10.6092/issn.2531-7342/15023
Diabetes is a metabolic disorder that affects 1 in 11 people. More than 1.5 million deaths worldwide each year are related to the disease. Many medications are used for diabetes, but these medications only prevent the disease from progressing and its symptoms. Medicinal mushrooms have been used to treat diabetes since 2,000 years ago in the traditional medicine of different countries. This study reviews the research conducted on the anti-diabetic effect of several medicinal mushrooms reducing blood sugar level by various mechanisms. Mushrooms affect carbohydrate metabolism by inhibiting α-amylase and α-glycosidase enzymes, affect cellular pathways involved in fat metabolism, insulin secretion, and cellular apoptosis. The antioxidant activity of mushrooms prevents oxidative damage to pancreatic beta cells, reduce blood sugar, cholesterol, and triglycerides and normalize liver enzymes levels. The anti-diabetic activity of medicinal mushrooms has been proven by in vitro and in vivo experiments, as well as by clinical trials. They were suggested as dietary food supplement in the treatment of diabetes.
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Medicinal mushrooms as potential therapeutic agents in the treatment of diabetes mellitus: a review with focusing on in vivo and clinical studies
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Medicinal mushrooms as potential therapeutic agents in the treatment of diabetes mellitus: a review with focusing on in vivo and clinical studies
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                   IJM - Italian Journal of Mycology
                   ISSN 2531-7342 - Vol. 51 (2022): 75-96
                   Journal homepage: https://italianmycology.unibo.it/

Review

              Medicinal mushrooms as potential therapeutic agents
                      in the treatment of diabetes mellitus:
              a review with focusing on in vivo and clinical studies

    Hale Alvandi1, Elham Ansari1!, Soheil Kianirad1!, Ashrafalsadat Hatamian-Zarmi1*,
          Zahra Beagom Mokhtari Hosseini2, Bahman Ebrahimi-Hosseinzadeh1
1
 Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
2
 Department of Chemical Engineering, Faculty of Petroleum and Petrochemical Engineering, Hakim Sabzevari University,
Sabzevar, Iran

!
    The authors contributed equally. Corresponding author e-mail: hatamian_a@ut.ac.ir



Article info
Received 09/06/2022; accepted 7/11/2022
https://doi.org/10.6092/issn.2531-7342/15023

Abstract
Diabetes is a metabolic disorder that affects 1 in 11 people. More than 1.5 million deaths worldwide each
year are related to the disease. Many medications are used for diabetes, but these medications only prevent
the disease from progressing and its symptoms. Medicinal mushrooms have been used to treat diabetes since
2,000 years ago in the traditional medicine of different countries. This study reviews the research conducted
on the anti-diabetic effect of several medicinal mushrooms reducing blood sugar level by various mechanisms.
Mushrooms affect carbohydrate metabolism by inhibiting α-amylase and α-glycosidase enzymes, affect
cellular pathways involved in fat metabolism, insulin secretion, and cellular apoptosis. The antioxidant
activity of mushrooms prevents oxidative damage to pancreatic beta cells, reduce blood sugar, cholesterol, and
triglycerides and normalize liver enzymes levels. The anti-diabetic activity of medicinal mushrooms has been
proven by in vitro and in vivo experiments, as well as by clinical trials. They were suggested as dietary food
supplement in the treatment of diabetes.

Keywords
Medicinal mushrooms, antidiabetic, antioxidant, in vitro, in vivo, clinical trials


1. Introduction

Diabetes is a set of metabolic disorders that cause high blood sugar levels. In this disease, pancreatic
cells cannot produce enough insulin, or the body’s cells do not respond to the insulin produced
(Veiseh et al., 2015; Chaudhury et al., 2017; Morikawa et al., 2021). In type 1 diabetes, insulin
production is inadequate, and in type 2 diabetes, the cells are resistant to insulin absorption, plus
inadequate insulin production. Gestational diabetes is the third type of this disease that increases
blood sugar levels in pregnant women without a history of diabetes (Patel et al., 2012; Friedman,
2016; Wang et al., 2016). According to the World Health Organization (WHO), about 422 million
people worldwide have diabetes and 1.6 million deaths are directly attributed to diabetes each year
(Prabu and Kumuthakalavalli, 2017; Jia et al., 2009). Due to hyperglycemic conditions, eight types of

