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The Potential Role of Mushrooms in The

Prevention and Treatment of Diabetes: A Review

Pritha Chowdhury & Santanu Paul

To cite this article: Pritha Chowdhury & Santanu Paul (2020) The Potential Role of Mushrooms in
The Prevention and Treatment of Diabetes: A Review, Journal of Biologically Active Products from
Nature, 10:5, 429-454, DOI: 10.1080/22311866.2020.1831958

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 TBAP 10 (5) 2020 pp 429 - 454 429
ISSN Print: 2231-1866
ISSN Online: 2231-1874

The Potential Role of Mushrooms in The Prevention

and Treatment of Diabetes: A Review

Pritha Chowdhury and Santanu Paul*

Laboratory of Cell and Molecular Biology, Department of Botany;
Centre of Advanced Study; University of Calcutta, Kolkata 700019, India
Received 24 February 2020; accepted in revised form 29 September 2020

Abstract: Diabetes mellitus is a highly complex disorder in which the blood glucose level is abnormally
high because the body does not produce enough insulin to meet its needs. This disease is now highly life-threa-
tening across the world and needs proper, low cost and easily available medication without or fewer side effects.
At present, there are many synthetic hypoglycemic agents used in the treatment of diabetes but they fail due to
harmful side-effects. Scientists are now aiming at mushrooms as they are known for a traditional repository of
natural bioactive compounds which may have a potential antidiabetic effect. Many reports documented so far
of the efficacy of bioactive metabolites isolated from mushrooms and their cultured mycelia that have shown
to be successful in the treatment of diabetes. This study aims to review those bioactive metabolites showing
antidiabetic potential resourcing from mushrooms. Relevant literature found in electronic databases and
published during 1995-2020 was studied. The study reveals that bioactive metabolites isolated from mushrooms
like polysaccharides, proteins, dietary fibers and many pharmacologically active compounds and different
solvent extracts of mushrooms with unknown metabolites have been reported to possess antidiabetic potential
both in vivo and in vitro studies, though only very few are on clinical trials. Out of thirty-nine reported mushroom
species having antidiabetic efficacy, three genus Pleurotus, Grifola and Agaricus show the highest number of
research publications. This review is focused on the current status and future possibilities of bioactive metabolites
resourcing from medicinal mushrooms in the treatment of diabetes.

Key words: Diabetes mellitus; mushrooms; bioactive metabolites, polysaccharides, extracts;

clinical trials.
Introduction
One of the most prevalent, chronic and complex
metabolic disorder, diabetes mellitus is characte-
rized by high blood glucose and insulin defi-
ciency. According to the latest report of the
International Diabetes Federation in 2019, 463
million adult people are suffering from diabetes
of which about 374 million people are at high risk
of developing type 2 diabetes (2DM) 1. According
to their survey, more than 1.1 million children and
adolescents are living with type 1 diabetes. Above
the age of 65, one out of five people has been
diagnosed with diabetes. One in every two persons
*Corresponding author (Santanu Paul)
E-mail: < spaul_1971@yahoo.com >
remains undiagnosed which makes up to 232
million with the death of approximately 4.2
million. The recent report shows, 79 % of adult
diabetic patients belong to low and middle-income
countries and are at high risk of diabetes. This
chronic syndrome is characterized by hyper-
glycemia, which is the main factor related to
macro (coronary artery disease, peripheral arterial
disease & stroke) and micro (diabetic nephro-
pathy, neuropathy & retinopathy) vascular
diseases in body 2 and β cell dysfunction which
causes a decrease in insulin synthesis and
secretion. People suffering from type 2 DM are
© 2020, Har Krishan Bhalla & Sons
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
at risk of nephropathy, nerve damage, excessive
weight loss, inflammation, high total cholesterol,
high free fatty acids, adipogenesis, high blood
urea nitrogen and high creatinine. The common
and widely used synthetic medicines are the
sulphonylureas class of drugs and miglitol (Alpha-
glucosidase inhibitors), metformin (Biguanides),
dopamine agonist (Bromocriptine), Dpp 4
inhibitors, glucagon-like peptides, SGLT-2
inhibitors 3. But long term accumulation of these
medicines may cause several side effects ranging
from weight gain, skin reactions, hair loss to
hypoglycemia and abdominal discomfort. Herb-
al medicines can restore the synthetic drugs availa-
ble for the treatment of this disease because of
their lesser side effects and more effectiveness 4.
That’s why several types of research are carried
out for the development of an antidiabetic drug
from natural resources. Many plants contain diffe-
rent natural antioxidants and other bioactive com-
pounds that can enhance the glucose uptake, β
cell performance for maintaining the blood sugar
level. Recently scientists are paying their attention
to the therapeutic value of mushrooms based on
their role in human health. Mushroom possesses
a wide range of secondary metabolites including
phenolic compounds, polyketides, terpenes and
steroids. Some of these compounds have shown
important pharmacological effects like anti-
oxidant, antitumor, antidiabetic and also less or
no toxic effects 5. In this review paper, we have
discussed the antidiabetic potential of bioactive
compounds and various extracts with undefined
metabolites resourcing from mushrooms. Very
few studies have been carried out so far looking
at them the indepth potential of mushrooms in
the treatment of diabetes type 2 for the last 15
years. The highest number of research has been
done on the edible mushroom Pleurotus sp.
Mushroom contains various types of extracellular
polysaccharides containing specially β- glucans
which can regulate several enzyme activities
related to diabetes and few mushrooms contain
special bioactive compounds like cordycepin,
ergothioneine, hispidin etc which show potent
antidiabetic effects. Many of the compounds or
extracts of mushrooms that have been reported to
date are applied on cell lines, diabetic mice, or
430
rabbits and only very few of them reached clinical
trials.
Pathophysiology of Diabetes
Diabetes is a multifactorial metabolic disorder,
which is characterized by inappropriate carbohy-
drate, protein and fat metabolism because of the
imbalance between insulin need and availability
of insulin 4. It affects human health as well as the
quality of life 6. This disease is mainly and comm-
only marked by elevated plasma glucose level 7.
There are mainly two types of diabetes: type 1
DM which is characterized by insulin-dependent
diabetes mellitus and type 2 diabetes which is non-
insulin-dependent diabetes mellitus. Type 1 and
type 2 DM are caused by the massive loss of insu-
lin secreting beta cells and insulin resistance,
impaired secretion respectively 8. In type 2 DM
high amount of dietary starch, secretion leads to
the release of glucose in the bloodstream. People
suffering from type 2 diabetes show a remarkable
reduction in insulin-mediated glucose
consumption. Insulin resistance is independently
related to obesity, which is more prominent in 80
% of type 2 diabetic patients, especially in Eastern
countries. Two main enzymes i.e α-amylase and
α-glucosidase play a major role in dietary starch
degradation 8 . Initially, salivary α-amylase
degrade the starch into a large number of maltose
and later these maltose molecules are separated
into glucose units by an α-glucosidase enzyme
in the intestine. So, inhibition of starch breakdown
by inhibiting these two enzymes play a major role
in controlling type 2 diabetes 9. Insulin is the
hormone that is needed to convert sugar, starches
and other foods into energy and regulates the sugar
levels in the blood. Hyperglycemia occurs when
the glucose level is higher than 10 mmol/l (80
mg/dl), but the symptoms become noticeable
when the value reaches 15-20 mmol/l (270-360
mg/dl) 10. Several factors including insulin
production, lacking insulin sensitivity, beta-cell
dysfunction is related to the pathogenesis of type
2 DM. Most of the diabetic patients suffering from
type 2 diabetes are obese with the central visceral
adiposity. Deposition of triglycerides in muscle,
liver, pancreas cells, secretion of various adipo-
cytokines, eleptin, adiponectin, TNFα, resistin all
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
these play a very important role in type 2 DM 11.
Diabetes mellitus is strongly affected by oxidative
stress that develops in the body due to an increase
in insulin resistance and impaired secretion of the
hormone 12. Antioxidants are the substance that
oxidized itself and give protection to our body
cells from oxidative damage. There is a strong
link between DM and antioxidants. Hyper-
glycemic condition enhances the autooxidation
of glucose and forms more free radicals, which
are beyond the scavenging ability of internal
antioxidant defense and leads to macro and
microvascular dysfunction. Scavenging of this
oxidative reaction may prove to be beneficial for
drug development in type 2 DM.
Methodology
This study of review literature on mushrooms
and their potentiality as antidiabetic was based
on the available electronic databases like PubMed,
Google, etc. Articles published between the year
1995 to 2020 on Mushroom and Diabetes was
studied and the related information was written
in this article with proper citations. During data
retrieving nonrelevant, non-English, duplicate
articles were excluded. Only the papers dealing
with research work on mushrooms having
antidiabetic potentiality were included. Out of 134
articles related to mushroom and antidiabetes 68
articles provide a detailed study about their mode
of action and out of which only 12 articles have
shown clinical trials (Figure 1).
Type of mushroom extracts having the anti-
diabetic property
Antidiabetic effect of Aqueous extracts
Water is known as a universal solvent, because
of its capability to dissolve more substances than
any other solvent system. It has been reported that
chronic administration of filtrate suspension of
Agaricus campestris in dilute dose can down
regulate hyperglycemia and enhance the transport
of glucose which is heat stable, acetone soluble,
alkali stable but which does not work properly in
acidic condition 13. This aqueous extract at a con-
centration of 0.25-1 mg/ml can gradually increase
3.5 to 4 fold insulin secretion in glucose-
responsive BRIN and BD11 cells. The author also
431
reported that 62.5 gm/kg of diet can decline hyper-
glycemia from 13.5±1.7 mM to 6.7±0.9 mM in
STZ induced diabetic mice by the 12th day
probably by the shielding of B-cells against the
cytotoxic action of STZ 13. Another report had
shown that administration of aqueous extract of
Ganoderma at dose 140 mg/kg to insulin
resistance KK mice can lower 25-37 % blood
glucose level within 8-12 & 16-18 hours after
application. According to the author, this extract
contains proteoglycan (beta-1, 6 main chain with
alpha-1,4 branching) which may reduce the sugar
absorption i.e down-regulate the glycemic index
14
. It has been reported that sitosterol and flavonoid
rich aqueous extract of Pleurotus tuberregium can
lower blood glucose, triglyceride and improve the
lipid profile in diabetic rabbit (Figure 2) 15.
Another report in 2014, had shown that 100 and
200 mg/kg extract of Pleurotus eryngii signi-
ficantly lowered HbAlc and blood glucose in
diabetic mice after 5weeks of treatment (Figure
2) 16. In type 2 diabetic patients, adipocytes are
insulin resistant and unable to accumulate lipids
and that’s why to increase the activity of PPARY,
C/ EBPα, which are adipogenic markers and
believed to be one of the target antidiabetic drugs.
Hot aqueous extract of Chaga mushroom
(Inonotus obliquus) can boost up the mRNA levels
of PPARY, C/EBPα and transcriptional activity
of PPARY, as well as GLUT 4 expression of 3T3-
L1 preadipocyte cell 17. It has been reported that
lyophilized hot water extraction of Lentinus
tigrinus fruit body had the potentiality to bring
down 26.9 % blood glucose in diabetic mice at
100 & 250 mg/kg dose within 21 days 18. Oral
administration of aqueous extract of Pleurotus
sajor caju at 750 mg/kg dose can decrease 41.3
% and 36.5 % blood glucose in normal and
diabetic rats respectively after 3 hours. The further
experiment had proved that 21 days treated mice
also showed 7.1 % degradation in the body weight
and urine sugar and also proved that this aqueous
extract is nontoxic up to 7.5 gm/kg 19. Oral
administration of Phellinus linteus hot water
extract in STZ induced mice could down-regulate
serum glucose nearly by 41.3 % and elevate the
number of Langerhans islets by 45.89 % 20. In
another report, it had been shown that only low
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454 432

