Content uploaded by Satoshi Takagi
Author content
All content in this area was uploaded by Satoshi Takagi
Content may be subject to copyright.
Available via license: CC BY 3.0
Content may be subject to copyright.
Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2012, Article ID 871495, 8pages
doi:10.1155/2012/871495
Review Article
Management of Diabetes and Its Complications with Banaba
(
Lagerstroemia speciosa
L.) and Corosolic Acid
Toshihiro Miura,1Satoshi Takagi,1and Torao Ishida2
1Department of Clinical Nutrition, Suzuka University of Medical Science, Mie 510-0293, Japan
2Department of Acupuncture and Moxibustion, Suzuka University of Medical Science, 1001-1 Kishioka, Suzuka,
Mie 510-0293, Japan
Correspondence should be addressed to Torao Ishida, ishida-t@suzuka-u.ac.jp
Received 22 May 2012; Accepted 5 September 2012
Academic Editor: Benny Tan Kwong Huat
Copyright © 2012 Toshihiro Miura et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Banaba (Lagerstroemia speciosa L.) extracts have been used for many years in folk medicine to treat diabetes, with the first published
research study being reported in 1940. This paper summarizes the current literature regarding Banaba and its constituents. The
hypoglycemic effects of Banaba have been attributed to both corosolic acid as well as ellagitannins. Studies have been conducted
in various animal models, human subjects, and in vitro systems using water soluble Banaba leaf extracts, corosolic acid, and
ellagitannins. Corosolic acid has been reported to decrease blood sugar levels within 60 min in human subjects. Corosolic acid
also exhibits antihyperlipidemic and antioxidant activities. The beneficial effects of Banaba and corosolic acid with respect to
various aspects of glucose and lipid metabolism appear to involve multiple mechanisms, including enhanced cellular uptake of
glucose, impaired hydrolysis of sucrose and starches, decreased gluconeogenesis, and the regulation of lipid metabolism. These
effects may be mediated by PPAR and other signal transduction factors. Banaba extract, corosolic acid, and other constituents may
be beneficial in addressing the symptoms associated with metabolic syndrome, as well as offering other health benefits.
1. Introduction
Banaba (Lagerstroemia speciosa L.) has been used as a
folk medicine to treat diabetes in various parts of the
world, primarily southeast Asia. The hypoglycemic affect
of aqueous (hot water) and methanol extracts have been
demonstrated in several animal models as well as a number
of human studies. Most studies have focused on corosolic
acid (Figure 1) which is isolated with an organic solvent
from the leaves of the plant, and corosolic acid is used to
standardize Banaba extracts [1,2]. Some studies indicate that
ellagitannins in water soluble fractions may be responsible
for at least some of the insulin-like activity of Banaba, and
the antioxidant and glucose regulatory properties of tannins
in general have been reviewed by Klein et al. [3].
Corosolic acid has also been isolated from a number of
other plant species including but not limited to Vaccinium
macrocarpon (cranberry) [4], Ugni molinae [5], Eriobotrya
japonica [6–10], Perilla frutescens [11], Weigela subsessilis
[12,13], Glechoma longituba [14], Potentilla chinensis [15],
Rubus biflorus [16], and Phlomis umbrosa [17]. Many of these
plants are native to Asia, although corosolic acid has also
been isolated from European and South American plants.
A discussion of the pharmacological effects of these plant
species is beyond the scope of this paper.
This paper summarizes studies that have been con-
ducted in animals, humans, and in vitro systems on
the antihyperglycemic, antihyperlipidemic, and antioxidant
activities of Banaba extracts, corosolic acid-standardized
Banaba extracts, and isolated and structurally characterized
corosolic acid and ellagitannins. Safety and mechanistic
studies conducted to date on these various preparations are
also summarized.
2. Human Studies
A human clinical study of Banaba was reported by Ikeda
et al. [18]. A proprietary product called Banabamin in tablet
2 Evidence-Based Complementary and Alternative Medicine
HO COOH
HO
Figure 1: Structure of corosolic acid.
form containing an aqueous extract of Banaba was used.
This product also contained extracts of green tea, green
coffee, and Garcinia. Twenty-four human subjects with mild
type 2 diabetes were given three tablets three times daily. A
13.5% average decrease in blood glucose levels was reported,
and no adverse effects were observed. The constituents in
the product responsible for the antidiabetic effect were not
determined.
Ikeda et al. also conducted a 1-year open label safety and
efficacy study on 15 subjects, administering 100 mg tablets
daily of a water soluble Banaba extract. The extract was
not standardized, and the constituent(s) responsible for the
antidiabetic effects was not determined. However, due to
the low aqueous solubility of corosolic acid, the amount of
corosolic acid in the water soluble preparation that was used
wouldbeexpectedtobelow,andthehypoglycemiceffects
of the product may have been primarily due to water soluble
ellagitannins [19].
A significant decrease (16.6%) in fasting blood glucose
levels was observed in individuals with fasting blood glucose
levels greater than 110 mg/dL [19]. After both 6 months
and 1 year, significant improvements were observed with
respect to glucose tolerance and glycated albumin following
treatment with the Banaba extract. The Banaba extract
did not cause hypoglycemia. No changes in hematological
or biochemical characteristics and no adverse effects were
observed over the 1-year course of the study.
The antidiabetic activity of a Banaba extract standardized
to 1% corosolic acid in a soft gel capsule formulation has
been examined [20]. Ten type 2 diabetic subjects were given
32 mg or 48 mg of the product (0.32 and 0.48 mg corosolic
acid, resp.) daily for 2 weeks. A 30% decrease in blood
glucose levels was reported after the 2 weeks. It is not clear
whether the observed effect was due to corosolic acid, the
tannin components or a combination thereof.
A 12 week lifestyle intervention study involving 56
subjects was conducted by Lieberman et al. that included
the use of dietary supplements, diet and exercise [21].