Department of Agricultural and Food Science in partnership with the Italian Mycological Society (UMI).
The journal is hosted and maintained by ABIS-AlmaDL. © 2022 The Authors. This work is licensed under CC BY 4.0
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pathophysiological mechanisms occur singly or in combination with each other. These conditions
include: 1) insulin secretion from pancreatic β-cells is reduced, 2) glucagon secretion from
pancreatic α cells is increased, 3) glucose production increases in the liver, 4) neurotransmitters
are inadequate in transmitting nerve messages and insulin resistance in the brain, 5) lipolysis
increased, 6) glucose reabsorption increased in the kidneys 7) incretin hormones is reduced in the
small intestine, 8) glucose uptake is reduced in peripheral tissues (Chaudhury et al., 2017; Sarmah
and Roy, 2022).
       Several drugs such as biguanides, sulfonylureas, meglitinides, thiazolidinediones, and
α-glucosidase inhibitors are used to control diabetes with different mechanisms of action. Due to
these drugs side effect, the focus has shifted from chemical to natural drugs derived from herbs
and medicinal mushrooms (De Silva et al., 2012; Chaudhury et al., 2017; Baker and Sardari,
2021; Deveci et al., 2021). These products contain flavonoids, terpenoids, alkaloids, polyphenols,
saponins, quinones, and glycosides with antidiabetic effects. One of the antihyperglycemic effects
of these compounds is associated with the inhibition of α-amylase and α-glycosidase. Also, plant
and medicinal mushrooms products improve pancreatic function and increase insulin secretion
(Alam et al., 2018; Afsharnezhad et al., 2021).
       The use of medicinal mushrooms to treat diseases has been common in traditional medicine
in different countries. The upward trend of studies in the field of medicinal mushrooms shows
their importance and application in the prevention and treatment of diseases (Fig. 1). Commercial
products of many medicinal mushrooms are also used as supplements or medicines in different
countries (De Silva et al., 2012). Medicinal mushrooms and their metabolites have antioxidant,
antidiabetic, and immune-enhancement properties (Alvandi et al., 2020a, b; Huang et al., 2020;
Yasrebi et al., 2020). The antidiabetic effect of fruiting bodies, mycelium, and mushrooms
polysaccharides have been studied in vitro, in vivo and clinical trials. Various mechanisms have
been proposed to explain the antidiabetic effect of medicinal mushrooms (Li et al., 2011). This
review studied the hypoglycemic effect of the most known medicinal mushrooms focusing on in
vitro, in vivo and clinical studies (Table 1).




             Fig. 1 - Documents published as medicinal mushrooms in Scopus for the last 50 years.




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Table 1 - Medicinal mushroom species with anti-diabetic effects.
                                                                                                                          Commercial
Species                               Antidiabetic effects                                                                           References
                                                                                                                          products*
Agaricus bisporus (White button Decrease TBARS, cholesterol, TG, LDL, MDA; increase antioxidants; increase                            Abou Zaid et al. 2017; Jeong et al. 2010;
                                                                                                           FB
mushroom)                       liver and body weight; repaire pancreatic tissue damage                                               Liu et al. 2013; Mircea et al. 2018
Agaricus subrufescens (A. blazei, A.
                                     Increase insulin resistance; increase adiponectin concentrations                     FB & E      Kim et al. 2005
brasiliensis)
Agaricus sylvaticus (Sun mushroom) Decrease TC, TG; increase AOA                                                          FB          Fortes 2011
Auricularia auricula-judae (Jew’s
                                  Decrease TC, TG, and plasma glucose concentrations                                      FB & E      Kim et al. 2007
Ear, Jelly Ear mushroom)
                                      Decrease cholesterol, TC, TG, MDA, and plasma glucose concentrations;
Coprinus comatus (Shaggy ink cap)                                                                                     FB & E          Yu et al. 2009
                                      increase HDL concentration and antioxidants in liver and kidney
                                      Decrease blood glucose level, lipid peroxidation, HbAlc; increase AOA; regulate                 De Silva et al. 2012; Ma et al. 2015; Rašeta
Ganoderma lucidum (Lingzhi)                                                                                           E
                                      liver enzymes; alter gut microbiota                                                             et al. 2020
                                      Decrease blood glucose level, HbAlc; decrease biomarkers of nephropathy                         De Silva et al. 2012; Jiang et al. 2020a;
Grifola frondosa (Maitake)                                                                                            FB & E
                                      (BUN, SCr, UA, NAG); alter gut microbiota                                                       Kou et al. 2019
Hericium erinaceus (Lion’s Mane
                                     Decrease serum glucose level; increase serum insulin level and antioxidants          E           Liang et al. 2013
mushroom)
Inonotus obliquus (White rot fungus/ Decrease blood glucose level, cholesterol, TG, LDL, MDA; increase antioxidants
                                                                                                                          E           Lu et al. 2010; Wang et al. 2017
Chaga)                               activity; increase PI3K-p85, p-Akt (ser473), GLUT expression
                                     Decrease blood glucose levels; increase glucose metabolism; decrease insulin                     Afiati et al. 2019; Hata 2021; Yang et al.
Lentinus edodes (Shiitake)                                                                                                FB & E
                                     resistance; modulation of the gut microbiome                                                     2018
Phellinus spp.                       Decrease blood glucose and TG levels; regulate lipid metabolism;                     E           De Silva et al. 2012; Kim et al. 2010
                                     Decrease blood sugar; increase Catalase activity; repairs the pancreas, liver, and               Balaji et al. 2020; Omale et al. 2020; Prabu
Pleurotus spp. (Oyster mushrooms)                                                                                         FB
                                     kidney tissues; inhibition of α-amylase and α-glucosidase activity                               and Kumuthakalavalli 2017
                                     Decrease blood glucose and MDA levels; increase the length of small intestine;                   Ekowati et al. 2018; Muthuramalingam et
Schizophyllum commune                                                                                                     E
                                     restoration of renal parameters; improved liver enzymes levels                                   al. 2019; Sharma et al. 2021
Tremella fuciformis (Snow fungus) Decrease blood glucose; increase glucose tolerance                                      E           De Silva et al. 2012
Tremella mesenterica (Yellow brain
                                     Decrease blood glucose, TC, TG; increase glucose tolerance                           Unknown     De Silva et al. 2012
mushroom)
                                     Decrease blood glucose, TC, TG, and LDL levels; decrease destruction of liver                    Alvandi et al. 2020a; Chen et al. 2015a;
Trametes versicolor                                                                                                       E
                                     tissue; increase HDL concentration; increase bone strength                                       Shokrzadeh et al. 2017
*FB = Fruiting bodies; E = Extracts
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2. Agaricus bisporus (J.E. Lange)
Agaricus bisporus (white button mushroom) with high amounts of dietary fiber, vitamins C, D, B12
and folate have the highest production globally (Atila et al., 2021). In most studies, the antidiabetic
properties of A. bisporus are associated with its antioxidant activity (AOA). The function of antioxidant
enzymes in type 2 diabetes is significantly reduced. Also, reactive oxygen species (ROSs) increase as
the disease progresses (Holy and Ngoye, 2016). The polysaccharides of this fungus with high phenolic
and flavonoid content significantly increased the activity of antioxidant enzymes in mice’s serum,
liver, and heart (Liu et al., 2013; Srivastava et al., 2017). Furthermore, intracellular ROS production
decreased with A. bisporus treatment (Vishvakarma and Mishra, 2020). Agarics bisporus flavonoids
prevented the oxidation of pancreatic β-cells DNA by reducing ROS production. In this way it regulated
pancreatic β-cells functions and improved insulin secretion. Agaricus bisporus polysaccharide is a
lectin-like molecule, which can stimulate insulin secretion by interaction with pancreatic β-cells. This
polysaccharide also appears to stimulate the uptake of Ca2+ in pancreatic β-cells, which ultimately
increases insulin production by affecting cell pathways (Abou Zaid et al., 2017; Ekowati et al., 2018).
The AOA of this fungus has also been studied clinically. Treatment of 37 pre-diabetics adults with
100 g A. bisporus significantly reduced oxidative stress factors in serum after 16 weeks (Calvo et
al., 2016). Agaricus bisporus also affects blood factors by regulationg carbohydrates and lipids
metabolism. Agaricus bisporus stimulated glucose uptake by fat cells similar to the rosiglitazone and
caused insulin-sensitizing in the presence of insulin (Mayasa et al., 2016; Vishvakarma and Mishra,
2020). Treatment of diabetic rats with 200 mg kg-1 of A. bisporus lowered blood glucose, cholesterol,
and triglyceride (TG) levels after 21 days. High cholesterol in diabetics causes damage to pancreatic
β-cells; by reducing cholesterol, this fungus prevented this damage and improved the function of
pancreatic β-cells (De Silva et al., 2012; Abou Zaid et al., 2017). Treatment with 500 mg kg-1 of A.
bisporus extract also reduced glucose and fructose absorption from the intestine in diabetic rats by
inhibiting glucose transporter 2 (GLUT2), a glucose transporter in the liver, pancreas, and intestine
(Abou Zaid et al., 2017; Ekowati et al., 2018). Figure 2 shows the mechanism of action of mushrooms
polysaccharide on diabetes.




