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Current anti-diabetes mechanisms and clinical trials using Morus alba L

Authors:

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 complement 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 molecular understanding of the treatment and prevention of diabetes with mulberry leaf.
Current anti-diabetes mechanisms and
clinical trials using Morus alba L.
Simin Tian
a
, Mingmin Tang
a
, Baosheng Zhao
b,
*
a
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
b
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
KEYWORDS
Mulberry leaf;
Anti-diabetes;
Molecular
mechanisms;
Clinical trials
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/
by-nc-nd/4.0/).
Introduction
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).
1
Traditional
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.
2
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: zhaobs1973@163.com (B. Zhao).
Peer review under responsibility of Beijing University of Chinese
Medicine.
http://dx.doi.org/10.1016/j.jtcms.2016.04.001
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
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able to eliminate cold and heat in the body, promote
perspiration, and have detoxifying properties.
3
With the
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.
4
In this
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
temperature.
Water extracts
Chen et al
5
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
6
investigated the
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
group.
7
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
conditions.
8
Ethanolic and other extracts
Aside from the water extract, the ethanol extract of mul-
berry leaf is effective at treating diabetes in STZ-induced
rats,
9,10
So is the acetone extract, however, it is not so well
as the ethanolic.
11,12
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-
cemic effects.
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
Alkaloids
Total alkaloids from mulberry leaf have hypoglycemic effects
in streptozotocin- (STZ-) induced diabetic mice.
13
Some al-
kaloids in mulberry leaf are potent inhibitors of mammalian
digestive glycosidases.
14
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.
15
DNJ-enriched mulberry extract may be useful in con-
trolling postprandial hyperglycemia in pre-diabetic or mild
diabetic individuals.
16
Oral administration of 0.24% DNJ and
its derivatives was found to inhibit absorption of sucrose
and polysaccharides in human and rat intestinal tissue
samples.
17
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.
18,19
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
was extracted
20
and water extraction versus extraction
using different concentrations of ethanol produced varying
contents of DNJ.
21
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).
22
Flavonoids
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.
23
Two flavonoids (isoquercitrin and
astragalin) were shown to inhibit a-glucosidase as for the
laboratory experiment.
24
Furthermore, chlorogenic acid (a
phenylpropanoid) and rutin were found to play an impor-
tant role in preventing diabetes, but not isoquercitrin.
25
Polysaccharides
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.
26
Polysaccharides from
mulberry leaf have also been found to inhibit a-glucosi-
dase activity.
27
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.
28
Glycosides and
their aglycons that were isolated from a water extract of
mulberry leaf were found to have potential type 2 anti-
diabetic activity.
29
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.
30
Under
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).
31
Using real time-PCR
analysis, DNJ plus polysaccharide (HDP) was found to
up/down-regulate glucokinase (GCK), PEPCK, and G-6-
ase.
18
All carbohydrates undergo glycolysis, but this process is
more active in healthy persons than in diabetics.
32
The
glycolytic enzymes hexokinase, operating partial inhibition,
phosphofructokinase-1, the important control point, and
pyruvate kinase are involved in gluconeogenesis.
33
Howev-
er, mulberry leaf extract did not significantly alter the ac-
tivities of hexokinase and phosphofructokinase-1, while
glucokinase did in STZ-induced diabetic rats.
34
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
glycogenolysis.
AMPK signaling
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.
35
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
involvedinphosphorylationofAktsubstrateof160kDa
(AS160) and acetyl-CoA carboxylase, without any energy
changes.
36
Anti-apoptosis of b-cells
Increased b-cell apoptosis leads to b-cell loss and results in
onset of type 2 diabetes.
37
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,
38
with the increased
ratio of Bax/Bcl-2 and caspase-3 showing an association
with diabetes.
39
Polysaccharides from mulberry leaf have
been shown to elevate the Bcl-2/Bax ratio to protect
pancreatic islet cells from apoptosis.