The dietary supplements were taken prior to each meal,
and contained 16 mg Banaba extract, 100 mg bitter melon
extract, 133 mg Gymnema extract, 1500 mg Garcinia cam-
bogia extract (60% hydroxycitric acid), 2.6 mg Bioperine
(from black pepper), 10 mg wheat amylase inhibitor, 167 mcg
elemental chromium, 50 mcg elemental vanadium, and
50 mg elemental magnesium. At the end of 12 weeks, the
subjects had lost an average of 6.29 kg (13.8 lb) including
3.72 kg (8.2 lb) body fat as determined by a bioelectric
impedance body fat analyser. Approximately, 73% of subjects
completed the study. The amount of corosolic acid and
ellagitannins in the Banaba extract was not reported, and it is
not clear what contribution to the weight loss was provided
by each constituent in the product.
In a study published by Tsuchibe et al. [22], 12
nondiabetic subjects with a baseline blood glucose level
of 104 mg/dL were given a soft gel capsule daily for 2
weeks containing 10 mg corosolic acid as a Banaba extract
standardized to 18% corosolic acid. A 12% decrease in fasting
as well as 60 min postprandial blood glucose levels was
observed after 2 weeks of administering the product. The
authors also reported an average three-pound weight loss
after the 2 weeks. No adverse effects were observed during or
after the trial. Although this product contained a high level
of corosolic acid, it is not clear if the effect was entirely due
to the corosolic acid or a combination of the corosolic acid
with tannin components.
In an unpublished study by Xu (“Action of helping
lower blood glucose level-clinical test”, Chinese Center for
Disease Control and Prevention, Beijing Hospital, 2008)
using the same soft gel product containing 10 mg corosolic
acid as described by Tsuchibe et al. [22], 100 subjects,
with prediabetes or type 2 diabetes were enrolled. Half the
subjects were given one soft gel containing the corosolic
acid-standardized Banaba extract and the other half received
a placebo for 30 days. Both fasting and 2 h postprandial
blood glucose levels in the treated group decreased by 10%
relative to the control (placebo) group. Also reported was
an improvement in diabetic symptoms including a decrease
in thirst, drowsiness, and hunger. Furthermore, no adverse
effects were observed, with no changes in blood pressure,
liver or kidney function, blood cell count, or hemoglobin.
Fukushima et al. published a study involving 31 subjects
in a double-blind cross-over design that were given a capsule
containing 10 mg corosolic acid or a placebo 5 min before
a 75 g oral glucose tolerance test. Blood glucose levels were
measured at 30 min intervals for 2 h. The authors reported
that corosolic acid treatment resulted in lower blood glucose
levels from 60 to 120 min compared with controls, the
difference being statistically significant (P<0.05) at the
90 min time point. According to the authors, the corosolic
acid that was used was 99% pure, thus indicating that
the blood sugar lowering effect was specifically due to the
corosolic acid [23].
A single report has suggested that corosolic acid may
have been involved in nephrotoxicity and lactic acidosis in
a diabetic patient with impaired kidney function who was
also taking diclofenac for joint pain [24]. Diclofenac is a
nonsteroidal anti-inflammatory drug, and this class of drugs
is known to cause renal damage and failure. The role of
corosolic acid, if any, is not clear. The use of a drug known
for its nephrotoxicity in conjunction with impaired kidney
function readily explains the resulting kidney failure. The
ability of corosolic acid to inhibit gluconeogenesis could
Evidence-Based Complementary and Alternative Medicine 3
favor lactic acid production. If corosolic acid impaired the
metabolism of diclofenac, it could theoretically have exacer-
bated the known nephrotoxicity of the drug. No evidence was
provided to specifically demonstrate this possible effect, and
no controlled clinical studies have reported nephrotoxicity in
diabetic subjects receiving corosolic acid.
The above clinical studies demonstrate that Banaba
extract, Banaba extract standardized to corosolic acid and
corosolic acid, itself decrease fasting as well as postprandial
blood glucose levels in humans. A decrease in blood glucose
levels has been observed within 2 h of dosing, and the
decrease is typically in the range of 10–15%, although a
decrease of 30% has been reported. No adverse effects have
been observed or reported in any studies involving human
subjects receiving Banaba, including one study involving 15
subjects who were given Banaba extract daily for up to 1 year.
3. Animal Studies
The first published research on the hypoglycemic, insulin-
like activity of Banaba was reported by Garcia [25,26]. An
aqueous extract equivalent to 1-2 g of dried leaves per kg
body weight given orally to rabbits lowered blood sugar for
4–6 h.
Various animal studies have subsequently shown that
Banaba extracts of unknown composition, Banaba extracts
standardized to corosolic acid, and highly purified corosolic
acid exert beneficial effects with respect to blood glucose
and lipid regulation. Kakuda et al. fed genetically diabetic
(KK-AY) mice diets containing 5% of a hot water extract
and 2% of a methanol extract of Banaba leaves for 5
weeks. The elevation of blood glucose levels was significantly
suppressed by feeding either of the two extracts. The levels
of serum insulin, plasma total cholesterol, and amount of
urinary glucose were all lowered by feeding the extracts, with
somewhat greater activity with the water extract that was
given at a higher concentration. The specific constituents in
the extracts responsible for these effects were not determined
[27].
A hot water extract of Banaba leaves suppressed blood
glucose elevation following starch administration but not
after glucose administration to rats [28]. These investigators
demonstrated that the extract inhibited the activities of var-
ious hydrolytic enzymes including α-amylase, glucoamylase,
isomaltase, maltase, and sucrase. The constituents in banaba
responsible for these enzyme inhibitory activities were not
determined.
Yamaguchi et al. fed 0.072% corosolic acid in the diet to
spontaneously hypertensive rats for 14 weeks. The investiga-
tors reported a significant decrease in blood pressure, serum-
free fatty acids, and oxidative stress markers relative to the
diet containing no corosolic acid. However, they observed
no effect of the corosolic acid in the diet on body weight
gainorbloodglucoselevels[29]. A study by Matsuura et al.
examined the abilities of various teas (aqueous decoctions),
including from Banaba leaves, to suppress the elevation of
blood glucose in rats from continuous intragastric infusion
of sucrose or maltose. Banaba had no significant effect on
glucose levels. The composition of the Banaba extract was
not reported. The reason for the lack of effect of Banaba
on blood glucose levels in these two rat studies is not
known. These results are in sharp contrast to the results
presented below that primarily involved mouse studies as
well as streptozotocin-induced diabetic rats, and the human
studies reported above [30].