           Fig. 2 - Possible cellular mechanisms of antidiabetic effect of medicinal mushrooms.


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3. Ganoderma lucidum (Fr.) Karst.
Ganoderma lucidum, known as “Lingzhi” in China and “Reishi” in Japan, is the most famous fungus
in traditional East Asian medicine. The antidiabetic properties of G. lucidum have been investigated
in many studies. This effect is associate with β-glucan, α-β glucan, protein and glucuronic acid
compounds in the fruit body, mycelium and polysaccharides of G. lucidum (Bach et al., 2018;
Kalantari-Dehaghi et al., 2019; Heydarian et al., 2021; Ahmad et al., 2022). Ganoderma lucidum
extract inhibit the activity of the α-glucosidase enzyme, which is involve in starch and disaccharides
hydrolyzes. Cho et al. (2021) found that the extraction conditions could affect this activity. Under
optimal conditions (65-70 °C for time 2.8-3 h) the α-glucosidase inhibitory activity was 39% (Cho et
al., 2021). Ganoderma lucidum triterpenoids are also α-glucosidase inhibitors (Ma et al., 2015).
       Consumption of G. lucidum polysaccharides reduced blood glucose in different animal models
such as Wistar rats, SD rats, pregnant rats, and Kunming species mouse (Zeng et al., 2018). Consumption
up to 5,000 mg kg-1 of G. lucidum polysaccharides was non-toxic in mice (Li et al., 2011). Ganoderma
lucidum polysaccharides increased plasma insulin levels and prevented high blood sugar by inhibiting
glycogen synthetase activity and reducing hepatic glucose production (Xiao et al., 2012; Singh et al.,
2016; Bach et al., 2018). In a study, diabetic mice were treated with G. lucidum polysaccharides (400
mg kg-1) for 8 weeks. Fasting blood sugar and glycosylated hemoglobin (HbAlc) concentrations in
the groups treated with polysaccharides were significantly lower than the control group. Also, these
polysaccharides lowered fasting blood glucose concentration in mice more than metformin (Pan et
al., 2021). Ganoderma lucidum polysaccharides significantly reduced the concentrations of alanine
aminotransferase (ALT), total cholesterol (TC), TG, low‑density lipoprotein cholesterol (LDL-C),
serum creatinine (Scr) and blood urea nitrogen (BUN) in the serum of diabetic mice compared to the
control group. It also increased the concentration of high‑density lipoprotein cholesterol (HDL-C) in
the serum of diabetic mice. Uric acid (UA), uric creatinine (Ucr) and urine microalbumin (U-LAB)
levels were also significantly lower in the urine of polysaccharide-treated mice (Pan et al., 2021). In
a clinical study, fasting blood glucose reduced significantly in type 2 diabetes patients treated with G.
lucidum polysaccharides after 12 weeks (three times daily, 1,800 mg) (Gao et al., 2004).
       Ganoderma lucidum also alters the cellular pathways involved in diabetes. Lee et al. (2020)
investigated the effect of G. lucidum extract in different doses for 12 weeks on C57BL/6 mice.
Treatment with G. lucidum improved glucose uptake, insulin receptor (IR), IR substrate 1 (IRS1)
and AKT serine/threonine kinase 1 (AKT1) phosphorylation. As a result, it increased the level of
glucose transporter types 4 and 1 (GLUT4 and GLUT1) and also activated AKT1 at phosphorylation
sites T308 and S473. Ganoderma lucidum supplementation attenuated the expression of lipogenesis-
related genes such as FAS, SCD1 and SREBP1c (Lee et al., 2020) and stimulated PI 3-kinase and
AMPK and increased glucose uptake into L6 skeletal muscle cells (Jung et al., 2006). Ganoderma
lucidum polysaccharides increased insulin secretion by facilitating Ca2+ influx in pancreatic β-cells
(Zhang and Lin, 2004). Ganoderna lucidum low molecular weight polysaccharides regulated Bcl-2
(anti-apoptotic protein) expression and reduced apoptosis in pancreatic β-cells (Ma et al., 2015). They
also prevented the pancreatic islets from damage by increasing superoxide dismutase and glutathione
peroxidase activities in the plasma and liver of diabetic rats (Jia et al., 2009). The polysaccharides of
this fungus reduced NOX expression and ROS production in vascular endothelial cells (Zeng et al.,
2018).
       As mentioned, in addition to polysaccharides, other compounds of this fungus also have
antidiabetic activity. Liang et al. (2020) found that the G. lucidum proteoglycan (200 mg mL-1) reduced
apoptosis in rat islet β cells (INS-1 cells) and intracellular ROS accumulation and NO release.
Ganoderma lucidum proteoglycan ultimately improved insulin secretion by deactivating NF-κB,
JNK, and p38 MAPK signaling pathways in streptozotocin (STZ)-induced INS-1 cells (Liang et al.,