40
However, the Bcl-2
family is divided into 3 subgroups,
41
thus further study is
needed to determine which proteins are altered when
mulberry leaf is administered.
PI3K/Akt signaling
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)
signaling pathway.
42
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
wortmannin,
43
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.
44
In addition, poly-
saccharides from mulberry leaf have been shown to up-
regulate PDX-1, insulin-1, and insulin-2 expressions in the
pancreas.
18
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
pathway.
45
PTP1B is a phospho-tyrosine protein phospha-
tase that negatively modulates insulin sensitivity and is a
substrate for Akt.
46
Polysaccharides from mulberry leaf
have been shown to inhibit PTP1B, activate the PI3KeAkt
pathway, and reduce oxidative stress resulting in anti-
diabetic effects.
47
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
48
; 2) PI3K/Akt
pathway inhibits Bax translocation and could promote sur-
vival
49
; Akt possibly promote cell survival through inacti-
vation of Bad with phosphorylation and up-regulation of
Bcl-2.
48,50,51
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
junctions.
52
The study has demonstrated the significant
crosstalk between the AMPK and PI3K/Akt in embryonic
cells,
53
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
metformin.
54
In the domain of physiopathology, AMPK enhances in-
sulin sensitivity involved in direct regulation of PI3K and
stimulates PI3K/Akt.
55
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,
52
may be deeper researches will
fulfill the finding that extracts from mulberry leaf could
have relations with crosstalk between AMPK and PI3K/Akt
pathways.
Peroxisome proliferator-activated receptors
(PPARs)
The peroxisome proliferator-activated receptors (PPARs)
are important in insulin resistance, hyperlipidemia, and
diabetes.
56
Water extract of mulberry leaf was found to
increase insulin sensitivity and attenuate hyperglycemia
through up-regulation of PPAR expression in diabetic
mice.
57
3T3-1Lcanbeusedtostudythedevelopmentof
insulin resistance because of a reduced GLUT4 pool.
58
It is
found that PPARgagonists have been found to strengthen
basal and insulin-stimulated glucose uptake in 3T3-L1
adipocytes.
59
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
secretion.
60
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-
inflammatory reactions.
61
Furthermore, Attenuation of
insulin resistance may contribute to regulation of the
genes in the c-Jun amino-terminal kinase (JNK) signaling
pathway.
62
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
through anti-inflammation.
Clinical trials
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.
63
Thirty-day treatment with mulberry powder was found
to significantly lower fasting blood glucose compared with
glibenclamide.
64
Other studies have found that treatment
with mulberry tea can cause malabsorption of
carbohydrates.
65,66
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.
67
In
contrast, significant differences in postprandial hypergly-
cemia can be analyzed alone.
68
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.
69
Mulberry tea has also
been shown to suppress postprandial hyperglycemia after
90 min of its consumption.
70
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
mulberry.
14
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.
Acknowledgments
This work was carried out with the support of National
Natural Science Foundation (No. 81374027), the People’s
Republic of China.
6 S. Tian et al.
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8 S. Tian et al.
... Over the past decade, there has been increased attention on the identification and investigation of herbal medicines for the management of various chronic diseases, including diabetes mellitus (Han et al., 2019). Due to its use in traditional systems of medicine, mulberry has recently emerged as a strong antidiabetic medicinal plant (Tian et al., 2016). Several studies have now investigated antidiabetic properties in different parts of mulberry. ...
... Polysaccharides isolated from the leaves of mulberry were reported to reduce plasma glucose level, improve glucose tolerance, increase the hepatic glycogen content, and inhibit a-glucosidase activity. The extracted polysaccharides a-arabinose, a-xylose, a-glucose, arhamnose, and a-mannose were found to repair pancreatic bcells, resulting in increased insulin secretion and reduced accumulation of liver fat in diabetic rats (130). A randomized, placebo-controlled study on 10 type 2 diabetic (age range: 59 -75 years) and 10 healthy subjects (age range: 24 -61 years) involving the ingestion of 1 g leaf extract of Morus alba showed remarkably reduced blood glucose levels after 2 hours in comparison to the placebo group (131). ...