In a study involving genetically diabetic mice given an
extract of Banaba (0.8 mg/kg body weight) for 12 weeks
orally, no effect was observed on fasting blood sugar levels,
hemoglobin A1C content, body weight or insulin levels
[31]. However, kidney glucose-6-phosphatase activity was
significantly lower than in control animals. The most likely
explanation for the poor antidiabetic effect is that the dose
of the extract was too low. In addition, the extract had not
been standardized or analysed with respect to potential active
constituents.
Yamada et al. examined the effects of feeding mice a
high fat diet for 9 weeks with and without 0.023% corosolic
acid (not a standardized extract of Banaba). Corosolic acid
treatment reduced fasting plasma levels of glucose, insulin
and triglycerides by 23%, 41%, and 22%, respectively. A 10%
decrease in body weight and a 15% loss in fat total mass were
also observed relative to control animals. In addition, the
corosolic acid in the diet increased the expression of peroxi-
some proliferator-activated receptor-alpha (PPAR-α) in the
liver and PPAR-γin white adipose tissues, thus providing
a mechanistic explanation for the loss in body weight and
the decrease in hepatic steatosis in these mice. These results
indicate that corosolic acid may be beneficial in addressing
various aspects of the metabolic syndrome that consists of
hyperlipidemia, obesity, hypertension, and insulin resistance.
The aspects of metabolic syndrome which may be addressed
by corosolic acid include obesity, insulin resistance, and
hypertriglyceridemia and hypercholesterolemia [32].
Yamada et al. also investigated the mechanism of
action of corosolic acid on gluconeogenesis in rat liver
using perfused livers and isolated hepatocytes. Corosolic
acid (20–100 μm) in a dose-dependent manner decreased
gluconeogenesis by increasing production of fructose-2,6
diphosphate by lowering cyclic AMP levels and inhibiting
protein kinase A activity. In addition, corosolic acid increased
glucokinase activity without affecting glucose-6-phosphatase
activity, suggesting an increase in glycolysis. The results
provide additional mechanistic information regarding the
antidiabetic actions of corosolic acid [33].
Deocaris et al. administered various Banaba leaf extracts
of unknown and unstandardized composition prepared with
80% ethanol, subcutaneously to alloxan-induced diabetic
mice. Banaba leaf extract had minimal effects on blood
glucose levels, but when combined with insulin, the activity
was synergistically enhanced. Gamma irradiation of Banaba
leaves led to extracts with higher hypoglycemic activity when
mixed with insulin than unirradiated extracts. Irradiation
appeared to lead to improved extraction efficiency of the
active component (s) [34].
A study was conducted involving genetically diabetic
(db/db) mice fed with a diet supplemented with a water
soluble extract of Banaba at a 0.5% concentration [35].
4 Evidence-Based Complementary and Alternative Medicine
At the end of 12 weeks, animals receiving the Banaba
extract exhibited significantly reduced blood glucose, insulin,
triglycerides, and hemoglobin A1C levels. Furthermore,
increased expressions of liver PPAR-αmRNA and lipoprotein
lipase (LPL) mRNA as well as adipose tissue PPAR-γmRNA
were observed. The results suggest that the Banaba extract
increased insulin sensitivity and blood sugar regulation by
regulating PPAR-mediated lipid metabolism. However, the
identity of the responsible factor(s) in Banaba was not
determined.
Miura et al. conducted several studies in genetically
diabetic (KK-AY) mice to which corosolic acid was admin-
istered. At a single dose of 10 mg/kg, corosolic acid signifi-
cantly reduced blood sugar levels. This effect was shown to be
associated with an increase in the muscle glucose transporter
(GLUT4) [36]. In a subsequent study, they showed that a
single dose of 2 mg/kg corosolic acid reduced blood sugar
levels for up to 2 weeks, supporting the hypothesis that
corosolic acid improves glucose metabolism by reducing
insulin resistance [37].
In a study in mice, Takagi et al. demonstrated that an oral
dose of 10 mg/kg corosolic acid suspended in water inhibited
the intestinal hydrolysis of sucrose but not maltose or lactose,
thereby at least in part facilitating the lowering of blood
glucose levels since sucrose is a disaccharide composed of
glucose plus fructose. In this study, a sugar solution was
administered 30 min orally after the corosolic acid, and blood
samples were drawn at 30, 60, and 120 min [38]. These results
agree with the observations of Suzuki et al. who showed that
an extract of Banaba leaves inhibited sucrase activity and
exerted hypoglycemic effects through multiple mechanisms
[27].
Takagi et al. have shown that when genetically diabetic
(KK-Ay) mice are fed a high cholesterol diet with and with-
out 0.023% corosolic acid for 10 weeks, the corosolic acid
significantly decreased blood cholesterol and liver cholesterol
content by 32% and 46%, respectively. Furthermore, the
diabetic mice were given corosolic acid (10mg/kg body
weight) orally in water followed by the oral administration
of a high cholesterol cocktail 30 min later. Corosolic acid
significantly inhibited mean blood cholesterol levels 4 h
after administration of the cholesterol relative to control
animals. The effect was believed to be due to inhibition
of cholesterol absorption via inhibition of the enzyme
cholesterol acyltransferase [39].
Several studies have examined the effects of aqueous
Banaba extracts on streptozotocin-induced diabetic rats. In
none of these studies were the active constituents deter-
mined. A hot water (75–90◦C) extract of Banaba leaves
was shown to depress the elevated blood glucose levels in
streptozotocin-diabetic rats by about 43%, while increasing
the activity of glucose-6-phosphate dehydrogenase as well
as glutathione content, and decreasing the activity of the
gluconeogenic enzymes glucose-6-phosphatase and fructose-
1,6-diphosphatase [40]. The dose of the extract used and the
duration of the study were not reported. The results suggest
that the hypoglycemic activity occurs through suppression of
gluconeogenesis and stimulation of glucose oxidation via the
pentose phosphate pathway.