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2020). In another study, the effect of 20 mg kg-1 ganoderic acid on streptozotocin-induced diabetic rats
was evaluated for two weeks. Treatment with ganoderic acid reduced blood glucose levels in a dose-
dependent manner. It also improved body weight and serum insulin levels. Other results included a
decrease of HbAlc levels, free fatty acids in adipose tissue, aspartate transaminase (AST) and ALT
(alanine transaminase) levels. Ganoderic acid also increased the size of β-cells, repaired tissue and
increased the volume of the pancreas (Ren, 2019).




             Fig. 3 - Medicinal mushrooms polysaccharides have antidiabetic effect via the gut
             microbiota. The duodenal environment is not suitable for the digestion of dietary
             polysaccharides. Dietary polysaccharides are digested into short-chain fatty acid
             (SCFAs) by microbiota after entering the large intestine. SCFAs stimulate intestinal
             cells to secrete glucagon-like peptide 1 (GLP‑1). SCFAs and GLP‑1 have direct and
             indirect anti-diabetic effects after entering the bloodstream. SCFAs and GLP‑1 prevent
             lipid accumulation. Fungal polysaccharides induce occludin and zonula occludens
             protein 1 (ZO-1) expression in intestinal cells, helping to maintain intestinal integrity
             and preventing the secretion of bacterial endotoxins into the bloodstream. Modified
             with permission from (Martel et al., 2017).



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        One of the most important mechanisms of action of fungal polysaccharides on diabetes is the
effect on intestinal bacteria. Studies show that disturbances in these bacteria cause diseases such
as intestinal syndrome, inflammatory bowel disease, obesity, depression, diabetes, anxiety and
neurodevelopmental disorders like autism and Parkinson’s disease (Marvasti et al., 2020; Mehrabadi
and Sadr, 2020; Mirmazloum et al., 2021; Zhang et al., 2022). The high molecular weight (> 300 kDa)
polysaccharides of G. lucidum are not digested in the stomach or small intestine. Digestion of these
polysaccharides by bacteria in the large intestine short-chain fatty acids (SCFAs) produced which
stimulate the secretion of glucagon-like peptide-1 by intestinal cells, regulated liver function and
induced β-cell proliferation (Martel et al., 2017) (Fig. 3). Consumption of G. lucidum changes the gut
bacterial population over time, reduce blood sugar level in diabetic rats by reducing harmful bacteria
such as Aerococcus spp., Ruminococcus spp., Corynebacterium spp. and Proteus spp. (Chen et al.,
2020), increase the levels of Blautia spp., Halobacterium spp., Parabacteroides spp., and Bacteroides
spp. and improve the metabolism of carbohydrates and fats in diabetic rats (Martel et al., 2017; Chen
et al., 2020).