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Diabetes, a chronic physiological dysfunction affecting people of different age groups and severely impairs the harmony of peoples' normal life worldwide. Despite the availability of insulin preparations and several synthetic oral antidiabetic drugs, there is a crucial need for the discovery and development of novel antidiabetic drugs because of the development of resistance and side effects of those drugs in long-term use. On the contrary, plants or herbal sources are getting popular day by day to the scientists, researchers, and pharmaceutical companies all over the world to search for potential bioactive compound(s) for the discovery and development of targeted novel antidiabetic drugs that may control diabetes with the least unwanted effects of conventional antidiabetic drugs. In this review, we have presented the prospective candidates comprised of either isolated phytochemical(s) and/or extract(s) containing bioactive phytoconstituents which have been reported in several in vitro, in vivo, and clinical studies possessing noteworthy antidiabetic potential. The mode of actions, attributed to antidiabetic activities of the reported phytochemicals and/or plant extracts have also been described to focus on the prospective phytochemicals and phytosources for further studies in the discovery and development of novel antidiabetic therapeutics.
... Over the past decade, there has been increased attention on the identification and investigation of herbal medicines for the management of various chronic diseases, including diabetes mellitus (Han et al., 2019). Due to its use in traditional systems of medicine, mulberry has recently emerged as a strong antidiabetic medicinal plant (Tian et al., 2016). Several studies have now investigated antidiabetic properties in different parts of mulberry. ...
Full-text available
Chapter
Diabetes mellitus is one of the world's significant wellness issues, affecting the urban population more than the rural areas. The prevalence of this disease is increasing speedily day by day. Effective regulation of blood glucose levels is the most critical factor in decreasing the dangers of diabetic complexities. Chemically synthesized anti-diabetic drugs available in the market have many side effects; therefore, plant-derived substances may provide a better alternative medicine to combat diabetes. These natural molecules are presumed to be effective, economical as well as with no side effects. Among different accessible plants, garlic (Allium sativum), a typical cooking flavor, and a long history as a people cure have anti-diabetic potential. According to several reports, garlic's antiglycation, antioxidative, and anti-inflammatory properties have been related to its function in preventing diabetes. Notwithstanding, there is no standard concession to utilizing garlic for anti-diabetic purposes, principally due to less logical proof from human examinations and discrepant information from animal studies. A promising approach to cure this disease by garlic plant molecules focuses throughout this chapter. In this book chapter, the authors collected the scientific evidence available throughout the various experimental platforms and literature related to the garlic plant's functional role in improving the blood sugar level of diabetic patients. This book chapter focuses on the pharmacology, secondary metabolite profiling, ingredients of garlic plant with insulin-mimetic activity, and its health benefits. Garlic supplements are useful in treating diabetic patients, and this chapter content may disclose a path for the researchers to combat this disease in the future. Keywords: Anti-diabetic; diabetes mellitus; insulin; Allium sativum; insulin secretagogue; metabolic syndrome
... High TPC, TFC and anthocyanins content in MF might slightly diminish its aamylase inhibition activity. According to Jeong, Lee, Cho, Jeong, and Jeong (2014) and Tian, Tang, and Zhao (2016), anti-diabetic potential of mulberry leaves is contributed by its 1deoxynojirimycin, fagomine, flavonoid and polysaccharide content. ...
