Current anti-diabetes mechanisms and
clinical trials using Morus alba L.
, Mingmin Tang
, Baosheng Zhao
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
Center of Scientiﬁc Experiment, Beijing University of Chinese Medicine, Beijing 100029, China
Received 21 April 2016; accepted 22 April 2016
Available online 2 June 2016
Abstract Backgrounds: Diabetes mellitus, especially type 2 diabetes, with its fast-rising
prevalence, has become a global epidemic. Mulberry (Morus alba L.) leaf has been known to
have hypoglycemic effects since ancient times. In Asia mulberry leaf is used as tea to comple-
ment the treatment of diabetes mellitus. The methods by which mulberry leaf affects the body
and its mechanism when combined with chemical agents have been studied extensively.
Conclusions: We summarize the possible mechanisms of the anti-diabetic effects of mulberry
leaf based on extraction procedures, in vitro and in vivo experiments, and clinical trials. We
also discuss the hypothesis that crosstalk and “critical nodes” may be useful for a deeper mo-
lecular understanding of the treatment and prevention of diabetes with mulberry leaf.
ª2016 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
Diabetes mellitus is a disease that affects the body’s
regulation of blood glucose, the main symptoms of which
include thirst, frequent urination, hunger, and weight loss.
Diabetes, especially type 2 diabetes metillus (T2DM), is
increasingly prevalent worldwide according to the WHO,
calling for a monitoring of diabetes rates and researches
into cost-effective treatments to slow its rise.
As for the medicinal interventions, certain traditional
plants have been proved to retard the development of
diabetic mice induced by streptozotocin (STZ).
Chinese herbs have been shown to have beneﬁcial effects
over Western pharmaceutical medications in treating dia-
betes, including duration effect, moderate hypoglycemic
effects, and fewer side effects.
In China, mulberry (Morus alba L.) leaf has been used to
treat various illnesses since ancient times. Its use was ﬁrst
recorded in Divine Husbandman’s Classic of Materia Medica
(Shennong Bencao Jing; 200e220 CE), which is the earliest
materia medica in China. The herb was described as being
* Corresponding author.
E-mail address: email@example.com (B. Zhao).
Peer review under responsibility of Beijing University of Chinese
2095-7548/ª2016 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
HOSTED BY Available online at www.sciencedirect.com
journal homepage: http://www.elsevier.com/locate/jtcms
Journal of Traditional Chinese Medical Sciences (2016) 3,3e8
able to eliminate cold and heat in the body, promote
perspiration, and have detoxifying properties.
wider use of mulberry leaf, more properties and effects
were recorded in Comprehensive Outline of the Materia
Medica (Bencao Gangmu; 1590), an extensive summary of
Chinese herbal pharmacology. The author, Li Shizhen,
indicated that brewed mulberry tea can treat wasting and
thirsting (xiao ke) syndrome. It is now recognized that
diabetes falls under this syndrome.
Pharmacological experiments have shown that the
active compounds in mulberry leaf with hypoglycemic ef-
fects including alkaloids, ﬂavonoids, polysaccharides,
amino acids, simple phenylpropanoids, and phenols.
brief review, we present the mechanisms of the anti-
diabetic effects of mulberry leaf from perspectives of ex-
tracts, their compounds, molecular mechanisms, and clin-
ical trials. We hope that this manuscript provides a
summary for future research on mulberry leaf as an herbal
supplement for T2DM.
Extraction conditions resulting in the best anti-
diabetic effects in vitro and in vivo
In ancient China, dried mulberry leaf was brewed in hot
water to make a tea for treating diabetes. Modern extrac-
tion methods are now able to maximize treatment hypo-
glycemic effects with increased glucose uptake attributed
to various factors during extraction, such as brewing time,
concentration of organic solution, and extraction solution
Chen et al
compared two extracts from mulberry leaf on
STZ-induced diabetic mice, and found that hot water ex-
tracts exhibited more potent hypoglycemic effects than
ethanol or n-butanol fractions. Attila et al
dichloromethane-soluble fraction from the hot water
extract of mulberry leaf had the potentiality to exert anti-
diabetic activity on the 3T3-L1 adipocytes. Powder of dried
mulberry leaf was given to diabetic rats by gavage, showing
no traces of lenticular opacity in diabetic-mulberry group
and no signiﬁcant differences of blood glucose in normal
When a mixture of mulberry leaf and mulberry tea
was steeped in hot water (98C) for 3e5 min, a stronger
inhibitory effect on a-glucosidase was observed in a Caco-
2 cell culture experiment, compared with other extraction
Ethanolic and other extracts
Aside from the water extract, the ethanol extract of mul-
berry leaf is effective at treating diabetes in STZ-induced
So is the acetone extract, however, it is not so well
as the ethanolic.