Thuppia et al. prepared an extract of Banaba leaves by
boiling for 2 h which was subsequently freeze-dried. The
extract was administered orally at doses up to 2000 mg/kg
body weight for 12 days to streptozotocin-diabetic rats.
A dose of 1000 mg/kg decreased fasting blood glucose
levels by approximately 43% on day 12, which returned to
pretreatment levels by day 3 after cessation of treatment. The
Banaba extract produced no changes in blood glucose levels
in nondiabetic rats. The high doses of the extract needed
to produce a hypoglycemic effect may be reflected in the
extraction procedure where boiling may have destroyed some
of the active constituents [41].
An aqueous extract (150 mg/kg body weight) given to
streptozotocin-induced diabetic mice for up to 15 days
significantly decreased not only blood glucose levels but also
exhibited a potent antioxidant effect [42]. Administration
of the extract reduced streptozotocin-generated reactive
oxygen species (superoxide anion, hydrogen peroxide, and
nitric acid) by upregulating superoxide dismutase, catalase
and glutathione-S-transferase activities as well as reduced
glutathione levels.
Administration of a spray-dried extract of Banaba
(100 mg/kg body weight) for 28 days by gavage to alloxan-
induced diabetic mice resulted in significantly lower blood
and urine glucose levels [43]. In addition, lower food and
fluid intakes as well as lower body weights were observed in
response to the Banaba extract.
Oleanolic acid is a pentacyclic terpene acid that is
structurally related to corosolic acid, has been isolated
from Banaba leaves, and exhibits α-glucosidase activity [7].
Oleanolic acid and insulin were shown to decrease blood
glucose levels in control and streptozotocin-induced diabetic
rats given a glucose load after an 18 h fast [44]. Furthermore,
daily treatment for 5 weeks with oleanolic acid significantly
decreased blood glucose levels in diabetic animals with
concomitant restoration of hepatic and muscle glycogen
stores to near normal levels and in combination with insulin
provided even greater antihyperglycemic activity. Oleanolic
acid may act via a mechanism distinct from insulin including
its α-glucosidase activity, and the two may exert a synergistic
effect in the regulation of hyperglycemia.
The anti-inflammatory activity of various pentacyclic
triterpene acids including corosolic acid was assessed by
Aguirre et al. in vivo using a mouse ear assay, using
arachidonic acid and 12-O-tetradecanoylphorbol-13 acetate
as the inflammation-inducing agents. Corosolic acid was
effective against both inflammatory agents [5].
In summary, various studies have demonstrated that
Banaba extracts as well as corosolic acid significantly decrease
blood glucose levels in genetic as well as streptozotocin- and
alloxan-induced diabetic animals. Better responses appear
to occur in mice compared with rats. In these studies,
corosolic acid has also been shown to improve insulin
sensitivity, increase cellular uptake of glucose, decrease
serum triglycerides and cholesterol, facilitate weight loss,
and improve oxidative stress markers without production
of adverse or toxic effects. In addition, the animal studies
suggest that Banaba extracts and corosolic acid may have
additional health-enhancing benefits that extend beyond the
Evidence-Based Complementary and Alternative Medicine 5
effects observed to date in human subjects. The animal
studies also support the safety findings reported in human
studies and have provided extensive information on the
mechanisms of action of Banaba extract and corosolic acid.
4.
In Vitro
Studies
The antioxidant and free radical scavenging activities of
Banaba were demonstrated for an aqueous extract in in vitro
free radical generating systems in a concentration dependent
manner [45]. The Banaba extract was shown to have potent
radical scavenging activity on 1,1-diphenyl-2-picrylhydrazyl
(DPPH) radical and superoxide radicals generated by a
hypoxanthine-xanthine oxidase system. The extract also
inhibited lipid peroxidation in a rat liver homogenate system.
The tannin content of the extract was about 37% of dry
weight.
Liu et al. demonstrated that both water and methanol
extracts of Banaba stimulated glucose uptake by 3T3
adipocytes. The extracts also inhibited adipocyte differen-
tiation induced by insulin. The active components in these
Banaba extracts were not identified [46].
Tanaka et al. isolated and structurally characterized
various ellagitannins from the fruit and leaves of Banaba.
Lagerstannins A and B together with five known tannins
including lagerstroemin were isolated from the fruit, while
lagerstannin C was isolated and characterized from Banaba
leaves. The three lagerstannins possess a gluconic acid core
which is rarely found in the plants [47].
Three ellagitannins, lagerstroemin, flosin B, and reginin
were extracted from Banaba and shown to increase glu-
cose uptake by isolated rat adipocytes [48]. Lagerstroemin
exhibited glucose transport stimulation with a 50% effective
concentration (EC50)of80μm, with a maximum effect of
approximately 54% of that of insulin. However, it is doubtful
that this concentration of lagerstroemin can be achieved in
vivo following oral administration of the doses commonly
used for Banaba extracts. Furthermore, tannic acid, which
is commercially available and widely distributed in plants,
has been shown to exhibit glucose transport activity with an
EC50 of 17 μm, approximately five times more potent than
lagerstroemin [49]. Thus, it is not plausible to ascribe the
glucose regulatory activity of Banaba extracts specifically to
lagerstroemin.
Subsequent studies with lagerstroemin demonstrated
that it exhibited insulin-like activities including increasing
glucose uptake and decreasing isoproterenol-induced glyc-
erol release in rat adipocytes, and increasing extracellular
signal-related kinase (Erk) activity in Chinese hamster ovary
cells [50]. It should be noted that these studies were
conducted in vitro, and similar activities have not been
demonstrated in animal or human systems.
More recently, Bai et al. have isolated and structurally
characterized seven ellagitannins and four methyl ellagic acid
derivatives from Banaba leaves. A number of polyphenolic
compounds including corosolic acid and quercetin were
also isolated. The ellagitannins all exhibited the ability to
stimulate insulin-like glucose uptake as well as to inhibit
adipocyte differentiation in 3T3-L1 adipocyte cells in culture.
