Review

Antidiabetic potential of Musa spp. inflorescence: a

systematic review
Raquel de Oliveira Vilhena, Mariana M. Fachi, Breno M. Marson , Bruna L. Dias,

via L. D. Pontes, Fernanda S. Tonin and Roberto Pontarolo
Fla
Department of Pharmacy, Federal University of Paran
a, Curitiba, Brazil

Keywords Abstract

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banana flower; biological activity; diabetes
mellitus; hypoglycaemic activity Objectives Extracts of parts Musa spp. have been used for the treatment of vari-
ous diseases in traditional medicine. Studies have shown that these extracts have
Correspondence hypoglycaemic properties. The aim of this work was to gather evidence on the
Roberto Pontarolo, Department of
antidiabetic effects of Musa spp. inflorescence.
Pharmacy, Federal University of Paran

a, 632
Loth

ario Meissner Avenue, 80210-170,
Methods A systematic review was conducted with searches in three electronic
Curitiba – PR, Brazil. databases, along with manual searches. Studies evaluating the antidiabetic prop-
E-mail: pontarolo@ufpr.br erties of extracts of flower or bract of the genus Musa (in vitro or in vivo) were
included.
Received February 16, 2018 Key findings Overall, 16 studies were found. The reported assays were of hypo-
Accepted September 2, 2018 glycaemic effects, oral glucose tolerance, inhibitory activities in carbohydrate
metabolism and digestive enzymes, enhanced glucose uptake activity and popular
doi: 10.1111/jphp.13020
use of the extract in patients with diabetes type 2. In vitro studies showed that
use of the extract was associated with antidiabetic effects (e.g. increased glucose
uptake and inhibition of carbohydrate digestion enzymes). In induced diabetic
models, Musa spp. extracts showed dose-dependent glycaemic level reductions
compared with pharmacological drugs (P < 0.05).
Summary In general, promising results regarding antidiabetic activity were
found for inflorescence of Musa spp., suggesting that this plant could represent a
natural alternative therapy for treating diabetes mellitus type 2.

out. Some compounds have already been identified in Musa

Introduction
Bananas and plantains (Musa spp.) belong to the Musaceae
family and are one of the most important fruit crops in the
world.[1] In traditional medicine, Musa spp. leaves, fruit,
inflorescence, root, peels and stalks have been used for the
treatment of several ailments such as diarrhoea, ulcers,
pain, inflammation and diabetes mellitus.[2] With regard to
diabetes mellitus, inflorescence is widely indicated[3,4]; for
example, the consumption of cooked flowers is considered
to have great potential for the control of diabetes.[5]
Over the years, many studies have been conducted to
investigate the biological effects of banana inflorescence.
These studies have shown several biological activities, such
as galactagogue,[6] anti-inflammatory,[7] antioxidant[8] and
antihyperglycaemic activity.[9] Among these applications,
the antidiabetic effects, including antihyperglycaemic,[10,11]
a-glucosidase and a-amylase inhibitory effects,[12,13] stand
spp., including anthocyanins,[14] phenolic acids,[14,15] fla-
vanones[16] and terpenoids.[16] It is known that compounds
belonging to these classes have antidiabetic effects.
Anthocyanins such as delphinidin-3-rutinoside,
cyanidin-3-rutinoside, petunidin-3-rutinoside, pelargonidin-
3-rutinoside, peonidin-3-rutinoside and malvidin-3-
rutinoside were identified in the bracts of Musa spp.[14]
These compounds have been reported to be potent a-gluco-
sidase inhibitors.[17] In addition, anthocyanins are involved
in mechanisms that contribute to increased insulin sensitiv-
ity and reduced blood glucose levels, as well as the preven-
tion of complications associated with diabetes.[18]
In the flowers of Musa spp., phenolic acids such as gallic
acid, catechol, protocatechuic acid, gentisic acid, vanillic
acid, caffeic acid, syringic acid, p-coumaric acid, ferulic
acid and epicatechin have been identified.[15,19] These com-
pounds have inhibitory activity on enzymes such as

© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595 1583
Antidiabetic potential of Musa spp. flowers
a-amylase and aldose reductase, contributing to the reduc-
tion in glycaemic levels and the prevention of complica-
tions.[20,21] Among these, vanillic acid has been shown to
have a protective effect against hyperinsulinaemia, hyper-
glycaemia and hyperlipidaemia in rats fed high-fat diets;
the mechanism of action involves decreasing hepatic accu-
mulation of nonesterified free fatty acid.[22]
Flavanones such as naringenin and hesperitin are also
present in the flowers of Musa spp.[16] and are known for
their high antioxidant power, which has been proposed as a
mechanism of action in the treatment of diabetes and its
complications.[23,24]
Terpenoids, which are a-glucosidase and a-amylase
inhibitors,[25] are also isolated from the flowers of Musa
paradisiaca (syringin, benzyl alcohol glucoside, (6S9R)-
roseoside, and 1.1 dimethylallyl alcohol b-glucoside),[26]
Musa balbisiana (31-norcyclolaudenone, cycloartenol, and
(24R)-4a, 24-trimethyl-5a-cholesta-8,25(27)-dien-3b-ol)[27]
and M. paradisiaca ((24R)4 a,14 a,24-trimethyl-5a-cho-
lesta-8,25(27)-dien-3b-ol).[28]
Therefore, considering the traditional use of this plant
and the presence of chemical constituents that point to the
antidiabetic potential of Musa spp. inflorescence, the aim
of this study was to appraise the literature through a sys-
tematic review, gathering available evidence about the use
of this natural product and highlighting its antidiabetic
potential.
Methods
A systematic review was conducted on the basis of recom-
mendations from the Cochrane Collaboration and Pre-
ferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA).[29,30] All steps were performed by two
authors independently before reaching a consensus, and
discrepancies were resolved by a third reviewer.
Search strategy and selection criteria
The search was performed in PubMed, Scopus and Web of
Science electronic databases (updated in March 2017). No
filters for date of publication or language were used. The
search strategy was structured and built around the ques-
tion ‘What are the antidiabetic effects evaluated for the
inflorescence extracts of Musa spp.?’ The complete search
strategy for PubMed is presented in the supplementary
material (Appendix S1). First, titles and abstracts of identi-
fied articles were independently reviewed by two research-
ers, according to the inclusion criteria, in order to identify
irrelevant records. The inclusion criteria were as follows:
(1) belong to the genus Musa; (2) evaluate at least one
in vitro or in vivo (in human or animal) antidiabetic activ-
ity; and (3) evaluate the inflorescence extract (flower or
1584 © 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595
Raquel de Oliveira Vilhena et al.
bract). In the second stage, full-text articles were indepen-
dently evaluated by the same two researchers to identify
any of the following exclusion criteria: studies that did not
prepare extract (the use of fresh vegetable material – in nat-
ura – or dried plant); studies that evaluated an extract con-
taining a mixture of several species; or articles reported in
non-Roman characters.
Data extraction and quality assessment
Key data, such as the article’s baseline characteristics (au-
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thors’ names, year of publication and country), type of
extract, biological activity, study methods and results, were
carefully extracted from the included articles. The risk of
bias in the animal studies included in this systematic review
was evaluated based on the SYRCLE’s RoB tool.[31] In order
to establish the risk of bias, the following aspects were anal-
ysed: selection bias, performance bias, detection bias, attri-
tion bias and reporting bias. Furthermore, in any study
conducted in patients with diabetes, the risk of bias was
determined using the Cochrane collaboration’s tool.[29]
Results and discussion
The search from electronic databases yielded a total of 2300
studies, after duplicates were removed. During assessment
of titles and abstracts, 2247 articles did not meet the inclu-
sion criteria and were excluded, leaving 53 records for full-
text screening. From these, 37 were excluded (see supple-
mentary material – Table S1) and 16 articles were consid-
ered suitable for data extraction and analysis. Figure 1
illustrates the systematic study selection process.
These 16 studies[9–13,15,19,32–40] were published between
1998 and 2017; 75% were from India. The majority of stud-
ies used in vivo antidiabetic models (56%). Regarding the
preparation of the extract, the most applied techniques
were maceration (37.5%) and Soxhlet (37.5%); ethanol was
the most commonly used solvent (56.3%). Among the 16
eligible studies, it is important to highlight that only four
studies evaluated the activity of a compound isolated from
the inflorescence (19%) (Figure 2).
In order to verify the biological activity of Musa spp.
inflorescence, the identified studies carried out various
approaches. Other characteristics of the 16 studies are pre-
sented in Table 1 and are further discussed in the results
section below.
Hypoglycaemic effects and prevention of
diabetic complications
Borah and Das,[33] Dhanabal et al.,[34] Jawla, Kumar, and
Khan,[9] Nisha and Mini,[11] Ramu et al.,[38] Sundaram
and Subramian,[40] and Sundaram et al.[39] performed
Raquel de Oliveira Vilhena et al. Antidiabetic potential of Musa spp. flowers

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Figure 1 Flow chart of search and selection of published articles. Note: *The sum of excluded articles is greater than 37 because some of them
met more than one exclusion criteria (see Table S1). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2 Distribution of articles according to the type of sample evaluated.

in vivo hypoglycaemic evaluation. The assessment of this extracts of flower of M. balbisiana, Musa sapientum,
biological activity was conducted using a methanolic M. paradisiaca, and Musa sp.,[9,13,33,34,39,40] and ethanol:
extract of M. paradisiaca inflorescence,[11] ethanolic water (1:1) extract of flower of M. paradisiaca.[9]

© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595 1585
Antidiabetic potential of Musa spp. flowers Raquel de Oliveira Vilhena et al.

Table 1 Summary of characteristics of included studies

Part of Extraction Extract/compound

Author (year) Species Country plant procedure Solvent concentration Biological activity

In vitro
Abdurrazak Musa paradisiaca Malaysia Dried Maceration MeOH/EtOH/W 15.6–1000 lg/ml a-glucosidase inhibition
(2015)[10] tepals
Arun (2017)[32] M. paradisiaca India Dried Sequential AcOEt/MeOH 50–250 lg/ml a-glucosidase and a-
inflor. amylase inhibition/
antiglycation/glucose
uptake capacity
Bhaskar (2011)[68] Musa sp. India Dried Sequential Ace/MeOH/ Doses of Glucose uptake capacity
flowers EtOH/W 2–1000 lg