From these studies, it is clear that the
mulberry extraction method plays a crucial role in pre-
venting diabetes, and each extract has different hypogly-
Mechanisms of the anti-diabetes effects of
mulberry leaf in vivo
After conﬁrming that crude extracts from mulberry leaf
have hypoglycemic effects, additional extracts are puriﬁed
for mechanistic studies. In these studies, various extracts
from mulberry leaf are separated with reagents under
different conditions, and active constituents are detected
and enriched. Here we summarize these mechanistic
studies with respect to their extracts.
Inhibition of a-glucosidase
Total alkaloids from mulberry leaf have hypoglycemic effects
in streptozotocin- (STZ-) induced diabetic mice.
kaloids in mulberry leaf are potent inhibitors of mammalian
These mulberry alkaloids, espe-
cially 1-deoxynojirimycin (DNJ), decrease a-glucosidase ac-
tivity by competitive inhibition through binding to the
enzyme active site to mimic natural substrates.
DNJ-enriched mulberry extract may be useful in con-
trolling postprandial hyperglycemia in pre-diabetic or mild
Oral administration of 0.24% DNJ and
its derivatives was found to inhibit absorption of sucrose
and polysaccharides in human and rat intestinal tissue
Other investigations on the pharmacokinetics
and bioavailability of DNJ showed that oral mulberry DNJ
administered to rats is absorbed intact from the gastroin-
testinal tract, diffuses into the liver, and is then excreted
with a short half-life.
Thus, studies such as the afore-
mentioned on the metabolism of DNJ help lay the founda-
tion for developing mulberry leaf as a dietary supplement
for diabetes. As such, extracting the highest DNJ content as
possible from mulberry is a high priority. In studies that
investigated extraction of DNJ, when temperature was
sustained at 98C for 400 s, 95% of DNJ in dry mulberry tea
and water extraction versus extraction
using different concentrations of ethanol produced varying
contents of DNJ.
Other studies are exploring ways to in-
crease production of DNJ during fermentation of mulberry
leaf, such as inoculating the fermentation broth with the
fungus ganoderma (Ganoderma lucidum).
Flavonoids from mulberry leaf also have in vitro inhibitory
effects on a-glucosidase activity and can suppress blood
glucose level after oral administration of starch and sucrose
in Kunming mice.
Two ﬂavonoids (isoquercitrin and
astragalin) were shown to inhibit a-glucosidase as for the
Furthermore, chlorogenic acid (a
phenylpropanoid) and rutin were found to play an impor-
tant role in preventing diabetes, but not isoquercitrin.
Polysaccharides from mulberry leaf have been shown to
decrease blood glucose level, improve glucose tolerance,
4 S. Tian et al.
and increase the hepatic glycogen content, thus regu-
lating glucose metabolism in diabetic mice and promoting
insulin secretion in normal rats.
mulberry leaf have also been found to inhibit a-glucosi-
The highly-puriﬁed polysaccharides a-
arabinose, a-xylose, a-glucose, a-rhamnose, and a-
mannose that were extracted from mulberry leaf were
able to induce regeneration of pancreatic b-cells, which
were then able to effectively secreted insulin and reduce
liver fat accumulation in diabetic rats.
their aglycons that were isolated from a water extract of
mulberry leaf were found to have potential type 2 anti-
While the inhibition of a-glucosidase plays a crucial role
in the anti-diabetes effect of mulberry leaf, an individual
compound cannot elucidate metabolic mechanisms, thus
molecular mechanisms need investigating.
Gluconeogenesis and glycolysis
The rate of hepatic glycogenolysis decreases after an
overnight fast, such that an increase in blood glucose in
type 2 diabetics is caused by gluconeogenesis.
similar conditions in diabetic rats, mulberry leaf was
shown to decrease the activities of key hepatic gluco-
neogenic enzymes, glucose-6-phosphatase (G-6-ase),
fructose 1,6-diphosphatase (FDPase), and phosphoenol-
pyruvate carboxy kinase (PEPCK).