4. Grifola frondosa (Dicks.) Gray
Grifola frondosa or Maitake mushroom, is one of China’s most popular edible mushrooms (Ma et
al., 2014; Chen et al., 2019). This polypore possesses antioxidant and anti-hyperlipidemic properties
(Jiang et al., 2020a) and contains oleic acid, which inhibits α-glucosidase activity and prolongs
carbohydrates’ digestion in the intestine (Su et al., 2013). Grifola frondosa polysaccharides have
antidiabetic effects by acting on cellular pathways. These polysaccharides stimulated intracellular
glycogen synthesis via the Akt/GSK-3 pathway (Wu et al., 2020; Xiao et al., 2021). Polysaccharides
from the fruiting bodies increased glucose uptake in a hepatocellular carcinoma cell line (HepG2) by
improving mRNA and protein expression of IRS1 and phosphatidylinositol-3-kinase (P13K), which
are involved in the insulin signaling pathways. These polysaccharides also affect the expression levels
of GLUT-4, IRS1, P13K and c-Jun N-terminal Kinase (JNK1). IRS1 activates P13K by binding to
it, which is a key kinase in glucose uptake and insulin-induced glucose transport. P13K also inhibits
JNK activity and affects glucose metabolism. GLUT-4 also facilitates the penetration of glucose into
muscle cells (Chen et al., 2018).
       Consumption of 900 mg kg-1 G. frondosa polysaccharides decreased TG and LDL-C levels and
increased hepatic glycogen levels (p < 0.05) (Guo et al., 2020). After four weeks, treatment of diabetic
mice with 150 mg kg-1 body weight polysaccharides significantly reduced hemoglobin A1c (HbA1c).
Jiang et al. (2020) investigated the inhibitory effect of G. frondosa polysaccharides on the progression
of renal fibrosis in rats with diabetic nephropathy. Consumption of 500 mg kg-1 polysaccharides of this
fungus caused a significant reduction in blood sugar after 60 days (p < 0.05), and helped to recover
the weight of diabetic rats. Grifola frondosa polysaccharides improved glomerular filtration capacity
and glomerular blood flow by reducing the biomarkers of nephropathy such as BUN, SCr, UA, and
urinary N-acetyl-beta-D glucosaminidase (NAG). These polysaccharides improved nephropathy by
regulating IL-2, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interferon α (IFN-α) levels.
At the same time, they repaired the epithelial cells in the proximal convoluted tubule and kidney
tissue (Jiang et al., 2020a; Kou et al., 2019). Consumption of G. frondosa polysaccharides with a
molecular weight fewer than 5,000 Da reduced fasting serum glucose, liver enzymes AST and ALT,
and total serum cholesterol. Lipid accumulation in the liver, which is caused by diabetes, was also
reduced (Xiao et al., 2021). Studies have shown that G. frondosa α-glucan has an antidiabetic effect
in mice by improving immune function and preventing pancreatic β-cells damage (Friedman, 2016).
Chromium (III) is one of the important trace minerals that is useful for improving type 2 diabetes.
This element is one of the components of glucose tolerance factor and plays an important role in

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regulating blood glucose levels and insulin resistance. Grifola frondosa polysaccharides contain
single electron pairs such as C=O, C-O-C, C-O-H, which can be suitable for ligand-binding with Cr
(III). Oral administration of 900 mg kg-1 day of G. frondosa polysaccharide-Cr (III) complex returned
liver glycogen levels to normal in diabetic Kunming mice. It also lowered fasting blood sugar and
lipid accumulation in these mice (Guo et al., 2019).
       Grifola frondosa polysaccharides regulated blood glucose by altering the gut microflora and
significantly increasing the population of Bacteroidetes (Chen et al., 2019) and increased Firmicutes/
Bacteroidetes in diabetic rats. The Firmicutes/Bacteroidetes ratio is a biomarker in diabetes that is
negatively correlated with plasma glucose (Magne et al., 2020; Xiao et al., 2021). The polysaccharides
of this fungus caused a significant increase in Porphyromonas gingivalis, which affected glycemic
levels in diabetes (Chen et al., 2019). Grifola frondosa also increased Alistipes spp. population,
which play an important role in the glucose and fat metabolism (Guo et al., 2020). Grifola frondosa
polysaccharides also increased the population of Turicibacter spp. in diabetic rats. These bacteria
improved insulin sensitivity by increasing intestinal butyric acid (Zhong et al., 2015; Xiao et al.,
2021).

5. Lentinus edodes (Berk.) Singer
One of the most important mushrooms in traditional Asian medicine is L. edodes (Shiitake), widely
used today due to its good taste and hypoglycemic effect (Sheng et al., 2021; Hatamian Zarmi et al.,
2022). The L. edodes extract inhibited glucose transfer up to 37.2% in Caco-2 cells and reduced adipose
tissue accumulation in the intestine (Nisar et al., 2017; Hata, 2021). Lentinus edodes mycelium extract
with AOA reduced the degree of INS-1 cells damage and Bax expression was reduced in cells treated
with this fungus. Lentinus edodes also affected the expression of cleaved caspase 3, cleaved caspase
1 and the NF-κB signaling pathway and prevented cell damage (Cao et al., 2019). The polysacchride
lentinan (400-800 kDa) has AOA and reduced apoptosis of pancreatic β-cells (Jiang et al., 2020b).
       Consumption of L. edodes polysaccharides (50 mg kg-1 body weight) could significantly (p <
0.05) reduced blood glucose, TG and cholesterol levels in streptozotocin-induced diabetic rats after 7
days (Kim et al., 2001). Lentinus edodes is a good source of β-glucans, which lowers blood glucose
levels by 55.87% in diabetic mice. β-Glucans also reduced cholesterol absorption in the stomach and
intestines (Afiati et al., 2019). Due to effect of the L. edodes polysaccharides on fat and carbohydrate
metabolism, its consumption alters the intestinal bacterial population (Martel et al., 2017).
       Gestational diabetes is a glucose intolerance and insulin resistance seen during pregnancy. There
is currently no specific treatment that affects the mother and fetus, increasing the risk of preterm birth,
birth defects, miscarriage, and the risk of developing type 2 diabetes in the future. Laurino et al. (2019)
examined the use of Shiitake (100 mg kg-1) in two forms of gestational diabetic rats: 1) exposure to L.
edodes from days 1 to 19 of pregnancy (before fetal implantation) and 2) exposure to L. edodes from
days 9 to 19 of pregnancy (after fetus implantation). The fungus did not reduce hyperglycemia in the
mother, but improved maternal glucose tolerance in amniotic fluid and placenta and increased insulin
levels. It also lowered cholesterol and TG levels and reduced liver damage (Laurino et al., 2019).