Articles published during 1995-2020

Pub Med - 250
116 articles
irrelevant excluded
134 reports
relevant to this study
8 reports 46 articles
related to our study excluded due to lack
and reviews of information
10 reports
25 reports show works on anti-
contains anti-diabetic diabetic potential of
pharmacologically active
potentiality of mushroom
small compounds form
polysaccharides (table 2)
mushroom (Table 3)

9 Patents 12 reports
related to diabetes 24 reports cocerned with
and mushroom cocerned with mushroom proper clinical
extracts (Table 1) trials

Figure 1. Screening and selection procedure for data collection

molecular weight Grifola gargal extract notably
decreased the blood glucose and body fat of diabe-
tic mice although both high and low molecular
weight hot aqueous extract was studied on STZ
induced diabetic mice 21,22. Application of low
molecular weight extract at 2.0 mg/ml markedly
repressed the expression of the cytokinin, IL6 in
3T3 L1 cells compared to control one 22. In in-
vitro alpha-amylase enzyme inhibitory assay
dichloromethane, ethylacetate, butanol and
aqueous extract of Calvatia gigantea have shown
low IC50 value of 5.3 μg/ml, 6.5 μg/ml, 5.7 μg/
ml and 6.2 μg/ml respectively 23. Another report
in 2011 has shown that aqueous extract of
Hypsizygus ulmarius can prevent the damage
caused due to streptozotocin by regulating the
serum and tissue marker enzymes and glucose to
a normal level and suppress the activity of gluco-
neogenic enzymes like glucose-6 phosphatase,
fructose-1, 6 bis phosphatase in mice model 24.
Hot water extract of Trametes pubescens could
inhibit both alpha-amylase and alpha-glucosidase
in in vitro assay. It has been reported that 0.125-
0.5 mg/ml concentration can inhibit 10.05 % to
53.82 % alpha-amylase enzyme action and 0.125-
2.0 mg/ml concentration can inhibit 36.88 % to
53.05 % alpha-glucosidase enzyme activity.
Eleven phenolic compounds were reported from
fruiting bodies of Trametes pubescens. Authors
have suggested that moderate to high amounts of
phenolic compounds including gallic acid,
protocatechuic acid, epigallocatechin gallate,
caffeic acid, naringin, resveratrol, kaempferol and
biochanin-A may be responsible for this enzyme
inhibitory activity (Table 1) 25.
Antidiabetic effect of Ethanolic extracts
Ethanol is used to isolate the polar molecules
or polar fractions from any solute. So, the polar
molecules of mushroom can also be fractioned
by using ethanol as a solvent at various
percentages. It has been reported that at four times
dose, 95 % ethanolic extract from the dried
fruiting body of Antrodia cinnamomea was able
to enhance the glucose tolerance in diabetic mice
at an equivalent rate as that of Metformin. This
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454 433

Figure 2. In-vitro anti-diabetic effect of one of the most studied mushroom Pleurotus
A) Pleurotus eryngii; B) Pleurotus sajor caju; C) Pleurotus tuber-regium
Table 1. Type of mushroom extracts having anti diabetic property

No. Name of mushroom Type of extract Mode of action Reference

1 Agaricus campestris Boiling water Down regulate hyperglycemia 13

and enhance the transport of
glucose. In in vitro assay insulin
secretion from glucose responsive
BRIN and BD11 cells increases
depending on the dose of this
extraction.
2 Ganoderma sp. Aqueous Lowers blood glucose level in 14
extraction kk mice.
3 Inonotus obliquus Hot aqueous Enhance GLUT 4 expression 17
extraction in 3T3-L1 pre adipocyte cell.
4 Lentinus tigrinus Lyophilized hot Lowers blood glucose level in mice. 18
water extraction
5 Pleurotus sajor Aqueous Decrease blood glucose level and 19
caju extraction increase body weight of mice.
6 Phellinus linteus Hot aqueous Down regulate serum glucose, 20
extraction upregulate number of Langerhans
islets.
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454 434
table 1. (continued).