Using real time-PCR
analysis, DNJ plus polysaccharide (HDP) was found to
up/down-regulate glucokinase (GCK), PEPCK, and G-6-
All carbohydrates undergo glycolysis, but this process is
more active in healthy persons than in diabetics.
glycolytic enzymes hexokinase, operating partial inhibition,
phosphofructokinase-1, the important control point, and
pyruvate kinase are involved in gluconeogenesis.
er, mulberry leaf extract did not signiﬁcantly alter the ac-
tivities of hexokinase and phosphofructokinase-1, while
glucokinase did in STZ-induced diabetic rats.
Results from studies such as those, it appears mulberry
leaf likely suppresses gluconeogenesis and promotes
glycolysis. Although some studies focused on gluconeogen-
esis and glycogenolysis, their results are insufﬁcient to
explain why mulberry leaf could have an anti-diabetic ef-
fect, and how it affects each step in gluconeogenesis and
AMP-activated protein kinase (AMPK) is a regulator of
intracellular and systemic energy metabolism. Research
has found that AMPK can be targeted in the treatment of
diabetes and metabolic syndrome.
One study found that
a hot water extract of mulberry leaf could activate
skeletal muscle AMPK signaling, as shown by increased
uptake of 3-O-methyl-D-glucose transport and was also
(AS160) and acetyl-CoA carboxylase, without any energy
Anti-apoptosis of b-cells
Increased b-cell apoptosis leads to b-cell loss and results in
onset of type 2 diabetes.
Apoptosis is a fundamental
mechanism for homeostasis and a form of programed cell
death, with 2 large protein families involved in the process:
the caspase family and the B-cell lymphoma 2 (Bcl-2) pro-
teins. These two protein families are linked with the
development of insulin resistance,
with the increased
ratio of Bax/Bcl-2 and caspase-3 showing an association
Polysaccharides from mulberry leaf have
been shown to elevate the Bcl-2/Bax ratio to protect
pancreatic islet cells from apoptosis.
However, the Bcl-2
family is divided into 3 subgroups,
thus further study is
needed to determine which proteins are altered when
mulberry leaf is administered.
The glucose transporter GLUT4 is an insulin-sensitive
transporter that can facilitate a decreased plasma glucose
level. GLUT4 is translocated to the plasma membrane via
the lipid kinase phosphatidylinositol 3-kinase (PI3K)
Additionally, pancreatic duodenal
homeobox-1 (PDX-1) is a regulator of beta cell identity and
function in pancreatic islets. Glucose-simulated PDX-1 DNA-
binding activity is inhibited by inhibitors of PI3K, such as
which was used to validate the hypoglyce-
mic mechanism of mulberry leaf. Therefore, mulberry leaf
extract might mediate hyperglycemia by increasing glucose
uptake via the PI3K pathway and translocation of GLUT4 to
the plasma membrane, with gallic acid the speciﬁc com-
pound that mediates this effect.
In addition, poly-
saccharides from mulberry leaf have been shown to up-
regulate PDX-1, insulin-1, and insulin-2 expressions in the
The serine/threonine protein kinase Akt is a major
target downstream of PI3K, and PI3K and Akt appear to
activate islet b-cells. Thus, islet-cell damage caused by
oxidative stress may be attenuated via the PI3KeAkt
PTP1B is a phospho-tyrosine protein phospha-
tase that negatively modulates insulin sensitivity and is a
substrate for Akt.
Polysaccharides from mulberry leaf
have been shown to inhibit PTP1B, activate the PI3KeAkt
pathway, and reduce oxidative stress resulting in anti-
The early studies cited in the text have illustrated that
polysaccharides from mulberry leaf could activate PI3K/Akt
pathway and elevate Bcl-2/Bax ratio to protect pancreatic
islet cell from apoptosis. There are some important facts to
support our hypothesis: 1) Akt has direct effects on regu-
lating apoptosis, and there also exists connections between
PI3-kinase pathways and control of apoptosis
; 2) PI3K/Akt
pathway inhibits Bax translocation and could promote sur-
; Akt possibly promote cell survival through inacti-
vation of Bad with phosphorylation and up-regulation of
Thus we hypothesize that polysaccharides from mul-
berry leaf initiate Akt in PI3K/Akt pathway, which could
inhibit Bax translocation and phosphorylate and up-
Anti-diabetes mechanisms and clinical trials using Morus alba L. 5
regulate of Bcl-2, but as for which isoform of Akt exerts
such function needs the research.