Furthermore, the methyl ellagic acid derivatives exhibited
inhibitory activity with respect to glucose transport. These
studies clearly demonstrate the antihyperglycemic activity of
well characterized ellagic acid derivatives from Banaba, show
that this activity is not restricted to a single compound, and
indicate that multiple mechanisms of action are involved
[51].
Hosoyama et al. conducted a quantitative analysis of an
α-amylase inhibitor in aqueous Banaba leaf extracts. The
extracts were hydrolysed with hydrochloric acid, extracted
with an organic solvent and subjected to high performance
liquid chromatography. Using bioassay-guided analysis of
various fractions, the polyphenolic valoneic acid lactone
was isolated and identified as an α-amylase inhibitor with
an IC50 of approximately 108 μg/mL. However, no standard
α-amylase inhibitor was used. The authors measured the
valoneic acid content of eight Banaba leaf decoctions,
and showed that the α-amylase inhibiting activities were
correlated with the content of this polyphenolic acid. The
α-amylase inhibiting activity of corosolic acid was not
determined, and may not have been present in large amounts
since water was used to make the initial leaf extracts [52].
The corosolic acid content of Banaba leaves, Banaba
methanol extracts and various commercial dosage forms
have been determined using high performance liquid chro-
matography (HPLC) as well as high performance thin layer
chromatography (HPTLC) by Vijaykumar et al. [53]. Several
Banaba leaf samples were shown to contain 0.31–0.38 mg
corosolic acid/100 mg, while methanol extracts of leaves
contained up to 11.3 mg/100 mg.
Using a Chinese hamster ovary cell system, Shi et al.
demonstrated that corosolic acid stimulated glucose uptake
via enhancing insulin receptor phosphorylation. Further-
more, corosolic acid inhibited several diabetes-related nonre-
ceptor protein tyrosine phosphatase enzymes. These studies
provide supporting and mechanistic information regarding
the ability of corosolic acid to exert a hypoglycemic effect
[54]. Although these studies showed the phosphorylation of
the insulin receptor directly, other studies could not repeat
this result.
The ability of an aqueous Banaba extract to block the
activation of nuclear-factor- (NF-) κB by tumor necrosis
factor (TNF) in a dose- and time-dependent manner was
demonstrated using the cardiomyocyte cell line H9c2 [55].
The authors suggested that this anti-inflammatory action
might explain the ability of Banaba extract to inhibit
diabetes-induced cardiomyocyte hypertrophy. This study
provides mechanistic insight into the anti-inflammatory
activity demonstrated by corosolic acid and other pentacyclic
terpene acids in mice [5].
Six pentacyclic triterpene acids (oleanolic acid, arjunolic
acid, asiatic acid, maslinic acid, corosolic acid, and 23-
hydroxyursolic acid) were isolated from Banaba leaves by
ethyl acetate extraction [7], and their abilities to inhibit
α-amylase and α-glucosidase activities were determined.
Corosolic acid exhibited the greatest inhibitory activity
against α-glucosidase with an IC50 of 3.53 μg/mL, while
all of the six pentacyclic triterpenes exhibited weak or no
6 Evidence-Based Complementary and Alternative Medicine
inhibitory activity against α-amylase. These results provide
additional information regarding the mechanisms of action
of Banaba with respect to its antidiabetic activity.
An interesting study regarding the anabolic effects of
corosolic acid on osteoblastic bone formation was reported
by Shim et al. [56]. Concentrations up to 5 μm corosolic acid
significantly stimulated differentiation of mouse osteoblasts.
This effect was shown to be mediated by activation of
mitogen activated protein kinase (MAPK), NF-κBand
activator protein-1. These results suggest that corosolic acid
may be useful in conjunction with bone diseases such as
osteoporosis and periodontitis.
In summary, various in vitro studies involving cell-free
systems and cell cultures have demonstrated antioxidant
and osteoblastic activities of Banaba extracts and corosolic
acid. In addition, various ellagitannins and methyl ellagic
acid derivatives have also been isolated from Banaba and
have been shown to exhibit antihyperglycemic activity.
Furthermore, much information and insight regarding the
mechanisms of action of Banaba extracts, corosolic acid and
ellagitannins have also been obtained using these in vitro
systems.
5. Conclusions
A growing body of evidence involving animal and human
studies as well as in vitro systems indicates that Banaba leaf
extracts exert antidiabetic and antiobesity effects. There is
strong evidence to indicate that corosolic acid as well as
ellagitannins is responsible for these effects. Other polycyclic
terpene acids such as oleanolic acid and valoneic acid may
also contribute to the antihyperglycemic effects. With the
development of techniques to purify various components
of Banaba, studies are now being conducted with more
highly purified and structurally characterized materials. As
a consequence, information is being obtained regarding the
specific effects of the various constituents, particularly with
respect to corosolic acid.
A number of studies in animals and human subjects
using highly purified corosolic acid and corosolic acid-
standardized preparations indicate that this component of
Banaba exhibits properties that are beneficial in address-
ing various factors involved in glucose regulation and
metabolism, including the enhanced cellular uptake of
glucose, improved insulin sensitivity, decreased gluconeoge-
nesis, and inhibited intestinal hydrolysis of sucrose, thereby
lowering blood glucose levels. Furthermore, decreased serum
cholesterol and triglycerides have been observed in response
to corosolic acid.
Based on the studies conducted to date, no adverse effects
have been reported in animals using either corosolic acid or
standardized Banaba extracts, nor have adverse events been
observed or reported in controlled human clinical studies.
However, no animal studies have been designed specifically
to assess toxicity or LD50 values for corosolic acid or Banaba
extracts standardized to specific concentrations of corosolic
acid.
The above studies indicate that corosolic acid and
corosolic acid standardized Banaba extracts may be beneficial
in addressing issues associated with elevated blood sugar
levels and obesity. Furthermore, corosolic acid exhibits
anti-inflammatory and antihyperlipidemic, antiviral effects.