No. Name of mushroom Type of extract Mode of action Reference

7 Grifola gargal Hot aqueous Low mol weight hot water extract 21
extraction can decrease blood glucose and
body fat of diabetic mice.
8 Calvatia gigantea Dichloro-methane Reduce 28 % blood glucose in 23
Ethyl-acetate in-vivo assay. All fraction
ButanolAqueous possesses in-vitro α-amylase
inhibitory activity.
9 Antrodia 95 % ethanol Up- regulate glucose tolerance 26
cinnamomea in diabetic mice, lowered the total
cholesterol and triglyceride. Down
regulate lipid peroxidation, the
expression of RAGE on plasma
membrane and enhanced the
superoxide dis mutase activity.
10 Pleurotus albidus 70 % ethanol Modulate complex 1 activity by 27
regulating SIRT3 and decrease
the ROS production, oxidative
damage of lipid and protein.
11 Pleurotus Ethanol Lowers blood glucose, triglyceride, 28
ostreatus LDL and VLDL,serum cholesterol,
SGPT & SGOT, serum creatinine
and increased HDL cholesterol in
diabetic mice after 15th day of
administration.
12 Grifola frondosa Ethanol Regulate PPARS target genes in 29
skeletal muscle, glucose intolerance,
decrease the blood cholesterol level.
Enhance glucose uptake under
sodium palmitite induced insulin
resistant cell line.
13 Amillariella mella NAOH solution Lowered the fasting blood glucose, 31
serum triglyceride and enhance
glucose intolerance.
14 Pleurotus Methanol Increase the adipogenic 32
giganteus differentiation and glucose uptake
by GLUT 1 & GLUT 4 expression
in 3T3 L1 cells.
15 Trametes Hot water and α-amylase and α glucosidase 34
pubescens methanolic extract inhibitory activity, inflammation
inhibitory activity on cell line
RAW 264.7.
16 Inonotus Hexane, chloro- Few compounds may have anti- 36
obliquus form,ethyl acetate, diabetic property.
methanol, water
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454 435
table 1. (continued).

No. Name of mushroom Type of extract Mode of action Reference

17 Grifola n hexane Inhibit α glucosidase activity stro- 37

frondosa ngly but α amylase activity weakly.
18 Poria cocos Chloroform Down-regulate post-prandial 70
fractions blood glucose in diabetic mice
disregarding PPAR-Y.
19 Pleurotus Methanolic Regulate blood glucose level, 33
citrinopileatus extract insulin, catalase, stimulate insulin
production from pancreas in STZ
induced rat.
20 Hypsizygus Aqueous Decrease the activity of gluconeo- 24
ulmarius extract genic enzyme (glucose-6-phosphate,
fructose 1,6 bis phosphate) in STZ
treated diabetic mice model.
21 Pleurotus Aqueous Lowers blood glucose, triglycerides 15
tuberregium extract and improve lipid profile in diabetic
rabbit.
22 Pleurotus Aqueous extract Significantly decrease blood glucose 16
eryngii and HbAlc in diabetic mice model
after 5 weeks of treatment.
23 Lactarius Ethanolic extract Improve hyperglycemic condition in 30
deterrimus STZ induced rats via protecting
pancreatic cells and beta cell mass
by activation of CXCL12/Akt
pathway.