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Objective Mulberry (Morus spp.) fruits and leaves have been proven to possess nutraceutical properties. Due to its fast and easy growing characteristics, mulberry fruits (MF) and leaves (ML) potentially emerge as a great source of functional foods. This study aims to enhance bioactivities (antioxidant, anti-inflammation, and hypoglycemic activity) of MF and ML via submerged fermentation using bacteria (Lactobacillus plantarum TAR 4), yeast (Baker’s yeast and red yeast) and fungi (Tempeh and Tapai starter). Methods In this study, 25% (mass to volume ratio) of MF and ML were fermented (48 h) with 1% (mass to volume ratio) of different microbial cultures, respectively. Effects of different fermentations on MF and ML were determined based on the changes of total phenolics (TPC), flavonoids (TFC), anthocyanins, total sugar, DPPH activity, ferric reducing antioxidant power (FRAP), albumin denaturation inhibition activity (ADI), anti-lipoxygenase activity and α-amylase inhibition activity (AI). Results Generally, ML had higher AI than MF. However, MF exhibited higher DPPH, FRAP and anti-lipoxygenase activity than ML. After all forms of fermentation, DPPH and AI activity of MF and ML were increased significantly (P < 0.05). However, the effects of fermentation on TPC, FRAP, ADI and anti-lipoxygenase activity of MF were in contrast with ML. TPC, FRAP and anti-lipoxygenase activity of ML were enhanced, but reduced in MF after fermentation. Although the effects exerted by different microorganisms in MF and ML fermentation were different, the bioactivities of MF and ML were generally improved after fermentation. Fermentation by Tempeh starter enhanced TPC (by 2-fold), FRAP (by 2.3-fold), AI (at 10% increment) and anti-lipoxygenase activity (by 5-fold) of ML, whereas Tapai fermentation effectively enhanced the DPPH (at 17% increment) and ADI (by 2-fold) activity of MF. Conclusion Findings of this study provide an insight into the future process design of MF and ML processing into novel functional foods.
... The fruits, seeds and callus of Momordica charantia contain some insulin-like proteins [118] which are homologous to human insulin, and it produced consistent hypoglycemic effect when tested on rats, gerbils, langurs and human beings [119]. M. charantia was believed to be a treatment for diabetes mellitus for thousands of years in India and China [120]. Consumption of dried powder of M. charantia fruit revealed reduction in fasting blood sugar of 10 Type 2-Diabetes mellitus patients with no history of previous medication and 10-T2DM patients with history of taking oral hypoglycemic agents. ...
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Plants have provided man with all his needs in terms of shelter, clothing, food, flavors and fragrances as not the smallest amount, medicines [1]. According to the estimation of the World Health Organization, 80% of the population in developing countries still depends on folk medicine for prevention or treatment of illnesses [2]. Chronic diseases have resulted from the radical change in the lifestyle choices of people over the century. [3] The use of herbal and traditional medicines may be a common practice because the option of traditional medicines within the treatment of lifestyle associated diseases (such as hypertension and diabetes mellitus) are found to be more practical due to its cheaper cost [4]. Diabetes mellitus is a public health problem which leads to serious complications over time [5]. Diabetes mellitus (DM), both insulin-dependent DM (IDDM) and non-insulin dependent DM (NIDDM) may be a common and high disorder throughout the planet. The use of traditional plant remedies has been practiced throughout the world for diabetes mellitus [6]. As mentioned in the review article of Bahare et. al in 2019[7] traditional knowledge of antidiabetic Asian plants were found in different countries in Southeast Asia like Iran; Malaysia; Philippines; Saudi Arabia; Sri Lanka and India, to name a few. A compiled review on the information about medicinal plants used for the treatment of diabetes mellitus was done comprehensively and was proven that plants are a potential source of anti-diabetic drugs through ethnobotanical information reports of several plants that may possess anti-diabetic potential. The present review aims to examine some of the important plant species and their constituents, showing their beneficial effects such as the potential antidiabetic activity that can be used in the management of diabetes.
