondosa, and a method
for preparing same
US 7214778 Zhuang C, Kawagishi H, Preuss HG, (2007)
Method for processing chewing gum containing extracts of
(Grifola frondosa, Auricularia auricular) traditional Chinese
medicines for preventing and treating diabetes
CN 2010-10587474 Zheng, Gaoyu (2010)
Mushroom extracts from Agaricus, Hericium erinaceum, and
Hypsizigus marmoreus as insulin secretion stimulators and
health foods for prevention and therapy of diabetes mellitus
JP 2012077004A Takeshi I, Hiroshi H, Satoshi I, Aya K (2012)
Table 3 Examples of marketed products of mushroom extracts with claimed blood glucose lowering activity (The co-authors of the present paper
have not confirmed these claims)
Product name Product function claim Fungus/extract present Web page
Cordyceps sinensis capsules Control blood glucose levels Cordyceps sinensis http://curingherbs.com
Dr. Myco San products
DIMEMYKON
Optimally regulate blood sugar
levels and keep diabetes mellitus
under control
Mixed of several mushroom species www.mykosan.com
Jakopovich 2011
Ganoderma herbal
antidiabetes capsules
Enhance human bodys overall
immunity, accelerate recovery
of diabetes
Extract from young shoots of organic
Ganoderma lucidum and cell-wall
broken G. lucidum spore powder
Fujian Xianzhilou
Biological Science &
Technology Co., Ltd.
Increase the efficacy of medicinal
treatments
Triterpenes 8 % Polysaccharide 10 %
GlucoSANO-Diabetes
Health Formula
Specifically formulated for diabetic
health, the nutrients promotes
increased insulin sensitivity and
balanced blood sugar levels
Agaricus blazei, ErgoD2(Enriched
Pleurotus eryngii), White Beech,
Brown Beech (Hypsizygus tessellates),
Cordyceps militaris, Vitamin D2
(Ergocaliciferol)
http://www.totalnutraceutical.
com/glucosano-diabetes-
health-formula
ORIVEDA® Agaricus
blazei Murill extract
Anti-hyperglycemic, anti-
hypercholestromic and anti-
lipidperoxidative effects.
Concentrated hot water Agaricus blazei
Murill (ABM) extract (60 % of
polysaccharides)
http://www.chaga.us.oriveda.
com/agaricus.php
Great potential in normalizing blood
glucose levels and help to prevent
diabetes
ReishiMax capsules Inhibits adipocyte differentiation,
stimulates glucose uptake and
activates AMPK
Polysaccharides extracted from
Ganoderma lucidum
Thyagarajan-Sahu et al. 2011
SX-Fraction® Maintain healthy blood sugar
levels and insulin sensitivity
Glycoprotein from Maitake mushroom http://www.mushroomwisdom.
com
16 Fungal Diversity (2012) 56:129
been investigated including β-cell improvement and insulin
releasing activity, antioxidant defences, carbohydrate
metabolism pathways, α-glucosidase and aldose reductase
inhibitory activities, but more conclusive data is needed
(Lo and Wasser 2011).
As there are many complicated signalling pathways and
the involvement of a number of systems in regulating
glucose homeostasis in the human body, the identification
of the effect and activity of these metabolites is still uncer-
tain. Specific recommendations and standards for the use of
medicinal mushrooms in treating diabetes is lacking, which
is mainly due to insufficient data concerning the efficacy of
individual mushroom species and their products on diabetes.
Currently, submerged culturing of basidiomycetes is
Plate 1 Examples of products marketed with claimed anti-
hyperglycemic properties containing mushrooms or their extracts* 1.
Cordyceps sinensis capsules 2. Dr. Myco San products DIMEMYKON
3. Ganoderma herbal anti diabetes capsule 4. GlucoSANO-Diabetes
Health Formula 5. ORIVEDA® Agaricus blazei Murill extract 6.
ReishiMax capsules 7. SX-Fraction®. * The co-authors of the present
paper have not confirmed these claims
Fungal Diversity (2012) 56:129 17
preferred as the best technique for producing stable, safe
mushroom biometabolites (Reshetnikov et al. 2001; Lee et
al. 2004; Wasser and Akavia 2008;Kwonetal.2009;
Komura et al. 2010). Importantly, submerged culturing is
less time consuming than mushroom cultivation and leads to
the production of a consistent make up of mushroom metab-
olites in products as compared to fruiting bodies. The cor-
rect identification of metabolites with high quality specific
constant compositions allows for the development of stan-
dard medicinal products with targeted activity (Abraham
2001; Shu et al. 2004; Zhong and Tang 2004; Lin and Liu
2006; Ferreira et al. 2010; Wasser 2011; Lo and Wasser
2011; De Silva et al. 2012). Most evidence regarding the
beneficial effects of medicinal mushrooms has been
obtained from in vitro and animal studies (Badole et al.
2006;Dingetal.2010;Lietal.2011a,b). Preliminary
evidence from several medicinal mushrooms and their prod-
ucts suggest that further randomized controlled trials, espe-
cially for long term use, with large sample sizes may be
warranted. Safety issues regarding the long term consump-
tion of mushrooms, and inter-crossing or interactions with
other drugs also needs further clarification. Therefore, future
investigations directed towards these issues are necessary to
rationalize the use of mushrooms and their products as
potential drugs or nutriceuticals used in diabetes treatments.
There are still numerous countries and regions where
mushroom diversity has not been well studied (Hyde
2001; Aly et al. 2010; Ge et al. 2010; Wu et al. 2010; Zhao
et al. 2011;OHanlon and Harrington 2011,2012; Sysou-
phanthong et al. 2010) and new taxa may contain biologi-
cally active metabolites with potential medicinal effects for
controlling and preventing diabetes (Aly et al. 2010). Thus
much research is needed on mushrooms, particularly in the
tropics which is proving to support numerous undescribed
mushroom species (Hawksworth 2001; Boonyanuphap and
Hansawasdi 2010; Hyde et al. 2010; Zhang et al. 2010b;
Welti and Courtecuisse 2010; Yang 2011; Zhao et al. 2010,
2011) and these need assaying for bioactive metabolites that
can be used as possible remedies for diabetes treatments.
Studies are needed to explore this un-tapped resource for the
isolation and production of novel anti-diabetic compounds
having medicinal and biochemical potential with therapeutic
importance.
Acknowledgments This study was supported by a grant of the 1551
French-Thai cooperation PHC SIAM 2011 (project 25587RA) and the
grants Taxonomy, Phylogeny and cultivation of Lentinus species in
northern Thailand(MFU/54 1 01 02 00 48) from Mae Fah Luang
University research division and financially supported by the project
Value added products from basidiomycetes: Putting Thailands biodi-
versity to use(BRN049/2553) by the National Research Council of
Thailand (NRCT) to study medicinal fungi.
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