Standardized Banaba extracts, corosolic acid, and/or ellag-
itannins in combination with other ingredients may be
useful in dealing with symptoms associated with metabolic
syndrome. Corosolic acid and standardized Banaba extracts
may also be highly effective either as stand-alone products
or in combination with other natural products possessing
hypoglycemic, antihyperlipidemic, and appetite suppressant
activities.
Additional human efficacy and safety studies are war-
ranted, particularly studies assessing the dose- and time-
dependent effects of corosolic acid or corosolic acid-
standardized Banaba extracts and ellagitannins alone or
in combination with other ingredients on blood lipids
(triglyceride and cholesterol), insulin and glucose levels as
well as weight loss, and weight management. Investigations
are needed to clearly define and understand the roles and
importance of corosolic acid and related pentacyclic terpene
acids relative to the ellagitannins present in Banaba [57].
Finally, additional acute and subchronic animal safety studies
are needed.
References
[1] C. Ulbricht, C. Dam, T. Milkin, E. Seamon, W. Weissner, and
J. Woods, “Banaba (Lagerstroemia speciosa L.): an evidence-
based systematic review by the natural standard research
collaboration,” Journal of Herbal Pharmacotherapy, vol. 7, no.
1, pp. 99–113, 2007.
[2] C. Park and J. S. Lee, “Banaba: the natural remedy as
antidiabetic drug,” Biomedical Research, vol. 22, pp. 127–131,
2011.
[3] G. Klein, J. Kim, K. Himmeldirk, Y. Cao, and X. Chen, “Antidi-
abetes and anti-obesity activity of Lagerstroemia speciosa,”
Evidence-based Complementary and Alternative Medicine, vol.
4, no. 4, pp. 401–407, 2007.
[4] E.Kim,A.Sy-Cordero,T.N.Graf,S.J.Brantley,M.F.Paine,
and N. H. Oberlies, “Isolation and identification of intestinal
CYP3A inhibitors from ranberry (Vaccinium macrocarpon)
using human intestinal microsomes,” Planta Medica, vol. 77,
no. 3, pp. 265–270, 2011.
[5] M. C. Aguirre, C. Delporte, N. Backhouse et al., “Topical anti-
inflammatory activity of 2α-hydroxy pentacyclic triterpene
acids from the leaves of Ugni molinae,” Bioorganic and
Medicinal Chemistry, vol. 14, no. 16, pp. 5673–5677, 2006.
[6] C. Hu, L. Chen, Y. Xin, and Q. Cai, “Determination of
corosolic acid in Eriobotrya japonica leaves by reversed-phase
high performance liquid chromatography,” Se Pu, vol. 24, no.
5, pp. 492–494, 2006 ().
[7] W. Hou, Y. Li, Q. Zhang et al., “Triterpene acids isolated
from Lagerstroemia speciosa leaves as α-glucosidase inhibitors,”
Phytotherapy Research, vol. 23, no. 5, pp. 614–618, 2009.
[8] H. Lu, J. Chen, W. L. Li, and H. Q. Zhang, “Studies on the
triterpenes from ioquat leaf (Eriobotrya japonica),” Zhang Yao
Cai, vol. 31, pp. 1351–1354, 2008 (Chinese).
[9] H. Lu, C. Xi, J. Chen, and W. Li, “Determination of
triterpenoid acids in leaves of Eriobotrya japonica collected at
Evidence-Based Complementary and Alternative Medicine 7
in different seasons,” Zhongguo Zhongyao Zazhi, vol. 34, no.
18, pp. 2353–2355, 2009.
[10] J. M. Rollinger, D. V. Kratschmar, D. Schuster et al., “11β-
Hydroxysteroid dehydrogenase 1 inhibiting constituents from
Eriobotrya japonica revealed by bioactivity-guided isolation
and computational approaches,” Bioorganic and Medicinal
Chemistry, vol. 18, no. 4, pp. 1507–1515, 2010.
[11] N. Banno, T. Akihisa, H. Tokuda et al., “Triterpene acids from
the leaves of Perilla frutescens and their anti-inflammatory and
antitumor-promoting effects,” Bioscience, Biotechnology and
Biochemistry, vol. 68, no. 1, pp. 85–90, 2004.
[12] P. T. Thuong, B. S. Min, W. Jin et al., “Anti-complementary
activity of ursane-type triterpenoids from Weigela subsessilis,”
Biological and Pharmaceutical Bulletin, vol. 29, no. 4, pp. 830–
833, 2006.
[13] M. S. Lee and P. T. Thuong, “Stimulation of glucose uptake by
triterpenoids from Weigela subsessilis,” Phytotherapy Research,
vol. 24, no. 1, pp. 49–53, 2010.
[14] N. Y. Yang, J. A. Duan, P. Li, and S. H. Qian, “Chemical
constituents of Glechoma longituba,” Yaox ue Xueb a o, vol. 41,
no. 5, pp. 431–434, 2006 (Chinese).
[15] Y. Shen, Q. H. Wang, H. W. Lin, W. Shu, J. B. Zhou, and Z. Y.
Li, “Study on chemical constituents of Potentilla chinensis Ser,”
Zhong Yao Cai, vol. 29, no. 3, pp. 237–239, 2006.
[16] S. H. Kang, Y. Q. Shi, and C. X. Yang, “Triterpenoids and
steroids of root of Rubus biflorus,” Zhong Yao Cai, vol. 31, no.
11, pp. 1669–1671, 2008 (Chinese).
[17] P. Liu, R. Deng, H. Duan, and W. Yin, “Chemical constituents
from roots of Phlomis umbrosa,” Zhongguo Zhongyao Zazhi,
vol. 34, no. 7, pp. 867–870, 2009 (Chinese).
[18] Y. Ikeda, J. T. Chen, and T. Matsuda, “Effectiveness and
safety of banabamin tablet containing extract from banaba
in patients with mild type 2 diabetes,” Japanese Pharmacology
and Therapeutics, vol. 27, no. 5, pp. 72–73, 1999 (Japanese).