Chapter
Natural products in the form of secondary metabolites have been applied for healing several ailments since prehistoric times. Secondary metabolites obtained from the medicinal plants are one of the main sources used as antidiabetic medicines. Diabetes mellitus is a group of metabolic orders remarked by hyperglycemia and disturbances in carbohydrate, fat, and protein metabolic processes. Diabetes is connected with insufficient insulin secretion by pancreatic β-cells or dubious insulin activity in insulin signal transduction. Plants can produce secondary metabolites with the help of plant growth-promoting rhizobacteria (PGPR). PGPR in colonies induce plant development by synthesizing indole-3-acetic acid, cytokine, and gibberellin hormones, making the soil rich in mineral nitrogen and also combating pathogenic microorganisms to protect their host plants. There is an indirect connection between PGPR and diabetes treatments. The vital role of PGPR in secondary metabolite production is making plants rich in bioactive compounds which consequently act as antidiabetic drug molecules. Many research papers have been published regarding ethnopharmacology of antidiabetes plants, but the involvement of PGPR in diabetes management still remained to be researched. The chapter consolidates the articles published in indexed journals describing the role played by PGPR in medicinal plants to produce bioactive compounds as secondary metabolites and their effectiveness in amending diabetes interventions.KeywordsDiabetesRhizobacteriaSecondary metabolites
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Medicinal plants have been proposed as rich yet unexploited potential sources for anti-diabetic drugs, even though used since ancient times for the treatment of diabetes mellitus. Many of the synthetic drugs were discovered either directly or indirectly from the plant source. The present study reviews of plants having anti diabetic property. Although many plants are recommendation, further pharmacological and chemical research should be done to elucidate the exact mechanism of hypoglycaemic activity
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The leaves of Morus alba L. (called Sangye in Chinese, ML), which belong to the genus Morus., are highly valuable edible plants in nutrients and nutraceuticals. In Asian countries including China, Japan and Korea, ML are widely used as functional foods including beverages, noodles and herbal tea because of its biological and nutritional value. Meanwhile, ML-derived products in the form of powders, extracts and capsules are widely consumed as dietary supplements for controlling blood glucose and sugar. Clinical studies showed that ML play an important role in the treatment of metabolic diseases including the diabetes, dyslipidemia, obesity, atherosclerosis and hypertension. People broadly use ML due to their nutritiousness, deliciousness, safety, and abundant active benefits. However, the systematic pharmacological mechanisms of ML on metabolic diseases have not been fully revealed. Therefore, in order to fully utilize and scale relevant products about ML, this review summarizes the up-to-date information about the ML and its constituents effecting on metabolic disease.
Chapter
Diabetes mellitus (DM) is a chronic degenerative disease that affects more than 450 million people in the world, with type 2 being the most prevalent. Type 2 diabetes mellitus (T2DM) is characterized by resistance to insulin, a hormone that is involved in glucose homeostasis. There are medications that prevent and control hyperglycemia, however, the continuous and long-term intake of some of these medications cause side effects on health. As an adjunct to treatment with synthetic drugs, the use of natural extracts with antidiabetic properties has been proposed as a complement to comprehensive treatment for the control of DM. The objective of this chapter is to show the general panorama of DM, the conditions associated with its development, and present some phytochemicals with the ability to intervene in a beneficial way of glucose metabolism. As a result of the research, natural compounds with antidiabetic action mechanisms such as inhibition of α-amylase and α-glucosidase enzymes were listed. In conclusion, the use of natural extracts with hypoglycemic characteristics works as a complementary treatment to control blood glucose levels in T2DM. However, more research is needed on the effect of phytochemicals on health that helps in the treatment of this disease.
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PI3K/AKT pathway has been shown to play a pivotal role on islet β-cell protection, enhancing β-cell survival by stimulating cell proliferation and inhibiting cell apoptosis. Accordingly, this pathway appears to be crucial in type-2 diabetes. Understanding the regulations of this pathway may provide a better efficacy of new therapeutic approaches. In this review, we summarize advances on the involvement of the PI3K/AKT pathway in hypothetical intra-cellular signaling of islet β-cells. As recent findings may show the nutritional regulation of the survival pathway in the islet β-cells through activation of the PI3K/AKT pathway, we also review studies on the features of several diets, correlated lifestyle, and its signaling pathway involved in type-2 diabetes. The molecular mechanisms contributing to the disease are the subject of considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies against a condition of the disease.