6. Oyster mushrooms (Pleurotus spp.)
Pleurotus spp. are also known as oyster mushrooms, which are widely used as food and prebiotics due
to their high fiber contant (Elkhateeb and Daba, 2021). These mushrooms are beneficial for human
health due to its antioxidant, anti-inflammatory, anti-tumor, and antidiabetic activities. One thousand
μg per mL fruiting body of oyster mushroom reduced glucose uptake by inhibiting α-amylase and
α-glucosidase enzymes by 94.93% and 84.90%, respectively. Pleurotus spp. also significantly reduced
cholesterol, TG, and LDL levels in diabetic rats (Friedman, 2016; Prabu and Kumuthakalavalli, 2017).

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       More than 200 species of this genus have been identified that have antidiabetic effects by different
mechanisms. One of the most important species is Pleurotus ostreatus (Jacq.) P. Kumm. Agunloye and
Oboh (2021) studied the diet of P. ostreatus on the blood sugar of diabetic rats. After 14 days, fasting
blood sugar decreased in diabetic rats. Also, the activity of superoxide dismutase and catalase in rats
treated with this fungus was significantly increased. Studies show that in diabetic rats, the activity
of the angiotensin-1 converting enzyme (ACE) and arginase increases, which is associated with high
blood pressure. The results showed that treatment with P. ostreatus reduced their activity (Agunloye
and Oboh, 2021). Pleurotus ostreatus extract at 5.0 mg mL-1 inhibited 2,2-diphenyl-1-picrylhydrazyl
(DPPH) free radicals by more than 80%. Also, 100 mg mL-1 of extract inhibited α-amylase activity by
more than 70% (Shamtsyan and Pogačnik, 2020). In one study, diabetic rats were treated with bread
containing 5%, 10% and 20% of P. ostreatus. Fasting blood sugar in the group treated with bread
containing 20% P. ostreatus was significantly reduced to 91 mg dl-1. Total cholesterol, HDL, LDL
and TG levels decreased after 28 days and rats lost weight from 149 to 122 g. This significant weight
loss in diabetic and obese rats indicated that this mushroom bread would be effective in managing
metabolic syndrome, as well as possibly cardiovascular disease (Okobiebi and Okhuoya, 2019).
       The antidiabetic effect of oyster mushrooms and other mushrooms or herbs, has been investigated.
Nnadiukwu et al. investigated the effect of the combination of ethanolic extract of Moringa oleifera
Lam. and P. ostreatus on the liver enzymes of alloxan-induced diabetic rats. The oral LD50 value
of M. oleifera and P. ostreatus was 5,000 mg kg-1 body weight. Increased liver enzyme activity in
diabetic rats is a sign of liver tissue damage. The combination of P. ostreatus and M. oleifera (3:2
w/w) significantly (p < 0.05) reduced ALT, AST, alkaline phosphatase (ALP), total bilirubin and
uric acid in diabetic rats (Nnadiukwu et al., 2017). Supplements of A. bisponus and P. ostreatus also
reduced blood sugar in diabetic rats after 30 days. The effect of these mushrooms was associated
with the presence of four proteins (profilin-like protein, glyceraldehyde-3-phosphate dehydrogenase-
like protein, trehalose phosphorylase-like protein and catalase-like protein), which affected the
metabolism of carbohydrates. This fungal supplement also modified the levels of AST, ALT and ALP
(Nweze et al., 2020). In clinical studies, a mixture of P. ostreatus and Pleurotus cystidiosus (50 mg
kg-1) significantly reduced fasting blood glucose levels (Jayasuriya et al., 2015). Table 2 summarizes
the clinical studies on the antidiabetic effect of mushrooms and Figure 4 shows this effect on human
organs.