can reduce glucose level from 133.33 mg/DL to
94.8 mg/DL, insulin level from 0.63 ng/DL to 0.39
ng/DL, and HOMA-IR value from 10.08 to 4.83
in STZ induced diabetic mice at 4x concentration.
This extract also suppressed the total cholesterol,
triglyceride, lipid peroxidation at 4x concentration
26
. The above report also showed that this ethanolic
extract at 2x and 4x concentration can diminish
the expression of the receptor for advanced
glycation end products (RAGE) on the plasma
membrane but enhanced the superoxide dismutase
activity in diabetic mice 26. 70 % ethanolic extract
of cultured and dried Pleurotus albidus was
subjected to lyophilization and this dried ethanolic
extract of Pleurotus albidus had shown to have
the potentiality to modulate complex 1 activity
by regulating SIRT3, the reactive oxygen species
(ROS) production, and oxidative damage of lipid
and protein 27 . Another report on Pleurotus
ostreatus pointed out that GC MS analysis of the
ethanolic extract revealed the presence of volatile,
thermally stable, low molecular weight com-
pounds. This mushroom extraction had the
potentiality to reduce blood glucose level from
309 mg/dL to 167.56 mg/dL, serum cholesterol
from 153 mg/dL to 104 mg/dL, low density lipid
(LDL) from 88.19 mg/dL to 31.92 mg/dL, very
low density lipid (VLDL) from 30.46 mg/dL to
23.39 mg/dL, triglyceride from 14 8 mg/dL to 106
mg/dL, serum creatinine from 13.12 mg/dL to
7.18 mg/dL and increase HDL cholesterol from
37.4 mg/dL to 59.4 mg/dL in alloxan-induced
diabetes mice after 15th day of treatment 28.
Ethanol has been reported to prepare the extract
of the Grifola frondosa fruit body and finally, the
soluble fraction was evaporated under less
pressure which was applied on both palmitate-
induced insulin-resistant C2C12 cell line and male
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
diabetic mice (C57Bl6/J). This extract can signi-
ficantly upregulate glucose uptake under sodium
palmitate-induced insulin resistant cell line. This
extraction can regulate the peroxisome proli-
ferator-activated receptors (PPARS) target genes
in skeletal muscle, glucose intolerance and also
decrease the blood cholesterol level 29. It was
reported that dried ethanolic extract of Lactarius
deterrimus can improve hyperglycemia, reduce
triglyceride and glycated hemoglobin at 60 mg/
kg dose for 4 weeks to STZ induced diabetic mice
and also increase β-cell mass via controlling
CXCL12/AKT pathway (Table 1) 30.
Antidiabetic effect of alkaline extracts
An alkaline solution of edible mushroom
Amillariella mella can down-regulate serum
insulin, HOMA-IR index in diabetic mice. Oral
administration of this extract at 200 mg/kg/day
to HFD / DEX-induced insulin-resistant mice
significantly lowered the fasting blood glucose,
serum triglyceride, and enhance glucose
intolerance (Table 1) 31.
Antidiabetic effect of methanolic extracts
Methanol is used as a solvent for the extraction
of various polar compounds and few non-polar
compounds which are also fairly soluble in metha-
nol, that’s why methanol is considered as a
common solvent for the extraction of bioactive
compounds. It has been documented that crude
methanolic extract of Pleurotus giganteus was
fractioned to obtain ethyl acetate extract.
Experiment on 3T3 L1 adipocyte proved this
extract can remarkably ameliorate the adipogenic
differentiation and glucose uptake by GLUT 1 &
GLUT 4 expression, and also regulate the
expression of sterol regulatory element-binding
protein and peroxisome proliferator-activated
receptor-Y 32. Methanolic extract of another
species i.e. P. citrinopileatus plays a major role
in controlling blood glucose via insulin production
from the pancreas and balanced their compli-
cations in STZ induced rats at 500 and 1000 mg/
kg body weight dose 33. Methanolic extract of
Trametes pubescens possessed in vitro α-amylase
activity which ranges from 27.75 % to 69.46 %
inhibition at a concentration from 0.125-0.5 mg/
436
ml. It also showed α glucosidase activity which
ranges from 36.64 % to 51.24 % inhibition at a
concentration from 0.125-2.0 mg/ml. Both α
amylase and α glucosidase inhibitory activity was
reported to be less than the standard drug
Acarbose. The mushroom extract also showed
inflammation inhibitory activity on lipopoly-
saccharide-induced murine macrophage cell line
(RAW 264.7) 34. Recent studies have shown that
Hericium erinaceus has important physiological
effects on human health. Application of 20-200
mg/kg dose of methanolic extract from this
mushroom can reduce blood glucose, serum
triglycerides in streptozotocin-induced diabetic
mice 35. Calvatia gigantea contains antidiabetes
efficacy with an IC50 value of 0.46 μg/ml. In in
vivo test 400 mg/kg dose the methanolic extract
causes significant reduction in blood glucose from
330 mg/dL to 235 mg/dL i.e 28 % within 30
minutes in diabetic mice (Table1) 23.
Antidiabetic effect of chloroform extracts
Another report on Inonotus obliquus focused
on chloroform extraction having dipeptidyl pepti-
dase 4 (DPP4) inhibitory activities 36. They
suggested that a few compounds from this extract
may possess antidiabetic efficacy (Table 1).
Antidiabetic effect of n-hexane extracts
n-Hexane extract of Grifola frondosa could
inhibit α glucosidase activity strongly but α amy-
lase activity weakly 37. It has been reported that
water, hexane and oil fraction of Grifola frondosa
inhibit alpha-amylase enzyme with IC50 value 3.75
mg/ml, 2.51 mg/ml and 0.56 mg/ml respectively
and also inhibit alpha-glucosidase enzyme activity
with IC50 value 0.04 mg/ml (water fraction), 0.17
mg/ml (hexane fraction) and 0.02 mg/ml (oil
fraction) (Table1) 37.
Polysaccharides isolated from mushroom
having antidiabetic potential
Polysaccharides are present in mushrooms as
structural components of cell-wall. Presently the
effects of mushroom polysaccharides have been
intensively studied regarding their antioxidant,
antihyperglycemic, antitumor, antiinflammatory
activities. Two extracellular polysaccharides were
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
reported from Pleurotus eryngii (Figure 2) by gas
chromatography of which EPS 1 showed both
alpha-amylase and alpha-glucosidase inhibitory
activity up to 62.36 ± 4.12 % and 34.82 ± 2.74 %
respectively 38. According to this report, the
extracellular polysaccharide 1 (EPS 1) and
extracellular polysaccharide 2 (EPS 2) signi-
ficantly lowered the blood glucose levels in the
mice by 49.15±5.52 % and 20.23±4.81 %
respectively. EPS played a key role in protecting
the kidney damage in mice by suppressing the
high level of albumin, urea nitrogen and creatinine
38
. Zinc polysaccharide was isolated from acidic,
alkylic and enzymatic extraction of mycelia of
Pleurotus djamor which can significantly lower
the blood glucose level, liver index and kidney
index of diabetic mice model. Administration of
this acidic zinc polysaccharide extract to strepto-
zotocin (STZ) induced diabetic mice at 800 mg/
kg lowered the glucose level by 34.74 % com-
pared to the control group 39. Polysaccharide
purified from aqueous extract of Pleurotus sajor
caju by ethanol precipitation was subjected to in
vivo experiment on mice model and the result
reflects its ability to upregulate the expression of
GLUT4 and adiponectin genes and downregulate
NF-kB (Figure 2) 40. Isolation of polysaccharide
from abalone mushroom i.e. Pleurotus abalonus
was reported and HPLC analysis of the poly-
saccharide confirmed the high amount of glucose
in it. 13C-NMR spectrum analysis of poly-
saccharide had shown the composition of the main
chain of polys-accharide is [→6)-α-D-Glcp-
(1→]n. This polysaccharide had high antioxidant
activity and can scavenge free radical (IC50 0.75
μm for DPPH and 0.93μm for OH radical) 41.
Administration of 1 mg/kg/day polysaccharide
showed up to a 22.9 % decrease in the blood
glucose level in drug-induced diabetes mice 41. It
has been reported that water-soluble poly-
saccharide of edible mushroom Pleurotus cit-
rinopileatus can lower total serum cholesterol,
triglyceride and 44 % fasting blood glucose level
at 0.4 gm/kg bw/day dose in STZ induced diabetic
mice. According to the author, the polysaccharide
digested as oligosaccharide and absorbed may
cause the inhibition of enzymes related to
saccharide metabolism 42. Western blot analysis
437
of polysaccharide isolated from aqueous extract
of Pleurotus ostreatus revealed that this poly-
saccharide can decrease hyperglycemia, hyper-
lipidemia and enhance the glycogen storage by
regulating the expression of GSK3 phospho-
rylation and GLUT 4 translocation in strepto-
zotocin-induced diabetic mice model at 400 mg/
kg dose 43. It has been documented that poly-
saccharide from the medicinal mushroom Pleu-
rotus florida could down-regulate blood glucose,
serum cholesterol, triglyceride, urine glucose and
ketones in streptozotocin-induced mice but toxic
above 4000 mg/kg dose. Polysaccharides from
this mushroom can also reduce malondialdehyde,
nitric oxide and helps in the restoration of super-
oxide dismutase (SOD), catalase and reduced
glutathione 44. Another report on Pleurotus tuber
regium polysaccharide showed that the appli-
cation of this polysaccharide in diabetic mice can
upregulate the peroxisome proliferator-activated
receptor (PPAR)-α mRNA and protein levels
which further down-regulate obesity, hyper-
glycemia, hyperlipidemia and progression of
diabetes 45. Only β-glucan rich polysaccharide of
dried Pleurotus sajor caju can enhance the
expression of 5 AMP-activated protein kinase
subunit γ-2 and γ-3 and the expression of
hormone-sensitive lipase, adipose triglyceride
lipase enzymes, leptin, adiponectin & GLUT 4
46
. It has been reported that 83.13 % pure
polysaccharide was extracted from hot aqueous
extract of Grifola frondosa by using 80 % ethanol.
Administration of 200 mg/kg polysaccharide
lowered 30.2 % of blood glucose levels of mice.
This polysaccharide can not only downregulate
high blood urea nitrogen (BUN), serum creatinine
(sCR), N ace-tyl-β-D-glucosaminidase (NAG) in
serum but also regulate high albumin in the urine
of diabetic rats. Western blot analysis of kidney
of treated diabetic mice revealed this poly-
saccharide can turn down the expression of
Phospho-NF kBp65 and Phospho-IkBα in the
kidneys. Grifola frondosa polysaccharide can
normalize inflammation regulating factors like IL-
2, IL-6, TNFα, IFNα in diabetic rats but the author
and his team failed to detect whether the poly-
saccharide influence insulin synthesis or not 47.
Lots of research revealed that Grifola frondosa
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
contained a bioactive glycoprotein of mol wt. of
20 kDa and had shown hypoglycemic activity in
mice model and diabetic type 2 patients. Poly-
saccharide contents of Grifola frondosa fraction
2 (F2) & fraction 3 (F3) were analyzed by the
phenol sulfuric acid method. Major constituents
of F2 and F3 were glucose, mannose, galactose,
xylose, arabinose and ribose. F2 and F3 can
control the fasting serum insulin and fasting serum
glucose level which in turn improves insulin
sensitivity. These polysaccharide fractions mainly
target PI3K-AKT Pathway 48. Another report was
emphasized on the isolation and characterization
of crude polysaccharide from hot water extraction
of Phellinus linteus mycelia by ethanol precipi-
tation and then separated by DEAE Sephadex. FT-
IR spectrum analysis confirmed the presence of
α linked glycosyl residue in the polysaccharide
as it generates a peak at 84.32 cm-1.
Administrations of this polysaccharide can
deplete 35.60 % of blood glucose levels in diabetic
mice after 28 days of administration and also
inhibit H2O2 induced apoptosis 49. Another recent
report in 2019, have shown that the execution/
application of polysaccharide enriched powder of
Phellinus linteus at 300 & 600 mg/kg BW dose
to diabetic mice significantly diminished the
fasting blood glucose level after 8 weeks as
compared that of control 50. Pyran ring polysac-
charide with α & β configurations isolated from
Cordyceps militaris efficiently improve the insulin
resistance in type 2 DM mice model 51. Selenium
polysaccharide of 1.6×105 Da isolated from Cata-
thelasm ventricosum could normalize physio-
logical damage in diabetic rats by protecting the
liver, kidney and pancreas from peroxidative
damage, increase the response of target cells in
diabetic mice to insulin and show hypolipidemic
activity 52. According to one report published in
2010, a polysaccharide extracted from an aqueous
suspension of Agrocybe chaixingu with (1:5 v/v)
1 % NaCl and ethanol artificially induce DNA
fragmentation in RINm5F cell. iNOS expression
level can be controlled by this polysaccharide and
histochemical analysis revealed that it enhances
pancreatic β-cells resistance to destruction by STZ
in mice model 53. Crude polysaccharide extracts
from mycelia and fermented broth of Grifola
438
frondosa were analyzed by the phenol-sulphuric
acid method. These polysaccharides were able to
control the glucose level, renal function, diabetic
nephropathy, serum fructosamine level but unable
to control serum insulin concentration in mice 54.
According to the author presence of abundant
fiber may suppress the glucose absorption from
intestines and prevent increases in blood glucose
level, but the diabetic rats had no significant
changes in pancreatic weight, though the
treatment can reduce 20-25 % of per gram insulin
content compared to normal rats 54. The water-
soluble polysaccharide was also reported from the
fruit body of Auricularia auricula judae Quel
which had the potentiality to down-regulate the
gaining of body weight and fasting plasma glucose
level after 5th week of treatment. Plasma glucose
level was reported to be down-regulated from 5.9
mmol/Lh to 1.8 mmol/Lh, urinary glucose from
9.4 mmol/24h/50g to 0.0 mmol/24h/50g, serum
glucose from 46. 0 mmol/L to 13.9 mmol/L, serum
insulin from 628 μU/mL to 365 μU/mL and HbA
from 3.4 % to 1.9 % in KK-Ay mice, but this
polysaccharide did not affect hyperinsulinemia
and glucose tolerance 55. Extracellular poly-
saccharide from the broth culture of Phellinus
baumii was filtered and precipitated by using
ethanol. This EPS could mitigate 52.3 % plasma
glucose level, repair the damage of pancreatic β
cells, and regulate insulin production after 14 days
of application on mice 56. Since 1995 Ophio-
cordyceps sinensis was considered as an herbal
drug in the Chinese pharmacopeia. Polysaccharide
fractions of both Ophiocordyceps sinensis and
Cordyceps militaris, had been orally applied to
streptozotocin-induced mice model and the result
proved that Ophiocordyceps sinensis can reduce
fasting plasma levels of glucose, insulin, enhance
the glucose tolerance, whole-body insulin
sensitivity, basal plasma insulin and inhibit hepatic
fibrogenesis. On other hand, a 0.5 g/kg diet of
Cordyceps militaris polysaccharide can down-
regulate fasting serum glucose and induce the
glucose utilization in skeletal muscles in rats 57.
Fruiting bodies of Ophiocordyceps at 1 gm/day
for four weeks of administration can down-
regulate weight loss, polydipsia and hyper-
glycemia in STZ induced diabetic rats. Both
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
Ophiocordyceps sinesis and Cordyceps militaris
can reduce 60-70 % of blood glucose in mice
model 57. It was reported that oral administration
of exopolysaccharides from Tremella fuciformis
and Phellenus baumii can minimize 52 % and 32
% blood glucose level in diabetic mice respecti-
vely at 200 mg/kg body weight 58. Acidic hetero-
polysaccharide and glucuronoxylomannan
isolated from yellow brain mushroom (Tremella
mesenterica) have the potentiality to down-
regulate blood glucose in STZ and both nicotin-
amide and STZ induced diabetic rats 59. It has been
reported that dried powder of Grifola frondosa
has been extracted with diethyl ether, ethyl
alcohol, distilled water, precipitated by 95 % ethyl
alcohol and finally fractioned by DEAE
Sepharose Fast Flow Chromatography for
isolation of MT-α glucan 60. Administration of
Table 2. Polysaccharides isolated from mushroom having anti-diabetic potential.
439
MT-α glucan can down-regulate serum lipid level
but at 450 and 150 mg/kg-1 enhance the number
of low-affinity insulin receptors on the liver
membrane, rather than the receptor affinity in KK-
Ay mice 60. From hot water extraction of Agaricus
blazei Murill, 30-40 kDa β glucans have been
analyzed by gel filtration chromatography. β-
glucans can decline the body-weight of diabetic
rats from 268 g to 252 g after the 5th week of
administration and also elevate insulin secretion
from pancreatic cells (0.62 ng dl-1 to 3.79 ng dl-1 )
at 20 mg ml-1 61. It has been reported that 50 KDa
exopolymer was isolated from Lentinus edodes,
which can deplete 21.5 % of plasma glucose, 25.1
% of plasma cholesterol, 44.5 % of triglyceride
and upregulate 22.1 % of plasma insulin in STZ
induce diabetic mice at 200 mg/kg BW 62 (Table
2).