Article
Aim: To observe the influence of flavonoids from Morus alba L. on activity of α-glucosidase and postprandial blood glucose of mice. Methods: The experiment was conducted at the Laboratory of Department of Nutrition and Animal Central Laboratory, General Hospital of Chinese PLA from July to October 2005. There were blank group, different doses glucobay group and different doses flavonoids group (final concentration of 0,7.81,15.63,31.25,62.50,125.00,250.00 mg/L). A drug, glucobay was used a positive inhibitor of α-glucosidase. Activity of α-glucosidase was defined relatively as 100% when no inhibitors of α-glucosidase were added in experiment in vitro, and effects of flavonoids (including total flavonoids, the adsorbed and non-adsorbed flavonoids isolated by HP-20 resin) from Morus alba L. on activity of α-glucosidase were measured. Totally 40 Kunming mice were randomly divided into 4 groups according to blood glucose, namely starch group, starch plus flavonoids adsorbed by HP-20 resin group, sucrose group, sucrose plus flavonolds adsorbed by HP-20 resin group, with 10 in each group, which received starch (3 g/kg), starch (3 g/kg) plus flavonoids adsorbed by HP-20 resin (500 mg/kg), sucrose (1.5 g/kg), sucrose (1.5 g/kg) plus flavonoids adsorbed by HP-20 resin (500 mg/kg). The blood glucose levels at hours 1 and 2 were-measured. Results: 1When the concentrations of glucobay and total flavonoids were 0,7.81,15.63,31.25,62.5,125.00 and 250.00 mg/L, the /C50 glucobay and total flavonoids was 70.43,82.11mg/L, respectively. 2The relative activities of α-glucosidase were 100.00%, 94.61%, 84.90%, 63.04%, 26.27%, 11.37% and 6.76%, respectively, when the flavonoids adsorbed by HP-20 resin were used as inhibitor at the same concentrations to the total flavonoids, and its /C50 was 59.26 mg/L. The relative activitfes of α-glucosidase were 100.00%, 90.55%, 88.55%, 85.91%, 78.00%, 69.91% and 56.36%, respectively, when the flavonoids non-adsorbed by HP-20 resin were used as inhibitor at the same concentrations to the total flavonoids, and its /C50 was 82.86 mg/L. 3The blood glucose levels at hour 1 after oral load in starch plus flavonoids adsorbed by HP-20 resin group were much lower than that in starch control group [(9.06±1.10), (11.13±1.45) mmol/L, t =2.100 9, P =0.002 09]. The blood glucose levels at hour 1 after oral injection in sucrose plus flavonolds adsorbed by HP-20 resin were much lower than that in the glucose control group [(9.88±1.01), (12.75± 1.17) mmol/L, t=2.1009, P = 0.000 014). Conclusion: In vitro experiment indicates that total flavonoids from Morus alba L., the flavonoids absorbed and non-absorbed by HP-20 resin have potent inhibitory effects on activity of α-glucosidase. The flavonids adsorbed by HP-20 resin is more potent than the glucobay. The flavonoid adsorbed by HP-20 resin can decrease levels of blood glucose 1 hour after oral administration of starch and sucrose.
Article
Many traditional treatments have been recommended in the alternative system of medicine for the treatment of diabetes mellitus. Mulberry (Morus alba) is a nontoxic natural therapeutic agent shown to possess hypoglycemic, hypotensive, and diuretic properties. The purpose of this study was to examine the histopathologic effects of Morus alba leaf extract on the pancreas of diabetic rats. The animals were treated with mulberry leaf extract at dosages of 400 and 600 mg/kg body weight for 35 days. The various parameters studied included blood glucose, the relative body weight of the pancreas, the diameter of islets, and the number of β cells in all groups. Blood glucose level, the diameter of the islets, and the number of β cells were increased in treatment groups as compared to the diabetic group. According to the histological and biochemical results obtained, it was concluded that the extract of this plant may reduce blood glucose levels by regeneration of β cells.