As for the current researches, crosstalk with signaling
cascades and the network among the pathways has been
introduced and the “critical nodes” are shown to deﬁne the
The study has demonstrated the signiﬁcant
crosstalk between the AMPK and PI3K/Akt in embryonic
and the mammalian target of rapamycin complex 1
(mTORC2) has been identiﬁed as a site of signaling crosstalk
and it has used to study the molecular mechanism of
In the domain of physiopathology, AMPK enhances in-
sulin sensitivity involved in direct regulation of PI3K and
As for the mulberry leaf, since
mulberry hot water extract could increase the phosphor-
ylation of AS160, however, without signiﬁcant change in
Akt in skeletal muscle cell. Two possible interpretations
might elucidate this result: 1) The active compounds in
the extracts under different extraction condition could
make a difference; 2) Researches have showed that the
primary role Akt2 is highlighted in adipocytes on insulin
responsiveness and the isoforms of Akt have their own
structures and functions,
may be deeper researches will
fulﬁll the ﬁnding that extracts from mulberry leaf could
have relations with crosstalk between AMPK and PI3K/Akt
Peroxisome proliferator-activated receptors
The peroxisome proliferator-activated receptors (PPARs)
are important in insulin resistance, hyperlipidemia, and
Water extract of mulberry leaf was found to
increase insulin sensitivity and attenuate hyperglycemia
through up-regulation of PPAR expression in diabetic
insulin resistance because of a reduced GLUT4 pool.
found that PPARgagonists have been found to strengthen
basal and insulin-stimulated glucose uptake in 3T3-L1
Mulberry leaf extract was shown to signiﬁ-
cantly increase secretion of adiponectin in 3T3-L1 and
enhanced the expression of PPARg. Therefore, the anti-
diabetic mechanism of mulberry leaf may be attribut-
able to stimulation of adipogenic activity and adiponectin
Mechanisms under investigation
Mulberry leaf continues to be investigated for its hypo-
glycemic mechanism. For example, the anti-diabetic
function of mulberry leaf is correlated with anti-
Furthermore, Attenuation of
insulin resistance may contribute to regulation of the
genes in the c-Jun amino-terminal kinase (JNK) signaling
As inﬂammation is closely associated with
metabolic disorder and the JNK pathway is an inﬂamma-
tory pathway, in the light of it, one hypothesis can be
assumed that mulberry leaf might be anti-diabetes
It is important to conduct studies with diabetic patients and
healthy volunteers to understand how natural products
such as mulberry leaf work in the body. This is because
botanical products have many pharmacologically-active
constituents that can interact with each other as well as
with pharmaceutical drugs.
Thirty-day treatment with mulberry powder was found
to signiﬁcantly lower fasting blood glucose compared with
Other studies have found that treatment
with mulberry tea can cause malabsorption of
Several clinical trials have focused on the enriched
compounds of mulberry leaf. To evaluate the effect of
mulberry leaf extract with enriched DNJ on postprandial
hyperglycemia, parameters, such as serum 1,5-
anhydrogluctol concentration, can be used as a sign for
positive improvement of impaired glucose metabolism.
contrast, signiﬁcant differences in postprandial hypergly-
cemia can be analyzed alone.
Results of a clinical trial
that combined dietary control, exercise, and the total al-
kali fraction from mulberry leaf showed a reduction of
blood glucose, regulation of lipids, and fewer side effects
compared with acarbose treatment.
Mulberry tea has also
been shown to suppress postprandial hyperglycemia after
90 min of its consumption.
While the aforementioned studies have shown that
mulberry leaf decreases blood glucose, regulates glucose
and lipid metabolism, has few adverse effects, and may
exert a wider treatment range than pharmaceuticals. There
is a lack of research focusing on the safety of mulberry leaf.
Therefore, investigations are needed on the absorption,
distribution, metabolism, and excretion of compounds in
Discussion and conclusion
The anti-diabetes mechanism of mulberry leaf remains
incompletely understood at the molecular level. However,
active compounds in mulberry leaf likely affect crosstalk
among the signal transduction pathways and networks. A
single pathway cannot explain the hypoglycemic effect of
mulberry leaf. Therefore, the crosstalk between AMPK and
PI3K/Akt may be worth exploring for the anti-diabetic ef-
fects of mulberry leaf compounds.
More extensive clinical research should also be con-
ducted on mulberry leaf’s potentiality as a hypoglycemic
agent. For example, well-designed randomized controlled
trials, the gold standard for evaluating whether an inter-
vention is effective, should be performed to validate and
conﬁrm ﬁndings of molecular studies.
This work was carried out with the support of National
Natural Science Foundation (No. 81374027), the People’s
Republic of China.
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