Table 2. Clinical trials of medicinal mushrooms for antidiabetic activity.
Species               Clinical trial              Results                                            References

                                              Increase antioxidant enzymes and anti-inflammatory
Agaricus bisporus 37 pre-diabetics (100 g, 16                                                    Calvo et al.
                                              hormones; decrease oxidative stress factors,
(fruiting body)   daily weeks)                                                                   2016
                                              carboxymethyl lysine, and methylglyoxal in serum

Agaricus        blazei 536 diabetic patients (1,500 Decrease HOMA IR index; increase plasma Hsu et al.
(fruiting body)        mg daily, 12 weeks)          adiponectin concentration and insulin resistance 2007
                    71 diabetic patients (1,800
Ganoderma lucidum                                                                                    Gao et al.
                    mg three times daily, 12      Decrease HbA1c and fasting blood glucose
(polysaccharides)                                                                                    2004
                    weeks)
                    56 patients with colorectal
                                                                                                     Fortes et al.
Agaricus sylvaticus cancer (30 mg kg-1, 6         Decrease fasting blood glucose, TG, cholesterol
                                                                                                     2008
                    months)
Pleurotus ostreatus
                    28 diabetic patients (50 mg   Decrease blood sugar levels; increase glucokinase Jayasuriya
& P. cystidiosus
                    kg-1 body weight)             and insulin secretion                             et al. 2015
(fruiting body)


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       Fig. 4 - Possible effects of medicinal mushrooms on the function of various human organs that
       improve diabetes.

      The antidiabetic effects of other species of this genus have also been studied. Oral administration
of Pleurotus tuber-regium (Fr.) Singer polysaccharides (20 mg kg-1 for 8 weeks) had hypoglycemic
effects by increasing peroxisome proliferator-activated receptor (PPAR)-α mRNA expression in the
diabetic rats liver. These polysaccharides increased lipid metabolism; as a result, they reduced TG
and prevented obesity in diabetic rats (Friedman, 2016). Consumption of 5,000 mg kg-1 Pleurotus
pulmonarius sensu auct. extract with acarbose had a significant anti-hyperglycemic effect (Badole
and Bodhankar, 2007). Pleurotus pulmonarius significantly repaired the pancreas, liver and kidney
tissues in diabetic Wistar albino rats (Balaji et al., 2020). Pleurotus nebrodensis (Pleurotus fossulatus
(Cooke) Sacc.) extract regulated liver enzymes function and reduced blood glucose levels by more
than 50% in diabetic albino Wistar rats (Dubey et al., 2020). Consumption of Pleurotus eryngii (DC.)
Quĕl extract (200 mg kg-1) significantly reduced blood glucose and HbA1c levels and increased
insulin secretion in alloxan-induced hyperglycemic mice after 5 weeks. Studies showed P. eryngii
and Pleurotus citrinopileatus Singer also recover damaged β-cells with their antioxidant properties
(Hu et al., 2006; Li et al., 2014). Pleurotus cystidiosus increased insulin expression and decreased
circulating glucose levels (Chen et al., 2015b). Studies showed that GLUT 4 expression was increased
in L6 cells treated with oyster mushrooms (Khursheed et al., 2020).

7. Other agaricoid and polyporoid medicinal mushrooms
Agrocybe spp. mushrooms has a wide range of growth in Europe, Asia, and North America (Yong et
al., 2018). The antidiabetic properties of Agrocybe chaxingu N.L. Huang in diabetic mice have been
studied (Lee et al., 2010). The results showed that the polysaccharide isolated from this mushroom
significantly prevents STZ damage to pancreatic β-cells (Lee et al., 2010). Antidiabetic and antioxidant
properties and α-glycosidase inhibitory effect were found in Agrocybe aegerita (V.Brig.) Singer (Wu
and Xu, 2015).
       Agaricus blazei Murrill can lower blood glucose by containing isoflavonoids such as genistein,
genistin, and daidzein (De Silva et al., 2012). Ethyl extract of A. blazei had significant glucose-
lowering activity on HepG2 cells, comparable to metformin (Wei et al., 2020). The mixture of A.
blazei and G. lucidum could reduce blood sugar and HbA1c concentration in diabetic rats after 14