Article
n-Hexane extract antioxidant properties from broccoli, sesame leaves, tomatos, black beans, coriander, and peels of apples, red grapes, carrots, and sweet potatos were determined in corn oil heated at 60 and 140°C. Broccoli, sesame leaves, and coriander showed high antioxidant properties. Carrots at 60°C showed prooxidative activities at both 1 and 5 mg concentrations. Red grape peels act as pro-oxidants at 1 mg, and as antioxidants at 5 mg. At 60°C, the antioxidant properties of hexane extracts were obvious, but not at 140°C. Broccoli and sesame leaves showed high anti-oxidative activities. Apple and sweet potato peels accelerated lipid oxidation rates.
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Five mulberry leaf extracts (water, 25, 50, 75, and 100% EtOH) were characterized for in vitro hypoglycemic activity and chemical profiles. According to chemical profiles obtained from 15Tesla Fourier transform ion cyclotron resonance mass spectrometry, water extracts contained more 1-deoxynojirimycin (DNJ) and fewer phytochemicals than other extracts. However, water extracts showed the highest inhibitory activity of glucose uptake. The degree of inhibition of α-glucosidase activity was similar for all extracts. The effect of mulberry leaf extracts on the glucose metabolism may be attributed to additional or cooperative effects of DNJ with other phytochemical compounds.
Article
Mulberry 1-deoxynojirimycin (DNJ), a potent alpha-glucosidase inhibitor, suppresses postprandial blood glucose, thereby possibly preventing diabetes mellitus. At present, mulberry dry teas are commercially supplied as functional foods in many countries, but these products may not provide an effective dose (6 mg DNJ/60 kg human wt) due to their low DNJ content (about 100 mg/100 g of dry wt). Therefore, development of tea with higher DNJ content is desirable. To do this, we investigated distribution of DNJ content and alpha-glucosidase inhibitory activity in 35 Thai mulberry varieties. DNJ content in young leaves varied among mulberry varieties from 30 to 170 mg/100 g of dry leaves. Varieties having highest DNJ content were Kam, Burirum 60 and Burirum 51. Leaf position affected DNJ content: shoots > young leaves > mature leaves. DNJ concentration and a-glucosidase inhibitory activity were highly correlated (r = 0.84), suggesting that alpha-glucosidase inhibitory activity of mulberry leaves is mainly due to DNJ. Consequently, high DNJ content mulberry tea was produced from shoots of varieties such as Burirum 60, which contains 300 mg/100 g of dry wt. Tea-making conditions were optimized for highest DNJ extraction using response surface methodology. Approximate 95% of total DNJ in high DNJ content dry tea was extracted when temperature was maintained at 98 degrees C for 400 s; these conditions could be applicable for preparation of commercial products with high DNJ content. One cup (230 ml, a normal serving) of DNJ-enriched mulberry tea contained enough DNJ (6.5 mg) to effectively suppress postprandial blood glucose.
Article
In the present study, a high-purity polysaccharide from mulberry leaf (MLP) was purified and characterized, and its anti-diabetic effects were investigated in streptozotocin (STZ)-induced diabetic rats. Our results showed that the obtained MLP (purity 99.8%) was determined to be composed of d-arabinose, d-xylose, d-glucose, d-rhamnose and d-mannose with molar ratio of 1:2.13:6.53:1.04:8.73. Oral administration of MLP at 50-200 mg/kg body weight daily for 5 weeks significantly reduced the levels of fasting blood glucose (FBG), glycosylated serum protein (GSP), serum total cholesterol (TC), and serum triglyceride (TG), and increased the body weight, fasting insulin (FINS), C-peptide (C-P), liver glycogen, liver glucokinase, and serum high-density lipoprotein cholesterol (HDL-C). Moreover, MLP promoted marked pancreatic β-cell regeneration and insulin secretion, and reduced liver fat accumulation in diabetic rats. The treatment effect of MLP on diabetes was similar to the effect of antidiabetic drug glibenclamide. These results clearly indicated that MLP may have a potential for the treatment of hyperglycemia and hyperlipidemia in diabetes.