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Dineshkumar Musa sapientum India Dried Maceration peth/hx/Chl/ 10–100 lg/ml a-amylase inhibition
(2010)[36] flowers EtOH/W
Marikkar Musa cuminata Malaysia Dried Maceration EtOH (80% v/v) 200 lg/ml a-glucosidase and a-
(2016)[37] Musa balbisiana flowers amylase inhibition
M. paradisiaca
Ramu (2014)[13] Musa sp. India Dried Soxhlet EtOH – a-glucosidase and
flowers aldose reductase
inhibition/antiglycation
Sheng (2014)[19] Musa spp. China Dried Fractionation EtOH – a-glucosidase inhibition
flowers (95% v/v)apeth/
AcOEt/BuOH
In vivo
Aguilara M. sapientum Mexican Fresh Decoction W 4 ml/kg bw Glucose tolerance on
(1998)[12] flowers temporarily
hyperglycaemic rabbits
Borah (2017)[33] M. balbisiana India Dried Soxhlet EtOH (95% v/v) 250 mg/kg bw Antidiabetic effect on
flowers streptozotocin-induced
type 1 diabetic rats
Dhanabal M. sapientum India Dried Maceration EtOH 200 mg/kg bw Hypoglycaemic effect on
(2005)[34] flowers alloxan-induced
diabetes mellitus in rats
Jawla (2012)[9] M. paradisiaca India Fresh Maceration EtOH (50% v/v) 100, 250, and Antihyperglycaemic
flowers 500 mg/kg bw effect on alloxan-
induced diabetes
mellitus in rats
Nisha (2013)[11] M. paradisiaca India Dried Soxhlet MeOH/AcOEt 200 mg/kg bw Hypoglycaemic effect on
flowers streptozotocin-induced
type 1 diabetic rats
Ramu (2016)[38] Musa sp. India Dried Soxhlet EtOH 100 and Hypoglycaemic effect on
flowers 200 mg/kg bw alloxan-induced
diabetes mellitus in rats
Sundaram Musa paradisiaca India Dried Soxhlet EtOH (95% v/v) 200 mg/kg bw Regulation of
(2012)[40] flowers carbohydrate
metabolism in hepatic
tissues of
streptozotocin-induced
diabetic rats
Sundaram Musa paradisiaca India Dried Soxhlet EtOH (95% v/v) 50 mg/kg bw Antidiabetic effect on
(2014)[39] flowers (syringin) streptozotocin-induced
diabetic rats
Dineshkumar M. sapientum India Dried Maceration W 5 ml/day Antidiabetic effect in
(2010)[35] flowers type 2 diabetic patients
inflor., inflorescence; AcOEt, ethyl acetate; BuOH, n-butanol; Chl, chloroform; EtOH, ethanol; hx, hexane; MeOH, methanol; peth, petroleum
ether; W, water. aFractions of ethanolic extract.