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days (Vitak et al., 2015).
       Auricularia auricula-judae (L.) Undrew mushroom has been used in traditional Chinese medicine
(TCM) for over 1,000 years. Recent clinical studies have been conducted on the therapeutic effects of
this mushroom and its polysaccharides. Treating diabetic Wistar rats with the polysaccharides of this
mushroom for four weeks improved their lipid metabolism and weight (Lu et al., 2018).
       Coprinus comatus (O.F. Müll.) Pers., the shaggy ink cap, regulates the immune system, lowers
blood sugar and lipids, and has anti-tumor and antibacterial activities. C. comatus extracts inhibit
α-amylase and α-glucosidase activity (Ding et al., 2010; Stojkovic et al., 2019). Yu et al. investigated
the antidiabetic effect of selenium-containing polysaccharides of this fungus. In addition to lowering
blood glucose, Se-polysaccharides significantly reduce malondialdehyde (MDA) levels and increase
the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in
the liver and kidneys of all diabetic mice (Yu et al., 2009).
       Fomes fomentarius (L.) Fr. has been used for thousands of years to treat gastrointestinal
disorders, liver cirrhosis, inflammation and various cancers (Alvandi et al., 2020b). Keshavarz-Rezaei
et al. (2022) observed that polysaccharide and selenium polysaccharide of F. fomentarius improve
insulin secretion and decrease HbA1c level in diabetic rats .
       Hericium erinaceus (Bull.) Pres. has antidiabetic properties in diabetic rats. After 28 days of
treatment (100 and 200 mg kg-1 BW), H. erinaceus extraction significantly increases insulin levels
and enzyme activity (AT, SOD, GSH-Px, and GSH level) (Liang et al., 2013). Hericium erinaceus
polysaccharides reduce fasting blood glucose, increase glucose tolerance, improve lipid metabolism
and inhibit lipid peroxidation. They also activate PI3K/Akt signaling pathway (Cai et al., 2020).
       Inonotus obliquus (Fr.) Pilăt has been used to treat heart disease and diabetes in Europe
and Russia since the 16th century (Cui et al., 2005). This fungus extract inhibited the activity of
α-glucosidase (IC50 = 220.31 μg mL-1) (Stojkovic et al., 2019). Treatment of alloxan-induced diabetic
mice with ethyl acetate extract of I. obliquus significantly (p < 0.05) reduced their water and food
intake. Inonotus obliquus lowered blood sugar, TG, and MDA and increased HDL and hepatic
glycogen levels (Lu et al., 2010).
       Phellinus linteus (Berkeley & M. A. Curtis) Teng has been used to treat diabetes and obesity
in traditional Japanese, Chinese, and Korean medicine (Khursheed et al., 2020). The P. linteus
polysaccharides also suppress inflammatory cytokines (such as TNF-α) production (Kim et al., 2010).
Oral administration of P. linteus (100 mg kg-1 body weight per day) reduces blood glucose by up to
35% in diabetic mice (p < 0.05) (Friedman, 2016).
       Schizophyllum commune Fr. is an edible fungus used in TCM to treat inflammation, obesity,
and weakness (Kamalebo et al., 2018; Sharma et al., 2021). Schizophyllum commune inhibit the
α-glucosidase activity more than 90% and decrease blood glucose levels (Sharma et al., 2021). The
hot water, methanol, and ethanol extract of S. commune had DPPH free radical scavenging properties
higher than that of ascorbic acid. Schizophyllum commune β-glucan also lowers cholesterol and
controls diabetes mellitus (Chandrawanshi et al., 2017; Muthuramalingam et al., 2019).
       Tremella spp. are also known as jelly fungi with more than 100 known species. Tremella
fuciformis Berk. and Tremella aurantialba (Naematelia aurantialba Bandoni & M. Zang) are
cultivated commercially for food and medicine (Du et al., 2010). Low molecular weight T.
aurantialba polysaccharides improved glucose metabolism and increased insulin secretion in type 1
and 2 diabetes. This fungus (50 mg kg-1) decreased plasma glucose and TG in genetic type 2 diabetic
KK-Ay mice after 10 weeks (Lo and Wasser, 2011). Zhang et al. (2009), showed that T. aurantialba
mushroom extract contains saponins. These compounds can reduce cholesterol and triglyceride in
alloxan-induced diabetic rats (Zhang et al., 2009).
       Trametes versicolor (L.) Lloyd. is one of the most important medicinal fungi whose

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polysaccharides are commercially produced. Krestin is the most important secondary metabolite of
this fungus, used as a supplement in many countries (Price et al., 2010). Alvandi et al. (2020) observed
that exopolysaccharides of T. versicolor reduced blood sugar, TG, and cholesterol in diabetic rats by
50%, 89% and 20%, respectively (Alvandi et al., 2020a). Methanolic extract of this fungus (1,500
mg kg-1) reduced serum blood glucose, TG, and ALT enzyme in male mice. Histopathological studies
showed T. versicolor extract improved liver tissue damage (Shokrzadeh et al., 2017).

8. Conclusions
The prevalence of diabetes is increasing dramatically worldwide and is the fifth leading cause of
death in the world. Complications of this disease include retinopathy, nephropathy, neuropathy, and
cardiovascular diseases (De Silva et al., 2012; Alvandi et al., 2020a). Medicinal mushrooms have long
been used in traditional medicine in Asian countries to treat diabetes. Various studies have shown the
effects of hypoglycemia, antioxidants and strengthening the immune system of fungi in vitro, in vivo
and clinically. These fungi protect and repair the tissue of the liver and pancreas. This effect appears
to be by lowering cholesterol, triglycerides, improving fat metabolism, improving enzyme function,
and reducing oxidative stress. Fungi also have anti-inflammatory effects by regulating the production
of cytokine (Yun et al., 2003; Friedman, 2016; Martel et al., 2017; Jiang et al., 2020b).
       Studies show that several factors can affect the production and properties of fungal metabolites
and their molecular weight (Alvandi et al., 2020c). Culture medium conditions (e.g. temperature,
pH and aeration), chemical compounds (e.g. Selenium and Zinc) or the use of elicitors can affect
the production and properties of these polysaccharides (Nojoki et al., 2016; Nojoki et al., 2017;
Kalantari-Dehaghi et al., 2019; Alvandi et al., 2021). Low molecular weight polysaccharides often
have antiproliferative and antioxidant properties, while metabolites with a molecular weight of
more than 100,000 Da stimulate macrophages to strengthen immune function. Therefore, the use of
purification methods in polysaccharides is of particular importance (Wasser, 2011).
       In recent years, the use of drug delivery nanosystems for loading fungal polysaccharides has
received much attention from researchers (Othman et al., 2021). In addition to solving the solubility
problem, these nanocarriers also allow polysaccharides to be targeted. Thus, low molecular weight
polysaccharides can purposefully target the pancreas and repair damaged islets of Langerhans (Xu
et al., 2011; Hu and Jiang, 2012). Although studies in this area are still ongoing, it seems that the
combination of fungal polysaccharides and nanotechnology can make a huge difference in the
treatment of diabetes.

Acknowledgements
The author would like to thank all colleagues who provided insight and expertise that considerably
helped the research.

Conflict of Interest
The authors report no conflicts of interest.

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