No. Name of mushroom Type of poly- Mode of action Reference

saccharide

1 Pleurotus eryngii Extracellular Shows α-amylase and α 38

polysaccharide glucosidase inhibition activity
in mice. Reduction of blood
glucose level by EPS 1 &
EPS2. Suppress the high level
of ALB, BUN, CRE, & UA.
Can protect kidney damage.
2 Pleurotus djamor Zinc Increase in SOD, GSH-PX & 39
polysaccharide CAT followed by, diminished
level of MDA, ALT, AST, BUN,
CRE, TC, LDL-C & HDL-C in
liver, kidney and serum of STZ
induced diabetic mice.Reduction
of blood glucose in mice
compared to control one.
3 Pleurotus sajor Glucan rich Up-regulate GLUT 4, adiponectin 40
caju polysaccharide and down regulate the expression
of IL-6, TNF-α, SAA2, CRP &
MCP 1 via reduction of NF-KB
transcription factor.
4 Pleurotus [→6)-α-D- Administration of polysaccharide 41
abalonus Glcp-(1→]n. lowers blood glucose level in
diabetic mice.
5 Pleurotus Water soluble Reduce fasting blood glucose 42
citrinopileatus. polysaccharide level in diabetic mice.
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454 440
table 2. (continued).

No. Name of mushroom Type of poly- Mode of action Reference

saccharide

6 Pleurotus Polysaccharide Reduces hyperglycemia, hyperlipi- 43

ostreatus demia levels. Up regulate the
expression of GSK3 phosphorylation
and GLUT 4 protein expression.
7 Pleurotus Polysaccharide Down regulate blood glucose, 44
florida serum, cholesterol, triglyceride,
urine glucose and ketones and
restoration of SOD, catalase,
and reduced glutathione in strep-
tozotocin induced diabetic mice
when treated with 200 & 400
mg/kg of polysaccharide.
8 Pleurotus tuber Extracellular Up- regulate PPAR-α mRNA, 45
regium polysaccharide protein levels which further down
regulate obesity, hyperglycemia,
hyperlipidemia and progression
of diabetes
9 Pleurotus sajor β-glucan rich Activate AMPK unit which 46
caju polysaccharide controls the lipid and glucose
metabolism in 3T3-L1 cells.
10 Grifola fron- Polysaccharide Lowers blood glucose level 47
dosa BUN, Scr, NAG in serum and
high albumin in urine of diabetic
rats, expression of P-NF kBp65
and P-IkBα in the kidneys. Nor-
malize inflammation regulating
factors in diabetic rats and
influence the insulin synthesis.
11 Grifola fron- Glucose, mannose, Control fasting serum insulin and 48
dosa galactose, xylose, fasting serum glucose level.
arabinose, ribose, Target PI3-AKT Pathway.
arabinose, xylose
12 Phellinus α linked glycosyl Lowers blood glucose level in 49
linteus residues diabetic mice and inhibits H2O2
induced apoptosis.
13 Catathelasma Selenium Normalize physiological damage 52
ventricosum polysaccharide in diabetic rats by protecting
liver, kidney pancreas, show
hypo-lipidemic activity.
14 Agrocybe Polysaccharide Inhibit artificially induced DNA 53
chaixingu fragmentation by sodium
nitropruside. Enhance pancreatic
β cells resistance to destruction
by STZ in mice model.
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454 441
table 2. (continued).