1586 © 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595
Raquel de Oliveira Vilhena et al.
Initially, to evaluate acute oral toxicity and to establish
dosage fixation, some studies[9,33,38] tested the administra-
tion of different concentrations of the extract. Moreover,
Ramu et al.[38] also analysed isolated exposure to two con-
stituents of Musa sp. flower: umbelliferone and lupeol,
which have significant antihyperglycaemic activity
in vitro.[13] Sundaram et al.[39] isolated and tested only syr-
ingin from the extract, which is considered to be an active
compound with different pharmacological activities.[41–45]
At the tested intervals, none of the concentrations showed
toxicity.
For the animal model tests, Wistar rats were separated
into different groups: normal control group (nondiabetic
rats treated only with the vehicle), diabetic control rats
(treated only with vehicle or untreated), diabetic rats (ani-
mals that received an antidiabetic drug – positive control)
and diabetic animals treated with extract or with isolated
compounds of M. paradisiaca (syringin, umbelliferone and
lupeol). The dose of extracts administered varied between
100 and 500 mg/kg body weight, and the antidiabetic drugs
used in the positive control group were insulin,[33] gliben-
clamide,[9,34] gliclazide[39,40] and metformin.[38] The dia-
betic state was induced via a single intraperitoneal injection
of streptozotocin[11,33,39,40] or alloxan monohydrate.[9,34,38]
The animals were considered as diabetic when blood glucose
values were above 200 mg/dl[11,34,38] or 250 mg/dl.[33,39,40]
For the evaluation of antidiabetic effects, different bio-
chemical markers were assessed to evaluate glycaemic levels.
Significant decreases in blood glucose levels were observed
with administration of the extract,[9,11,33,38,40] which were
comparable to the diabetic control group. Jawla, Kumar,
and Khan,[9] and Ramu et al.[38] consider this effect to be
dose dependent. In addition, oral administration of syrin-
gin,[39] umbelliferone and lupeol[38] also demonstrated
hypoglycaemic effects. These results are in accordance with
other studies that have evaluated these isolated compounds.
For example, syringin isolated from Eleutherococcus sentico-
sus presented hypoglycaemic action in diabetic rats induced
by streptozocin.[46] Further, many natural triterpenoids
and coumarins appear to have promising antidiabetic
properties and may be used for the prevention of diabetic
complications.[25,47]
The effects of hyperglycaemia, resulting from insufficient
secretion of insulin or insulin resistance, are possibly attrib-
uted to progressive b-cell failure. In untreated diabetic rats,
dilatation and degranulation in islet cells has been detected,
when compared to a normal control group. After treatment
with the extract and its constituents, changes in the archi-
tecture of pancreatic islet cells were observed, such that they
had almost returned to normal.[38]
Moreover, an increase in the activities of glucokinase,
pyruvate kinase and glucose-6-phosphatase-dehydrogenase
was achieved with the use of the extract of M. paradisiaca
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595
Antidiabetic potential of Musa spp. flowers
tepal,[40] which indicated an effective utilization of glucose.
Further, there was a reduction in the activity of two
gluconeogenic enzymes, glucose-6-phosphatase and fruc-
tose-1,6-bisphosphatase, showing a regulation of gluco-
neogenic flux by the extract.
In addition to these trials, Dhanabal et al.[34] also evalu-
ated the protective effect of the extract on alloxan induction
of diabetes mellitus. In this model, normal rats received
doses of extract (200 mg/kg) twice a day for 5 days.[34]
Comparing glucose values before induction with alloxan
(1st and 5th day) and after (10th day), between the treated
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and control groups, a protective effect promoted by the
extract was observed. Glucose values were elevated in the
control group, whereas in the treated group, there was
maintenance of glucose levels (P < 0.02). Additionally, the
extract prevented antioxidant reduction as evaluated with
the following parameters – catalase, superoxide dismutase,
protein, malondialdehyde and acid ascorbic estimation.
Oxidative stress contributes to the progression and patho-
logical complications of diabetes and seems to be related to
the development of the disease.[48] Therefore, the extract
possibly limited the damage caused by alloxan.
Prolonged high blood glucose levels lead to diverse sec-
ondary complications from diabetes. Among these compli-
cations, overproduction of sorbitol by the polyol pathway
can occur; this can be avoided by inhibiting the key aldose
reductase enzyme, and the formation of advanced glycation
end products (AGEs), resulting from the covalent interac-
tion between glucose and plasma proteins via a nonenzy-
matic process known as glycation.[49,50] The in vitro studies
of Ramu et al.[13] showed that the crude extract (95% etha-
nol flower extract of Musa sp. var. Nanjagud rasa bale) and
its constituents (umbelliferone and lupeol) as acted as bet-
ter inhibitors of aldose reductase than quercetin (positive
control). Further, the inhibitory effects on glycation were
evaluated using in vitro bovine serum albumin glycation
and analysis of the early glycation product (fructosamine),
intermediate products (protein carbonyls) and AGEs. Both
compounds exhibited higher inhibitory potential across all
levels, compared with the crude extract and the positive
control aminoguanidine.[13]
Another complication caused by chronic hyperglycaemia
is the acceleration of protein catabolism and excess lipoly-
sis, leading to total protein reduction, increased lipid pro-
file and weight loss.[51–53] Treatment with the extract and
the isolated compounds enhanced total protein[39] and hae-
moglobin levels.[38,39] Furthermore, at the end of the stud-
ies of Borah and Das[33] and Ramu et al.,[38] the treated
diabetic groups exhibited a significant reduction in total
blood cholesterol, serum triglycerides and serum low-
density-lipoprotein, while there were significant increases
in serum high-density-lipoprotein and body weight. Borah
and Das[33] attributed this antilipidaemic activity to the
1587
Antidiabetic potential of Musa spp. flowers
presence of pectins (which elevate the viscosity of the gas-
trointestinal contents, and hence, reduce the absorption
and digestion of carbohydrates), saponins (which reduce
the cholesterol absorption in the intestinal lumen and stim-
ulate excretion of bile acids), tannins (which decrease diet-
ary absorption of cholesterol) and gallic acid (which
inhibits cholesterol esterase and enhances faecal excretion
of bile acids). These results are in accordance with other
previous reports.[54–58]
In addition to excessive protein degradation in the dia-
betic rats, there was an augmentation of irreversible glyca-
tion of several proteins, including haemoglobin. This
produces glycosylated haemoglobin (HbA1c), considered
an important biomarker for diabetes.[54–58] The majority of
the included studies assessed this parameter and identified
a significant reduction in HbA1c (P < 0.05) in the group
treated with the extract and active compounds isolated
from the extract of banana flower/inflorescence, when com-
pared to the control group.[11,38–40]
Diabetes is also characterized by renal impairment, cul-
minating in glycosuria (excretion of glucose in the urine),
as well as elevated blood urea and serum creatinine
levels.[59,60] These abnormalities reverted to near normal
levels, that is, decreased renal glucose excretion, blood urea,
serum uric acid and serum creatinine levels after the use of
the extract and its constituents.[38,39]
Apart from renal impairment, the liver is also compro-
mised by hyperglycaemia, due to it being associated with
glucose storage and metabolism.[61] The histopathological
analysis conducted by Nisha and Mini[11] in diabetic ani-
mals demonstrated hepatocellular damage in the form of
severe macrovesicular steatosis, microcellular fatty
changes and extensive vacuolization, with disappearance
of nuclei and periportal inflammation. However, these
alterations were optimized back to near normal after
treatment with the extract. The hepatotoxic effect was
also confirmed by the elevation of alanine aminotrans-
ferase (ALT), aspartate aminotransferase (AST) and alka-
line phosphatase (ALP) enzymes in the diabetic groups,
while there was a reduction in the levels of these enzymes
in the groups treated with the extract[11,38] or its
constituents.[39]
Glycogen is a polysaccharide that is the principal storage
form of glucose, and its production is regulated through
insulin’s action. In the diabetic state, glycogen concentra-
tions are reduced; however, after the administration of the
extract and isolated compounds (umbelliferone and
lupeol), these polysaccharide levels were enhanced.[11,38]
Common symptoms described in diabetes mellitus are
polydipsia, polyphagia and polyuria, which are related to
osmotic alterations because of impaired glucose uptake.[62].
Ramu et al.[38] reported these symptoms in all diabetic
groups of rats. At the end of the experiment, these diabetic
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Raquel de Oliveira Vilhena et al.
signs were reversed due to the administration of the extract
and the isolated compounds.
Another parameter to assess the antidiabetic action is
delayed intestinal glucose absorption, which culminates in
a decrease in blood glucose levels, proposed in the work of
Borah and Das.[33] This mechanism was evaluated for a
flower and inflorescence stalk extract, culminating in a sig-
nificant reduction in both treatment groups, but with a
greater result with the flower extract. According to Borah
and Das,[33] this action of these extracts can be attributed
to the pectins found in the flower ethanolic extract, and the