[19] Y. Ikeda, M. Noguchi, S. Kishi et al., “Blood glucose controlling
effects and safety of single and long-term administration on
the extract of banaba leaves,” Journal of Nutrition & Food, vol.
5, pp. 41–53, 2002 (Japanese).
[20]W.V.Judy,S.P.Hari,W.W.Stogsdill,J.S.Judy,Y.M.
A. Naguib, and R. Passwater, “Antidiabetic activity of a
standardized extract (Glucosol) from Lagerstroemia speciosa
leaves in Type II diabetics: a dose-dependence study,” Journal
of Ethnopharmacology, vol. 87, no. 1, pp. 115–117, 2003.
[21] S. Lieberman, R. Spahrs, A. Stanton, L. Martinez, and M.
Grinder, “Weight loss, body measurements, and compliance:
a 12-week total lifestyle intervention pilot study,” Alternative
and Complementary Therapies, vol. 11, no. 6, pp. 307–313,
2005.
[22] S. Tsuchibe, S. Kataumi, M. Mori, and H. Mori, “An inhibitory
effect on the increase in the postprandial glucose by banaba
extract capsule enriched corosolic acid,” Journal for the
Integrated Study of Dietary Habits, vol. 17, pp. 255–259, 2006.
[23] M. Fukushima, F. Matsuyama, N. Ueda et al., “Effects
of corosolic acid on post-challenge plasma glucose levels,”
Diabetes Research and Clinical Practice, vol. 73, pp. 174–177,
2006.
[24] J. Q. Zheng, C. M. Zheng, and K. C. Lu, “Corosolic acid-
induced acute kidney injury and lactic acidosis in a patient
with impaired kidney function,” American Journal of Kidney
Disease, vol. 56, no. 2, pp. 419–420, 2010.
[25] F. Garcia, “On the hypoglycemic effect of a decoction of
Lagerstroemia speciosa leaves (banaba) administered orally,”
Philippine Medical Association, vol. 20, pp. 193–201, 1940.
[26] F. Garcia, “Distribution and deterioration of insulin-like
principle in Lagerstroemia speciosa (banaba),” Acta Medica
Philippina, vol. 3, pp. 99–104, 1941.
[27] T. Kakuda, I. Sakane, T. Takihara, Y. Ozaki, H. Takeuchi,
and M. Kuroyanagi, “Hypoglycemic effect of extracts from
Lagerstroemia speciosa L. Leaves in genetically diabetic KK-AY
mice,” Bioscience, Biotechnology and Biochemistry, vol. 60, no.
2, pp. 204–208, 1996.
[28] Y. Suzuki, K. Hayashi, I. Sukabe, and T. Kakuda, “Effects
and mode of action of banaba (Lagerstroemia speciosa L.) leaf
extracts on postprandial blood glucose in rats,” Japan Society
of Nutrition and Food Science, vol. 54, pp. 131–137, 2001.
[29] Y. Yamaguchi, K. Yamada, N. Yoshikawa, K. Nakamura, J.
Haginaka, and M. Kunitomo, “Corosolic acid prevents oxida-
tive stress, inflammation and hypertension in SHR/NDmcr-cp
rats, a model of metabolic syndrome,” Life Sciences, vol. 79, no.
26, pp. 2474–2479, 2006.
[30] T. Matsuura, Y. Yoshikawa, H. Masui, and M. Sano, “Sup-
pression of glucose absorption by various health teas in rats,”
Yakugaku Zasshi, vol. 124, no. 4, pp. 217–223, 2004.
[31] H. Hong and J. M. Won, “Effects of malted barley extract and
banaba extract on blood glucose levels in genetically diabetic
mice,” Journal of Medicinal Food, vol. 7, no. 4, pp. 487–490,
2004.
[32] K. Yamada, M. Hogokowa, and S. Fujimoto, “Effect of coroso-
lic acid on gluconeogenesis in rat liver,” Diabetes Research and
Clinical Practice, vol. 80, pp. 48–55, 2008.
[33] K. Yamada, M. Hosokawa, C. Yamada et al., “Dietary corosolic
acid ameliorates obesity and hepatic steatosis in KK-Ay mice,”
Biological and Pharmaceutical Bulletin, vol. 31, no. 4, pp. 651–
655, 2008.
[34] C. C. Deocaris, R. R. Aguinaldo, J. L. dela Ysla, A. S. Asencion,
and E. R. E. Mojica E, “Hypoglycemic activity of irradiated
banaba (Lagerstroemia speciosa L.) leaves,” Journal of Applied
Sciences Research, vol. 1, pp. 95–98, 2005.
[35] M.Y.Park,K.S.Lee,andM.K.Sung,“Effects of dietary mul-
berry, Koreanred ginseng, and banaba on glucose homeostasis
in relation to PPAR-α,PPAR-γ, and LPL mRNA expressions,”
Life Sciences, vol. 77, no. 26, pp. 3344–3354, 2005.
[36] T. Miura, Y. Itoh, T. Kaneko et al., “Corosolic acid induces
GLUT4 translocation in genetically type 2 diabetic mice,”
Biological and Pharmaceutical Bulletin, vol. 27, no. 7, pp. 1103–
1105, 2004.
[37] T. Miura, N. Ueda, K. Yamada et al., “Antidiabetic effects
of corosolic acid in KK-Ay diabetic mice,” Biological and
Pharmaceutical Bulletin, vol. 29, no. 3, pp. 585–587, 2006.
[38] S. Takagi, T. Miura, C. Ishibashi et al., “Effect of corosolic
acid on the hydrolysis of disaccharides,” Journal of Nutritional
Science and Vitaminology, vol. 54, no. 3, pp. 266–268, 2008.
[39] S. Takagi, T. Miura, E. Ishihara, T. Ishida, and Y. Chinzei,
“Effect of corosolic acid on dietary hypercholesterolemia and
hepatic steatosis in KK-Ay diabetic mice,” Biomedical Research,
vol. 31, no. 4, pp. 213–218, 2010.