No. Name of mushroom Type of poly- Mode of action Reference

saccharide

15 Grifola Polysaccharide Control the glucose level, renal 54

frondosa function, diabetic nephropathy.
Abundant fiber volume may
suppress glucose absorption from
intestines and prevent increases
in blood glucose.
16 Auriculaia Water soluble Down regulate plasma and uri- 55
auricularia polysaccharide nary glucose and up regulate
judae Quel hepatic glycogen level. Reduction
of overall body weight, urinary
glucose, serum glucose, serum
insulin and HbA.
17 Phellinus Extracellular After two weeks of oral adminis- 56
baumii polysaccharide tration it down-regulates AST,
ALT, serum tri-glyceride in STZ
induced diabetic rat. Decrease
blood glucose by 32 % in diabetic
mice model.
18 Ophiocordyceps, Polysaccharide Reduce 60-70 % of blood glucose 57
sinensis and in STZ induced diabetic mice.
Cordyceps militaris
19 Tremella Exo Reduce plasma glucose level by 59
fuciformis polysaccharides 52 % as compared to control mice
by improving insulin sensitivity
possibly via regulating PPAR- Y.
20 Tremella Acidic Glucuronoxylomannan Minimize 60
mesenterica polysaccharide high blood glucose in only strep-
Glucuronoxylo tozocin induced and both STZ
mannan and nicotinamide induced diabetic
rats.
21 Phellinus Polysaccharide Significantly reduce fasting 51
lintius enriched blood glucose level in in vivo
powder experiment at 300 and 600 mg/
kg body weight dose for 8 weeks
in diabetic rats.
22 Cordyceps Pyran ring Improve insulin resistance and 52
militaris polysaccharide protected liver, kidneys and pan-
with α and β creas in type 2 DM.
configuration.
23 Agaricus β-glucan Reduce the body weight of diabetic 62
blazei Murill mice at 20 mg ml-1 dose for 5
weeks and enhance the insulin
secretion from pancreas compared
to control one.
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
table 2. (continued).
No. Name of mushroom Type of poly-
saccharide
24 Lentinus edodes Exopolymer
25 Grifola frondosa MT-α glucan.
Small molecules from mushroom and their
antidiabetic properties
Mushrooms are the reservoir of a large number
of bioactive compounds. Hispidin (C13H10O5,) a
phenolic compound and a member of 2-
pyranones, is a fungal metabolite that has been
isolated from the liquid broth of Phellinus linteus
by ethyl acetate and column chromatography 63.
Hispidin (Figure 3) has been reported to scavenge
DPPH, superoxide & 2, 2’-azino-bis (3-ethyl-
benzothiazoline-6-sulphonic acid) or ABTS
radicals with IC50 values 0.65 mM, 3.84 mM, &
0.38 μg/ml respectively. It can improve β cell
condition by inhibiting H2O2 induced apoptosis
& also able to upregulate insulin secretion 63. 3 β
hydroxyl lanosta 8, 24-diene 21 al ( C30H48O2),
Inotodiol (C30H48O3) (Figure 3), Ergosterol pero-
xide (C28H48O3), Trametenolic acid (C30H48O3) and
lanosterol (C30H50O) represents the sterol com-
pounds that have been reported from ethyl acetate
fraction of Inonotus obliquus by thin-layer
chromatography (TLC), Fourier-Trans-form
Infrared Spectroscopy (FITR), Mass Spec-
trometry (MS) and H&C NMR. Among these five
compounds 3-β-hydroxy-lanosta-8, 24 diene 21-
al, inotodiol & trametenolic acid possess 4.14 %,
10.03 % and 9.93 % α-amylase enzyme inhibitory
activity and 9.54 %, 7.28 % and 9.54 % of DPPH
radical scavenging activity respectively 64. But
ergosterol peroxide and tetracyclic triterpenoid
type of compound lanosterol don’t show any
442
Mode of action Reference
Improve plasma insulin level, repair 63
damage of pancreatic β cells, up-
regulation of insulin synthesis,
lowers plasma glucose (21.5 %),
plasma cholesterol (25.1 %) and
triglycerides (44.5 %).
Enhance the number of low 61
affinity insulin receptor on liver
membrane; down regulate serum
lipid level of Kk mice. Improve
the peripheral insulin resistance
& insulin sensitivity.
enzyme inhibitory effect in diabetic mice model
64
. A comparative study between the effect of
lipopolysaccharide (LPS) and cordycepin, a
purine nucleotide analog of Cordyceps militaris
on murine macrophage cell line (RAW 264.7) has
been reported. Cordycepin (C10H13N5O3) (Figure
3) can potentially inhibit LPS induced generation
of nitric oxide(NO), proinflammatory cytokines
(IL-1beta, IL-6, TNF-alpha) as well as down-
regulate T2D regulatory genes (11 beta-HSD1,
PPARgamma) and costimulatory molecules
(ICAM-1, B7-1/-2) in RAW264.7 cells 65. A
report had shown that high content of acidic poly-
saccharide, dietary fiber, vitamins C, B12, folate,
ergothioneine (C 9 H 15 N 3 O 2 S) L-Histidine
derivative) (Figure 3), polyphenols of Agaricus
bisporus can enhance glucose uptake by upregu-
lating insulin secretion. Administration of
Agaricus bisporus powder to diabetic rats can
control both the total cholesterol and glucose con-
centration and lowers the liver and kidney weights
in diabetic rats. Probably the high fiber content
of this mushroom extract may prevent the
digestive enzyme actions resulting in down-
regulating the glucose response and the lectin-like
molecules in mushroom can stimulate the release
of insulin and glucagon from islet cells 66.
Another pharmacologically active natural novel
compound Antroalbol H has been reported from
ethyl-alcohol extract of Antrodiella albocinna-
momea. This compound can upregulate GLUT4
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
Figure 3: Important anti-diabetic small molecules from mushroom having anti-diabetic efficacies.
translocation, subcellular localization of liver
kinase B1 (LKB1) and AMPK activation by
phosphorylation of LKB1 at Thr189 in 3T3L1 cell
line 67.
Heptapeptide Ternatin (C19H18O8) (Fig. 3) and
its derivative (D-Leu7 ternatin) from Coriolus
versicolor were applied on diabetic mice at 8.5-
17 nmol/day and 68 nmol/day respectively in the
mice model which reduce the sterol regulatory
element binding protein 1 ( SREBP 1C) mRNA
in Hepa1-6 hepatocyte cell and inhibit hyper-
glycemia 68.
Antihyperglycemic efficacy of a novel
terpenoid, Dehydroeburicoic acid (C31H 48O3)
(Figure 3) isolated from Antrodia camphorata has
been reported 69. Active triterpenoid compounds
such as Antcin K (C 29 H 44 O 6) and Dehydro-
eburicoic acid from this mushroom can enhance
the levels of membrane glucose transporter
443
4(GLUT4) and phospho Akt in the C2C12 myo-
blast cell line. After the application of dehydro-
buricoic acid in diabetic mice, a 34.24 % reduction
in blood glucose takes place which is the same as
compared to metformin (36.5%). It can upregulate
glucose transporter 4, AMPK, PPARα, and
downregulate fatty acid synthase, mRNA levels
of hepatic adipocyte fatty acid-binding protein,
glycerol-3 phosphate acyl-transferase (GPAI) 69.
A study on STZ induced mice have shown that
triterpenoids such as dehydrotrametenolic acid
(C30H46O3), dehydro-tumulosic acid (C31H48O4)
and pachymic acid (C33H52O5) from Poria cocos
can significantly lower blood glucose via
increasing the muscle, fat and liver’s sensitivity
towards insulin in STZ induced diabetic mice 70,71.
From the chloroform extract of Inonotus
obliquus nineteen compounds were reported of
which the alkaloids 1,1-dimethyl-3,3-bis(2,2,6,6-
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454 444
tetramethyl-1-prop-2-en-1-ylpiperidin-4-yl) urea, di-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-
2,2-bis[2,2,6,6-tetramethyl-1(octyloxy) piperidin- benzazo-cine, are predicted to contain antidiabetic
4-yl]-hexa-nedioate, 3-(4-cyclohexylbutyl)-6,11- activity (Table 3) 72.
Table 3. Small molecules isolated from mushroom and their anti-diabetic properties