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saponins and tannins present in both extracts. These results
are in agreement with other reports described in the
literature.[54–57]
In summary, oral administration of the extract and its
constituents demonstrated hypoglycaemic properties.
Among the included studies, hypoglycaemic activity is attrib-
uted to different compounds, mainly related to the presence
of glycosides such as saponins,[9,33,34,40] polyphenols such
as gallic acid, epicathechin, and tannins,[9,33,34,40] flavo-
noids, e.g., quercetin,[9,11,34,40] polysaccharides, e.g., pec-
tin,[9,11,40] sterols,[34,40] triterpenes, and alkaloids.[40]
Furthermore, Ramu et al.[38] evaluated compounds iso-
lated from an extract of the banana flower. Umbelliferone
and lupeol were considered to be antidiabetic compounds,
justified by the regeneration of b-cells, and hence, leading
to an improvement in insulin secretion with subsequent
glycaemic reduction.[13,63–67] Syringin demonstrated
effects on glucose homeostasis that may be due to its
effects on glucose uptake and glycogen synthesis.[46]
Oral glucose tolerance
Jawla, Kumar, and Khan[9] conducted an in vivo hypogly-
caemic evaluation in rats with induced diabetes, and eval-
uated the effect of flower extract on glucose-loaded
normal rats. The assessment of this oral tolerance test was
conducted after overnight fasting (16 h) using distilled
water (vehicle), ethanol and ethanol:water (1:1) extracts of
flowers at three doses (100, 250 and 500 mg/kg). Gliben-
clamide was used as the standard oral hypoglycaemic drug
(0.2 mg/kg). In order to compare the results, rats were
separated into different groups: one control group (rats
treated only with vehicle), one positive group (rats that
received glibenclamide) and groups of animals treated
with different doses of different extracts of M. paradisiaca.
Glucose (4 g/kg) was fed to rats 60 min after treatment,
and for the evaluation of the effects, blood glucose levels
were measured after 0, 30, 60, 90, 120, 240 and 360 min.
A significant decrease in blood glucose levels was observed
with all three doses of the extract administered, after
30 min, in glucose-loaded rats; this was comparable to
glibenclamide. No difference was observed between the
Raquel de Oliveira Vilhena et al.
lowest and highest dose administered. In addition, the dif-
ferent extracts (ethanol and ethanol:water (1:1)) were sim-
ilar in their reduction of blood glucose over time.
Phytochemical screening of M. paradisiaca flowers
revealed the presence of glycosides, flavonoids, saponins,
and tannins in the ethanol and ethanol:water (1:1)
extracts. The authors suggested that the potent antihyper-
glycaemic properties observed may be attributed to these
components. Flavonoids are known for their high antioxi-
dant power, which has been proposed as a mechanism of
action in the treatment of diabetes and its complica-
tions.[23,24] However, further investigation is required to
better characterize the active principles.[9]
Aguilara et al.[12] also evaluated the effect of M. paradisi-
aca flower extracts on glucose tolerance; however, the test
was performed in temporarily hyperglycaemic healthy rab-
bits.[12] The assessment of this oral tolerance test was per-
formed with New Zealand adult male rabbits weighing
between 2.5 and 3.5 kg after overnight fasting (18 h). The
plant extract was obtained by decoction of 40 g of the dried
plant slowly boiled in 300 ml of water for 10 min. Then,
the liquid decoction was filtered and directly administered
to the animals (4 ml/kg using a gastric tube). Distilled
water was used as control, and tolbutamide was used as the
standard oral hypoglycaemic drug (40 mg/kg). Rabbits
were separated into different groups: two control groups
(rabbits treated only with vehicle), two positive groups
(rabbits that received tolbutamide) and one group of ani-
mals treated with M. paradisiaca extract. A 50% glucose
solution was applied subcutaneously (3 g glucose/kg), two
times, at time 0 and 60 min. The blood glucose levels were
measured at intervals of 60 min for 5 h after injection of
the first glucose load. The percentage of the decrease in gly-
cemia, caused by the hyperglycaemic peak and area under
the curve were estimated. A reduction in glucose levels was
observed 60 min after glucose load. A decrease of 17.0% in
the hyperglycaemic peak was observed in rabbits treated
with the plant extract, whereas for tolbutamide, the
observed decrease was 15.7%. Regarding the area under the
curve, the authors reported that the plant extract also
caused a significant reduction (18.0%) in their control
group. Tolbutamide caused a reduction in the area under
the curve of 16.6%. In this study, the authors evaluated the
extract produced according to its traditional use in Mexico,
and no phytochemical screening was performed. The
authors suggest that this plant must be considered as an
excellent candidate for future studies to elucidate the mech-
anisms of its hypoglycaemic activity, as well as for the isola-
tion and identification of its active hypoglycaemic
substances.[12]
Despite the differences between these studies in the pro-
cedures by which the extracts were obtained, the study
protocols, and the animal models used (rats or
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595
Antidiabetic potential of Musa spp. flowers
rabbits),[9,12] there are some similarities in the solvent
extractor and doses evaluated. Jawla, Kumar, and Khan[9]
evaluated the range of 100 to 500 mg/kg and Aguilara
et al.[12] used a dose of 4 ml/kg, equivalent to 259 mg/kg
of extract. Another difference is that one study used rats[9]
as experimental animals while the other rabbits.[12] Both
authors reported on the hypoglycaemic potential of
M. paradisiaca in the first hour after administration of the
extract, and results of the hypoglycaemic properties are
convergent.
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Improvement in glucose uptake
Two included articles evaluated the effect of Musa sp. cv.
Elakki bale and M. paradisiaca flowers on the improvement
in glucose uptake.[32,68] Both evaluated the uptake of glu-
cose using its fluorescent analogue 2-[N-(7-nitrobenz-2-
oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG).
They analysed phenolic acids via high-performance liquid
chromatography (HPLC) to determine the cytotoxic effect
of the extracts. However, they diverged in the cellular
model, type of positive control and extract composition.
Further, unlike Arun et al.,[32] the study of Bhaskar, Sali-
math, and Nandini[68] quantitated total phenolic com-
pounds using a Folin–Ciocalteu reagent.
Ehrlich ascites tumour (EAT) cells were chosen as a cel-
lular model by Bhaskar and colleagues.[68] This model was
also utilized in other studies of glucose transport.[69–71]
This model uses insulin (between 0.4–6 IU) as a positive
control in the glucose uptake test. The flower and pseu-
dostem of the Musa sp. were selected for extraction of phy-
tochemicals with different solvents.
The incubation period of the cells with different doses of
acetone, methanol, ethanol and aqueous extracts (between
2–1000 lg/ml) was 5 min at 37°C. Then, 2-NBDG (1 mM)
was added with buffer and incubated together for 30 min
at 37°C. In the sequence, the cells were centrifuged, washed
with buffer, lysed, suspended in buffer with Triton X-100
and sonicated. Finally, they were centrifuged again and the
supernatant was analysed by spectrofluorimeter to measure
the fluorescent analogue of glucose.[68]
The results were given as net glucose uptake. They were
obtained by subtracting the values of the control from that
of the cells pretreated with the extract and 2-NBDG. The
basal glucose uptake (EAT cells + 2-NBDG) was considered
as a control.[68]
At lower concentrations of extracts, a dose-dependent
increase in glucose uptake was observed for flower and
pseudostem extracts. However, the improvement in
uptake was not dose proportional with concentrations
above 50 lg/ml. Furthermore, uptake inhibition was
noted at higher doses of pseudostem extracts, which was
not due to cytotoxic effects. Experiments after staining of
1589
Antidiabetic potential of Musa spp. flowers
cells with Trypan blue confirmed the viability of cellular
function.[68]
The decreasing order of efficiency of the extracts, in
terms of glucose uptake, was aqueous, methanol, ethanol
and acetone extracts. Through the HPLC analysis, the fol-
lowing major phenolic acids were identified: gallic acid,
protocatechuic acid, gentisic acid, catechol and epicatechin.
Other unidentified substances were also observed. Further,
the methanol extract showed a higher amount of total phe-
nolic acids compared to aqueous extract. Thus, these results
suggest that other substances, in addition to phenolic phy-
tochemicals, could have influenced glucose uptake in the
EAT cells.[68]
In the research by Arun et al.,[32] the cellular model
was L6 myoblasts. These L6 skeletal muscle cells have
been extensively used in recent investigations of phyto-
chemical compounds with antidiabetic effects.[72,73] This
study used rosiglitazone (100 nM) as a positive control
and the entire inflorescence for the extractions. The L6
cells differentiated were pretreated with 50 and 100 lg/
ml methanol extract for 24 h, and were then washed
with buffer and incubated with 2-NBDG (0.1 mM) for
30 min. After that, the cells were washed with buffer,
trypsinized and resuspended in buffer. The quantitation
of the fluorescent analogue of glucose was completed by
fluorescence activated cell sorting (BD FACS Aria II, BD
Bioscience, USA) and BD FACS Diva software. The cyto-
toxic effects of the extracts were assessed using a 3-(4,5-
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) assay.[32]
The results showed a dose dependent increase in glucose
uptake of L6 myoblast cells pretreated with methanol
extract. The HPLC analyses highlighted the presence of gal-