[40]B.K.Saha,M.N.H.Bhuiyan,K.Mazumder,andK.M.
F. Haque, “Hypoglycemic activity of Lagerstroemia speciosa
L. extract on streptozotocin-induced diabetic rat: underlying
mechanism of action,” Bangladesh Journal of Pharmacology,
vol. 4, no. 2, pp. 79–83, 2009.
[41] A. Thuppia, P. Rabintossaporn, S. Saenthaweesuk, K. Ingkan-
inan, and S. Sireeratawong, “The hypoglycemic effect of
water extract from leaves of Lagerstroemia speciosa L. in
streptozotocin-induced diabetic rats,” Songklanakarin Journal
of Science and Technology, vol. 31, no. 2, pp. 133–137, 2009.
8 Evidence-Based Complementary and Alternative Medicine
[42] S. M. Saumya and P. M. Basha, “Antioxidant effect of Lager-
stroemia speciosa Pers (Banaba) leaf extract in streptozotocin-
induced diabetic mice,” Indian Journal of Experimental Biology,
vol. 49, no. 2, pp. 125–131, 2011.
[43] N. C. Tanquilut, M. R. C. Tanquilut, M. A. C. Estacio, E.
B.Torres,J.C.Rosario,andB.A.S.Reyes,“Hypoglycemic
effect of Lagerstroemia speciosa (L.) Pers. on alloxan-induced
diabetic mice,” Journal of Medicinal Plant Research, vol. 3, no.
12, pp. 1066–1071, 2009.
[44] C. T. Musabayane, M. A. Tufts, and R. F. Mapanga, “Synergistic
antihyperglycemic effects between plant-derived oleanolic
acid and insulin in streptozotocin-induced diabetic rats,”
Renal Failure, vol. 32, no. 7, pp. 832–839, 2010.
[45] T. Unno, I. Sakane, T. Masumizu, M. Kohno, and T. Kakuda,
“Antioxidant activity of water extracts of Lagerstroemia
speciosa leaves,” Bioscience, Biotechnology, and Biochemistry,
vol. 61, pp. 1772–1774, 1997.
[46] F. Liu, J. K. Kim, Y. Li, X. Q. Liu, J. Li, and X. Chen, “An extract
of Lagerstroemia speciosa L. has insulin-like glucose uptake-
stimulatory and adipocyte differentiation-inhibitory activities
in 3T3-L1 cells,” Journal of Nutrition, vol. 131, no. 9, pp. 2242–
2247, 2001.
[47] T. Tanaka, H. H. Tong, Y. M. Xu, K. Ishimaru, G. Nonaka,
and I. Nishioka, “Tannins and related compounds. CXVII.
Isolation and characterization of three new ellagitannins,
lagerstannins A, B and C, having a gluconic acid core, from
Lagerstroemia speciosa (L.) Pers,” Chemical and Pharmaceutical
Bulletin, vol. 40, no. 11, pp. 2975–2980, 1992.
[48] T. Hayashi, H. Maruyama, R. Kasai et al., “Ellagitannins from
Lagerstroemia speciosa as activators of glucose transport in fat
cells,” Planta Medica, vol. 68, no. 2, pp. 173–175, 2002.
[49] Y. Li, J. Kim, J. Li et al., “Natural anti-diabetic compound
1,2,3,4,6-penta-O-galloyl-D-glucopyranose binds to insulin
receptor and activates insulin-mediated glucose transport
signaling pathway,” Biochemical and Biophysical Research Com-
munications, vol. 336, no. 2, pp. 430–437, 2005.
[50] K. Hattori, N. Sukenobu, T. Sasaki et al., “Activation of
insulin receptors by lagerstroemin,” Journal of Pharmacological
Sciences, vol. 93, no. 1, pp. 69–73, 2003.
[51] N. Bai, K. He, M. Roller et al., “Active compounds
from Lagerstroemia speciosa, insulin-like glucose uptake-
stimulatory/inhibitory and adipocyte differentiation-
inhibitory activities in 3T3-L1 cells,” Journal of Agricultural
and Food Chemistry, vol. 56, no. 24, pp. 11668–11674, 2008.
[52] H. Hosoyama, A. Sugimoto, Y. Suzuki, I. Sakane, and T.
Kakuda, “Isolation and quantitative analysis of the α-amylase
inhibitor in Lagerstroemia speciosa (L.) Pers. (Banaba),” Ya k u-
gaku Zasshi, vol. 123, no. 7, pp. 599–605, 2003 (Japanese).
[53] K. Vijaykumar, P. B. Murthy, S. Kannababu, B. Syamasun-
dar, and G. V. Subbaraju, “Quantitative determination of
corosolic acid in Lagerstroemia speciosa leaves, extracts and
dosage forms,” International Journal of Applied Science and
Engineering, vol. 4, pp. 103–114, 2006.
[54] L. Shi, W. Zhang, Y. Y. Zhou et al., “Corosolic acid stimulates
glucose uptake via enhancing insulin receptor phosphoryla-
tion,” European Journal of Pharmacology, vol. 584, no. 1, pp.
21–29, 2008.
[55] H. Ichikawa, H. Yagi, T. Tanaka, J. C. Cyong, and T. Masaki,
“Lagerstroemia speciosa extract inhibit TNF-induced activa-
tion of nuclear factor-κB in rat cardiomyocyte H9c2 cells,”
Journal of Ethnopharmacology, vol. 128, no. 1, pp. 254–256,
2010.
[56] K.S.Shim,S.U.Lee,S.Y.Ryu,Y.K.Min,andS.H.Kim,
“Corosolic acid stimulates osteoblast differentiation by acti-
vating transcription factors and MAP kinases,” Phytotherapy
Research, vol. 23, no. 12, pp. 1754–1758, 2009.
[57] S. J. Stohs, H. Miller, and G. R. Kaats, “A review of the efficacy
and safety of Banaba (Lagerstroemia speciosa L.) and Corosolic
acid,” Phytotherapy Research., vol. 26, pp. 317–324, 2012.