No. Name of Type of poly- Mode of action Reference

mushroom saccharide

1 Phellinus Hispidin Improve β cell condition, up regu- 63

linteus late insulin secretion via cyto
protection against oxidative
damage in H2O2 treated
RINm5F cell line
2 Inonotus 3 β hydroxyl Possesses α- amylase inhibition and 64
lanosta 8, 24-diene free radical scavenging activity.
21 al, Inotodiol,
Trametenolic acid
and Inotodiol
3 Cordyceps Lipopolysaccharide LPS induced NO production has 65
militaris and Cordycepin been inhibited by Cordycepin. Cor-
dycepin has the potentiality to regu-
late the genes (11 β HSD1, RAN-
TES & PPAR Y ) related to type 2
diabetes. Cordycepin decreased
LPS induced NF KB p65 in
RAW 264.7 cells.
4 Agaricus Polysaccharide, Enhance insulin and glucagon release 66
bisporus dietary fiber, vitamins from islet cells, enhance glucose up-
C,B12, folate, take. High fiber inhibit digestive
ergothioneine, poly- enzyme action & lectin like molecule
phenols, Lectin stimulate the insulin and glucagon
secretion.
5 Antrodiella AntroalbolH Up regulate GLUT4 translocation, 67
albocinnamomea APMK activation by phosphoryla-
tion of LKB1 at Thr 189
6 Coriolus Ternatin Supress hyper-glycemia and fatty 68
versicolor acid synthesis in KK(Y) mice and
3T3L1 cell line by regulating
PPAR-Y, SERBP-1C, FAS, ACC.
7 Antrodia Dehydroeburicoic Enhance GLUT 4, AMPK, PPARα 69
camphorata acid and reduce glucose level, Fatty acid
synthase,m-RNA levels of hepatic
adipocyte fatty acid binding protein,
Glycerol-3 phosphate acyl trans-
ferase (GPAT).
8 Poria cocos Dehydrotrametenolic Insulin sensitizer activity.in STZ 70, 71
Wolf acid, induced diabetic mice.
Dehydrotumulosic
acid, Pachymic acid
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
Clinical trials
According to the American Herbal Products
Association Botanical Safety Handbook, Gano-
derma lucidum and Ophiocordyceps sinensis, both
the mushrooms are considered the safest drug.
There is a lack of scientific data on the dosage of
Ganoderma, but Chinese medicine experts recom-
mended 1.5-9 gms of dried Ganoderma extract /
day 73. In 2004, polysaccharide fraction of Gano-
derma lucidum was applied to 71 diabetic patients.
The result showed decreased HbA1c from 8.4 at
baseline to 7.6 % and PPG value from 3.6 mmol/
L to 11.8 mmol/L after 12 weeks of treatment 74.
G. lucidum was given to 50 people having type 2
diabetes for 12 weeks at a dose of 3 gm /day. In
the end, a point means fasting plasma glucose
level of the placebo group was reported to be
187.9 mg/dL 75.On the other hand experiment by
Ganoderma lucidum, and combined application
of Ganoderma lucidum and Ophiocordyceps
sinensis on 84 types 2 diabetic patients did not
show any statistically or clinically significant
results 73. Another clinical trial was reported in
BIRDEM Hospital from July 2005 to January
2006 with 30 people (male-17, female-13) of
average 46 years of age. Application of Oyster
mushroom on these patients for 24 days consti-
tutes 7 days mushroom,7 days no mushroom and
then 7 days mushroom had revealed a decrease in
systolic blood pressure (SBP, P< 0.01), diastolic
blood pressure (DBP, p< 0.05) and both the plasma
glucose (FPG & 2-hPG, p< 0.001) 76. A clinical
trial on antidiabetic efficacy of mushroom on 72
diabetic patients in Taiwan has been reported
where capsule containing 500 mg Agaricus blazei
was applied to patients at a dose of three times
per day with gliclazide and metformin 77. Patients
subjected to this trial have shown low insulin
resistance scores (HOMA IR) indicating their
improvement in insulin resistance after 12 weeks
77
. It has been reported that oral administration of
Pleurotus ostreatus and P. cystidiosus to type 2
diabetes patients at dose 50 mg/kg/body weight
upregulate the serum insulin levels and downregu-
late postprandial serum glucose levels 78. Another
report has shown that 726 Japanese Type 2
diabetes patients were studied based on their
different dietary patterns of which patients having
445
mushrooms in their diet uptake showed low
medication and healthy life style 79. Bangladesh
Institute of Research and Rehabilitation in
Diabetes, Endocrine and Metabolic Disorders
(BIRDEM) has conducted a clinical trial from
January 2009- to September 2010 with 73 diabetic
housewives who were administered 200 gm of
Pleurotus ostreatus daily for 360 days. This trial
has shown P. ostreatus significantly reduces blood
glucose, total cholesterol, low-density lipo-
proteins, blood pressure without any deleterious
effect on liver, kidney and hemo-poietic tissues
80
. Medicinal mushroom Grifola gargel powder
had proven its antidiabetic efficacy already in in
vitro cell line and in vivo mice model. But first
human clinical trial regarding this potential one
has been published recently in the International
Journal of Medicinal Mushroom. Low molecular
weight extract of Grifola gargal was applied on
10 prediabetic patients at a dose of 9.2 gm for up
to 4 weeks. The result showed a significant
decrease in triglyceride level 57.
Patented and marketed antidiabetic products
from medicinal mushrooms
Medicinal mushrooms have been traditionally
used for different purposes mostly in Eastern
countries. Few researchers have already patented
their formulations, compounds, and their possible
antidiabetic activity from popular medicinal
mushrooms (Table 4).
Few mushroom extracts are commercially avail-
able in the market that claimed to have antihyper-
glycemic activity. One such product is
Dimemykon, a medicinal mushroom preparation
has been invented by Dr. MykoSan. This product
contains two highly active medicinal mushrooms
such as Lentinus edodes and Pleurotus ostreatus.
As per product details, this is beneficial for any
diabetic patient with high cholesterol, trigly-
cerides except the people allergic to fungi 90. We
have already discussed the immense potentiality
of Ophiocordyceps and one of its bioactive
compound cordycepin as an antidiabetic agent in
both cell lines and mouse models. ESULIX is one
such herbal capsule which contains
Ophiocordyceps manufactured by Aifa Herbs for
the last 10 years. This capsule has been tasted with
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454 446
Table 4. Patented mushroom products having anti-diabetic properties.