lic acid, catechol, chlorogenic acid, caffeic acid, syringic
acid, p-coumaric acid, ferulic acid, ellagic acid, myricetin,
cinnamic acid, kaempferol and apigenin in this extract.[32]
Thus, considering the results of both studies, it is possi-
ble to associate the in vitro improvement in glucose uptake
activity in a cellular model to the phenolic compounds of
Musa sp. The aqueous and methanol extracts of inflores-
cence of this genus have promising antidiabetic potential.
However, divergence between the results of Arun et al.[32]
and Bhaskar, Salimath, and Nandini[68] was observed when
higher doses of the extracts were considered. A possible
cause for this is the evaluation of glucose uptake on differ-
ent glucose transporters. EAT cells have GLUT1 and
GLUT3 while L6 myoblast cells have GLUT1 and
GLUT4.[69,74] In the literature, other cellular types have
been used to analyse glucose uptake, such as 3T3-L1 cells
and sheep erythrocytes.[75–77] Another possibility could be
differences in the extract composition, since Bhaskar, Sali-
math, and Nandini[68] selected parts of the inflorescence
while Arun et al.[32] used the entire inflorescence. In
1590 © 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595
Raquel de Oliveira Vilhena et al.
addition, the authors used very distinct contact times
between the extracts and the cells.
Inhibition of carbohydrate digestion
enzymes
Inhibition of carbohydrate digestion is a basic pathway used
in antidiabetic drugs such acarbose and miglitol.[78] Six
studies[10,13,19,32,36,37] included in our systematic review
reported data on the determination of the a-glucosidase
inhibitory activity of Musa spp. These researchers used a
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spectrophotometric method with p-nitrophenyl-a-D-gluco-
pyranoside (pNPG) as a substrate and a-glucosidase from
baker’s yeast.[10,13,19,32,37] The inhibition of a-amylase activ-
ity was also determined by a spectrophotometric method,
using starch solution as a substrate, porcine a-amylase, and
DNS reagent,[13,37] iodine,[32] or no reagent.[36] Acarbose
was chosen as positive control in all the six studies.
Ramu et al.[13] evaluated a 95% ethanol flower extract of
Musa sp. var. Nanjagud rasa bale. Further, two compounds
were isolated from this extract by silica gel column chro-
matographic separation (umbelliferone and lupeol) and
tested.[13] Both compounds and their families have been
reported to be compounds with a-amylase and a-glucosi-
dase inhibition properties,[21,79,80] which was confirmed by
this study. The crude extract and its compounds exhibited
strong inhibition of a-glucosidase (IC50 7.79 lg/ml – crude
extract; 9.68 lg/ml – acarbose) and a-amylase (IC50
36.05 lg/ml – crude extract; 29.71 lg/ml – acarbose).
Comparing the isolated compounds, umbelliferone was a
more potent inhibitor than lupeol. A kinetic study of a-glu-
cosidase inhibition was conducted to clarify the mechanism
of binding of the compounds. The enzyme was incubated
with different concentrations of pNPG (0.25–4 mM) with
and without umbelliferone and lupeol at IC20, IC40, and
IC50 concentrations. From the interpretation of
Lineweaver–Burk plots, both compounds appeared to inhi-
bit the enzyme via a noncompetitive mechanism.[13]
Another study[19] also investigated the inhibitory activity
of a 95% ethanol extract of Musa spp. var. Baxijiao flowers.
These authors evaluated petroleum ether, ethyl acetate, n-
butanol and aqueous fractions, with the objective of identi-
fying compounds related to this activity. The crude extract
presented with the highest inhibitory activity, followed by
the fractions of ethyl acetate and petroleum ether. These
fractions were then subjected to fractionation, purification
and isolation of compounds. The identified compounds
were as follows: vanillic acid, ferulic acid, and b-sitosterol
in the petroleum ether fraction, and daucosterol and 9-(40 -
hydroxyphenyl)-2-methoxyphenalen-1-one in the ethyl
acetate fraction. Among these isolated compounds, the lat-
ter three showed superior activity compared to acarbose.
The mechanism of binding of these compounds was
Raquel de Oliveira Vilhena et al.
studied by Lineweaver–Burk plot analysis, indicating a
competitive mode for the sterols and a mixed-type inhibi-
tion for phenylphenalenone.[19]
Comparing the IC50 values obtained by these two above-
mentioned studies, we verified that the extract evaluated by
Sheng et al.[19] presented with a-glucosidase inhibitory
activity three times greater than acarbose, while the other
extract presented as 1.2 times greater than the same control.
This result can be attributed to a difference in the profile of
chemical constituents between the assessed plants. This is
supported by the different activities of the isolated com-
pounds in the study by Ramu et al.,[13] which showed
activity very close to the crude extract, and the study by
Sheng et al.,[19] which presented with much higher activity
than the control, about 200 times.
This kind of comparison between different species and
cultivars of Musa sp. was performed by Marikkar et al.[37]
Hydroalcoholic extracts (80%), at 200 lg/ml, of six differ-
ent cultivars of banana flowers (Musa acuminata cv. P.
berangan, cv. P. susu, and cv. P. ma; M. balbisiana cv. P.
abu and P. nipah; M. paradisiaca cv. P. rastali) showed inhi-
bitory activity on carbohydrate-hydrolysing enzymes.[37]
Susu also showed a high phenolic and flavonoid content
and antioxidant capacity among the six cultivars, which
could contribute to its strong antihyperglycaemic activity.
This is in accordance with studies on the potent a-glucosi-
dase inhibitory activity of some flavonoids and
phenolics.[21,67]
In the study conducted by Dineshkumar, Mitra, and Man-
junatha,[36] which evaluated the extract of flowers of M. par-
adisiaca prepared by successive maceration with petroleum
ether, hexane, chloroform, ethanol and water, only the
extract in chloroform presented with a-amylase inhibitory
activity (IC50 97.80  0.73 lg/ml).[36] On the other hand, a
study comparing the a-glucosidase inhibitory activities of
tepal extracts of ethanol, methanol, and water of M. paradisi-
aca, showed that methanol was the most potent inhibitor
(IC50 200, 60, and 360 lg/ml, respectively).[10] However,
under this assay, acarbose (positive control) was not potent
enough to inhibit a-glucosidase. The methanol extract exhib-
ited higher inhibitory activity of carbohydrate digestive
enzymes when compared to the ethyl acetate extract (metha-
nol extract: IC50 166.14 and 106.37 lg/ml, and ethyl acetate
extract: IC50 183.96 and 140.03 lg/ml, for a-amylase and a-
glucosidase, respectively).[32] In addition, methanol extract
showed antiglycation properties, as in the study by Ramu
et al.[13] This activity was related to the presence of the
polyphenol compounds in the extract, such as kaempferol.
Antidiabetic effects in humans
Among the selected articles, only one evaluated the
antidiabetic activity of Musa spp. flowers in humans.[35]
© 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595
Antidiabetic potential of Musa spp. flowers
This study evaluated the antidiabetic potential of an
aqueous extract of M. sapientum in volunteers diagnosed
with type 2 diabetes (n = 40; random selection). The
extract was prepared in water by overnight maceration
using 500 g of dried plant and one litre of purified water,
and unlike the animal studies, the administered extract
was not dried and resuspended in a vehicle for adminis-
tration. The volunteers were divided into an experimental
group (20 volunteers received the extracts, 5 ml/day, over
2 months) and a control group (20 volunteers received
water only). Anthropometrical, clinical and blood bio-
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chemistry parameters (fasting blood glucose, triglycerides,
total cholesterol, high-density-lipoprotein, low-density-
lipoprotein, and very low-density-lipoprotein; 12 h fast-
ing) were evaluated prior to the study and at the end of
the study. The results were statistically analysed, but the
method for doing so was not specified (statistical signifi-
cance = P < 0.05). According the authors, no significant
differences in biochemical parameters were observed
between the experimental and the control group.[35]
However, when compared to studies with animal models,
the administered dose was much lower: 100 to 500 mg of
dry extract per kilo for animals versus only 5 ml of the
prepared extract per day for volunteers (mean weight of
76 kg). Thus, further clinical studies with higher doses
should be conducted in order to strengthen this
evidence.
Assessment of studies
The sequence generation and allocation concealment were
not detailed in any included experimental studies, con-
tributing to the occurrence of high risk of bias. Further-
more, none of the studies executed adequate blinding
between the animal caregivers and investigators.
The assessment of similarity in baseline characteristics
between the experimental and control groups was consid-
ered in the distribution of groups in the included studies,
leading to a low risk of bias for this domain. Housing con-
ditions of animals in different treatment groups were simi-
lar in seven studies (87.5%), with only two studies (25%)
not reporting these conditions. The results of assessment of
the methodological quality of the animal intervention stud-
ies included in this systematic review are presented in
Figures 3 and 4.
Regarding the human study by Dineshkumar, Mitra, and
Manjunatha,[35] random sequence generation, incomplete
outcome data, selective reporting and other biases were
considered to be of low risk of bias.[35] The authors were
not clear when reporting allocation concealment and the
items ‘blinding of participants and personnel’ and ‘blinding
of outcome assessment’ were classified as high risk of bias
(Figures 5 and 6).
1591
Antidiabetic potential of Musa spp. flowers Raquel de Oliveira Vilhena et al.

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Figure 3 Risk of bias graph for animal intervention studies. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4 Summary of results of consensus risk of bias assessments
for the animal studies. [Colour figure can be viewed at wileyonlinelib
rary.com]
Conclusions
The identification of novel compounds and the evalua-
tion of potentially useful natural therapies are para-
mount for clinical practice. Our systematic review
evaluated the proprieties of Musa spp. as a natural alter-
native for management of diabetes mellitus. In total, 16
articles evaluating the antidiabetic activity of Musa spp.
and its cultivars were included. Only one study evalu-
ated the antidiabetic effect in humans, but there were
no significant differences observed between the treated
and the control groups. However, the administered dose
was low (5 ml of fresh extract). In the animal-induced
diabetic models, the plant extracts showed an equivalent
glycaemic level reduction, considered to be dose depen-
dent, when compared to various pharmacological drugs
(e.g. insulin, glibenclamide, gliclazide and metformin).
Additionally, the administration of this plant extract was
able to reverse abnormalities in the pancreatic islet
caused by elevated levels of insulin. These effects are
probably due to the regulation of enzymes in carbohy-
drate metabolism and gluconeogenic flux caused by the
extract components. Moreover, antioxidant properties of
the extracts were related to a protective effect against

Figure 5 Risk of bias graph for human intervention study. [Colour figure can be viewed at wileyonlinelibrary.com]