No. Patent No. Inventers Claimed product / Reference

extract name

1 US 6383799 Wasser, S.P., Process for producing, methods 81

Reshetnikov, S.V. and compositions of glucuronoxy
(2002) lomannan as neutriceutical agent
from higher basidiomycetes
mushroom.
2 US 20060270626A1 Hwang, H.J., Kim, W., Crude exopolysaccharides 82
Yun, J.W., Choi, J.W. produced from Phellinus
(2006) baumii mycelium having
hypoglycemic activity and
preparation method thereof
3 US 7087233B2 Chung, C.K., Tong, Anti-mutagenic effects of 83
S.K. (2006) Ganoderma lucidum spores
4. US 7214778 Zhuang, C., Glycoprotein with antidiabetic, 84
Kawagishi, H., Preuss, antihypertensive, anti-obesity
H.G., (2007) and anti-hyperlipidemic effects
from Grifola frondosa and a
method for preparing same
5. US 20070166320A1 Yamazaki, K., Agent for preventing/ameliora- 85
Nakagawa, E. ting diabetes and functional
(2007) food for preventing/ameliorating
diabetes (Agrocybe aegerita
(Brig.) Sing)
6 US 20080171104 Zhu, Y., Sonnenberg, Health promoting dairy and 86
A.S.M., Van Loo, food products containing mush-
E.N. (2008) room glucan produced through
fermentation of Grifola frondosa
7 CN 2010-10587474 Zheng, Gaoyu (2010) Method for processing chewing 87
gum containing extracts of (Gri-
fola frondosa, Auricularia auri-
cular) traditional Chinese medi-
cines for preventing and treating
diabetes
8 JP 2012077004A Takeshi, I., Mushroom extracts from Agari- 88
Hiroshi, H., cus, Hericium erinaceum and
Satoshi, I., Hypsizigusmarmoreus as insulin
Aya, K. (2012) secretion stimulators and health
foods for prevention and therapy
of diabetes mellitus
9 US 9758595B2 Ko, Y.F., Martel, J,M Method to prepare Ganoderma 89
Liau, J.C., Chang, I.T., lucidum polysaccharides posses-
Jian, W.T., Mei-Feng, sing anti-obesity properties and
L.I.N. Yang, C.J., uses thereof.
Chiu, C.Y., Chang,
C.J., Lin, C.S.,
Wu, T.R. (2017)
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
thousands of diabetic patients under the super-
vision of experts since 2009. It instigates the cell’s
sensitivity to insulin and usage of glucose by cells
and thus reduces the sugar level in the blood. It
shows a similar effect to synthetic medicine
Thiazolidinediones (TZDs) but this herbal
medicine takes one to two weeks to improve the
blood glucose levels significantly. As per medical
guideline two capsules to be taken three times a
day to anyone concerned about preventing the
development of diabetes or people at high risk
for developing diabetes except pregnant and
breastfeeding women. This capsule can markedly
reduce fasting blood glucose, insulin, C-peptide
level, HbA1c level and other complications 91.
A popular company named TOTAL NUTRA-
CEUTICAL SOLUTIONS has marketed 5 mush-
rooms blended antidiabetic product-Gluco SANO
Diabetes Health Formula which promotes insulin
sensitivity and balanced the sugar level in the
blood. GlucoSANO is enriched with Agaricus
blazei, Pleurotus eryngii, White Beech, Brown
Beech, Cordyceps militaris and also bioactive
enzymes nutrients, antiinflammatory substances
like L-Ergothioneine, polyphenols, Beta-glucans,
glycoprotein and selenomethionine. According to
usage guidelines, 4 capsules can be taken once
daily with a full glass of juice or water as a dietary
supplement 92. Ganoderma is a popular fungus
widely used in Eastern medicine. A renowned
Company Ganoherb has produced many herbal
products for curing or controlling many diseases.
One such GMP certified product is Blood Sugar
Adjust Oral Drink containing Ganoderma
lucidum spore powder and extract in combination
with Bitter melon showing excellent blood-
glucose-lowering effect 93. Natural nutraceutical
product manufacturing company ‘Pharmanex’ has
marketed an immune defense dietary supplement
‘ReishiMax’. In 2011, Anita Thyagarajan Sahu
and her colleagues Bradon Lane, Daniel Sliva
have documented that, dietary supplement
ReishiMax contains triterpenes and poly-
saccharides from Ganoderma lucidum which
affects glucose uptake and adipocyte differen-
tiation in 3T3L1 cells via activation of AMPK
pathway and inhibition of SREBP-1C, PPAR-Y
and C/EBP-α receptors respectively 94. Mushroom
447
Wisdom, Inc. a world-famous company in the
development, production, and research of
mushroom supplements had launched their
product SX-FRACTION, which was prepared
according to US Patent 7214778. As per product
details, this supplement contains glycoprotein rich
fraction of Maitake mushroom and has been
shown to aid healthy blood sugar and insulin
fraction 95.
Future perspective
Medicinal mushrooms have been recommended
as a source of natural bioactive compounds and
have been targeted as potential hypoglycemic and
antidiabetic agents from ancient times 10. Polysac-
charides, proteins, dietary fibers and other
biomolecules isolated from medicinal, edible, or
nontoxic mushrooms have already proved their
blood glucose reducing proficiency both in in-
vivo and in an in-vitro model. Unfortunately,
diabetes remains undiagnosed for long periods
without showing major symptoms but ends up
with serious and complicated disorders, which are
very much influenced by diet pattern 10. Edible
and medicinal mushrooms can be used as
functional foods with a potent source of com-
pounds with antidiabetic efficacy. Intake of
mushrooms remarkably lowers the lipid levels,
total cholesterol and total triglycerides, low-
density lipoprotein cholesterol and upregulate the
high-density lipoprotein 96,97,98,99,100,101 .
Polysaccharide (β-glucans) present in many
mushrooms can restore the functions of pancreatic
tissues resulting in an upregulation in insulin
output by β-cells and lowering blood glucose. So,
medicinal mushrooms give us a boundless
opportunity for the development of new
therapeutics against one of these most prevalent
diseases, diabetes. But there are many complicated
signaling pathways related to several systems in
regulating the glucose metabolism 10. Though
many types of research are going on this burning
topic, the mechanism of action by these bioactive
molecules in detail needs more and more research
and clinical trials. Currently submerged culturing
of these mushrooms is more favorable to scientists
for the production of stable mushroom bio-
metabolites safely in large amount 10. Truly
 Pritha Chowdhury et al., / TBAP 10 (5) 2020 pp 429 - 454
speaking there are approximately 300-315 edible
mushroom species (Basidiomycetes) documented
only in India, and 357 genera of Basidiomycetes
are reported throughout the Globe still antidiabetic
research has been done in detail with maximum
39 mushroom species. There are still numerous
regions where diversity is not well studied or
remains unexplored and those new taxa may
contain more valuable antidiabetic active meta-
bolites. Future investigations and more research
are needed for bioprospecting of new taxa for
antidiabetic efficacies and subsequent isolation of
active biomolecules. Application of lead bioactive
molecules in clinical trials and research on cyto-
toxicity issues and understanding the mechanism
of drug action will be helpful for the development
of noble therapeutics resourcing from mushroom
to improve the lifestyle of millions of people of
the World.
Conclusion
Till now 250 papers published on the mushroom
with antidiabetic potential are in the electronic
database; of which about 134 papers are relevant
to our concern. This study reveals that out of 134
papers 86 papers contain detailed studies about
the antidiabetic potentiality of mushroom extracts
448
or compounds. From 1995-2020 only 39 species
of mushrooms are reported in detail of which the
highest number of reports was published on edible
and most common Pleurotus, Grifola, Ophiocor-
dyceps, Agaricus species. Though there are
approximately 14,000 mushroom species
recorded around the globe 102, only 0.28 % has
been explored so far exhibiting antidiabetic
efficacy. Mushrooms are also used as food and
dietary supplement and till today no side effect in
a clinical trial has been reported so far, though
more research regarding detailed pathways of
activity needs to be conducted in the future.
Taking account of all the publications documented
so far it can be concluded that mushrooms, a
repository of various bioactive molecules can be
tapped in the future as a source of novel drugs for
the treatment of diabetes.
Acknowledgement:
The authors are indebted to the DST-FIST pro-
gram, the Government of India, and the UGC-
CAS program at the Department of Botany, the
University of Calcutta for support.
Conflict of interest:
The authors report no conflict of interest.

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