1592 © 2018 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 70 (2018), pp. 1583–1595
Raquel de Oliveira Vilhena et al. Antidiabetic potential of Musa spp. flowers

to an increase in glucose uptake and inhibition of carbo-

hydrate digestion enzymes.
In general, promising results regarding antidiabetic
activity were found with inflorescence of Musa spp.
However, more studies with higher methodological qual-
ity and low risk of bias for some domains (e.g. sequence
generation and allocation concealment, blinding, blinding
of participants and personnel, and blinding of outcome
assessment) are necessary to clarify the phytochemical
diversity of this plant and its mechanism of action.
Musa spp. might represent a natural alternative therapy

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for diabetes mellitus in the future, and its isolated phy-
tochemicals may contribute to the development of new
drugs.

Declarations

Figure 6 Risk of bias identified in the included human study. [Col-
our figure can be viewed at wileyonlinelibrary.com]
the damage caused by toxic inducers of diabetes. In vitro
studies associated the antidiabetic effects of the extracts
Acknowledgements
The authors thank the Coordenacß~ao de Aperfeicßoamento
de Pessoal de N
ıvel Superior (CAPES) for the scholarship
and Dr. Michel Leandro de Campos for help in reviewing
the manuscript.

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Supporting Information
Additional Supporting Information
may be found in the online version of
this article:
Appendix S1. Complete search
strategy performed in PubMed
Appendix S2. PRISMA checklist
Table S1. Justification of full-text
articles exclusion
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