Journal of Medical Hypotheses and Ideas (2013) xxx, xxxxxx

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Journal of Medical Hypotheses and Ideas

journal homepage: www.elsevier.com/locate/jmhi

Role of various avonoids: Hypotheses on novel approach

to treat diabetes
S. Mohan a, L. Nandhakumar b,*

a
Swamy Vivekanandha College of Pharmacy, Elayampalayam, Tiruchengode 637205, Tamilnadu, India
b
Extramural Scholar, Shri JJT University, Churella, Jhunjhunu 333001, Rajasthan, India

Received 1 May 2013; revised 3 June 2013; accepted 13 June 2013

KEYWORDS Abstract Basically avonoids are naturally occurring phenolic compounds that are distributed in
Flavonoids; plants. They contain wide range of biological activity and lot of research has been carried out on
Diabetes; their potential role in treating diabetes and other diseases. Most importantly the avonoids and
Nanoparticles; their related natural compounds are known to encompass antidiabetic potential, demonstrated in
Antidiabetic activity various animal models. Such benecial avonoids are less utilized on account of its deprived solu-
bility, decreased bioavailability; rst pass metabolism and intestinal degradation. However, avo-
noids are capable of improving, stabilizing and long sustaining the insulin secretion, human islets
and pancreatic cell respectively. In this article we propose, remarkable antidiabetic activity of avo-
noids as well as few approaches on nanoparticulate systems in diabetes induced animal models. The
proposed nanoparticulate system of avonoids is projected to improve the solubility, bioavailabil-
ity, by passing the rst pass metabolism and decreasing susceptibility to intestinal environment as
compared to pure avonoid isolates. Further, this hypothesis exemplies to enhance the efcacy of
avonoids in a novel way of antidiabetic treatment.
Crown Copyright 2013 Tehran University of Medical Sciences. Published by Elsevier Ltd. All rights
reserved.

Introduction owers tea etc., [6]. As for as diabetes mellitus is concern,

The most ubiquitous part of plant constituents are avonoids,
so far about 8000 varieties of avonoids have been identied
[1]. The avonoids are bioactive phenols with low molecular
weight and play a major role in the cell synthesis [25]. Flavo-
noids are highly present in fruits, vegetables, nuts, seeds, stem,
avonoids play a vital role in all aspects and its mechanism
is well known [7].
Diabetes is a metabolic disorder leads to hyperglycemia and
hindrance in carbohydrate, protein and fat metabolisms result-
ing in deprived insulin prole [8]. The effective control of
blood glucose level is an effective strategy in reducing clinical

* Corresponding author. Tel.: +91 9042939644.

E-mail address: nandha_pharm@hotmail.com (L. Nandhakumar).

2251-7294 Crown Copyright 2013 Tehran University of Medical Sciences. Published by Elsevier Ltd. All rights reserved.
URL: www.tums.ac.ir/english/
doi:http://dx.doi.org/10.1016/j.jmhi.2013.06.001

Please cite this article in press as: Mohan S, Nandhakumar L, Role of various avonoids: Hypotheses on novel approach to treat
diabetes, J Med Hypotheses Ideas (2013), http://dx.doi.org/10.1016/j.jmhi.2013.06.001
2 S. Mohan, L. Nandhakumar

Table 1 Remarkable endeavors to surmount the limitations of various avonoidal nanoparticulate system.
S. No Endeavors Flavonoids Result Refs.
1 b-cyclodextrin nanoparticles of propolis Kaempferol, rutin, quercetin, apigenin, Lower release pattern of avonoids from [11]
extract acacetin, chrysin b-cyclodextrin cavity
2 Enhancement of dissolution of Kaempferol Improved solubility of kaempferol [12]
kaempferol nanoparticles
3 Biodegradable poly-D,L-lactide (PLA) Quercetin Biphasic release of nanoparticles followed [13]
nanoparticles of quercetin by sustained slow release
4 Stevioside pluronic-F-68 copolymer PLA- Stevioside (non caloric sweetener) Increased intestinal absorption, [14]
nanoparticles biocompatibility and bioavailability and
caused a controlled release
5 PLGA Nanohydrogel matrix for oral Silymarin Enhanced dissolution and Bioavailability [15]
delivery of avonoid

Table 2 Remarkable endeavors to surmount the limitations of various avonoidal isolates in animal models.
S. No. Endeavors
1 Averrhoa carambola isolated
avonoid on glycogen synthesis
and insulin secretion
2 Acacia auriculiformis poly
avonoids on antidiabetic factor
3 Eect of Bauhinia forcate on
serum glucose
4 Icariin in diabetic rats on
mitochondrial oxidative stress
5 Kaempferitrin on glucose uptake
on skeletal muscles
6 Isolates from Euonymus alatus in
glucose uptake
7 An isolate exposure on chronic
hyperglycemic b-cell
8 Flavonoid isolate as
insulinomimetic on glycemia and
glucose uptake
9 Inhibition of intestinal and renal
Na-glucose cotransporter
10 Combined eect of avonoid in
type 2 diabetic rat
11 Antidiabetic activity of isolate in
normoglycemic rats
12 Enhancement of bioavailability and
anti-diabetic ecacy
Flavonoids Result Refs.
Apigenin-6-C-b-L- Increased insulin secretion and [16]
fucopyranoside potentiated glucose-induced
insulin secretion in
hyperglycemics rats
Gallic acid, caeic acid, catechin, Signicant suppression on a- [17]
rutin, quercetin, myricetin and amylase and a-glucosidase.
kaempferol
Kaempferol-3,7-O-(a)- Hypoglycemic eect was [18]
rhamnoside observed in alloxan induced
diabetic rats
Icariin Improvement in overall [19]
complication of diabetes in
steptozotocin induced rats
Kaempferitrin Insulin-mimetic role of [20]
kaempferitrin in glucose
homeostasis
Kaempferol and quercetin Potential ameliorated [21]
hyperglycemia observed, due to
glucose uptake in mature 3T3-L1
adipocytes
Kaempferol Restoration of high glucose- [22]
attenuated intracellular cAMP
and ATP production
Kaempferitrin Lowering blood glucose level and [23]
14
C uptake of glucose in
peripheral muscles of rat
Naringenin Inhibition of intestinal glucose [24]
uptake and renal glucose
reabsorption was observed
Naringin and hesperidin Synergistic insulin releasing eect [25]
Naringenin Diminishing the carbohydrate [26]
absorption from intestine and
reduced post prandial glucose
levels
Berberine Increased bioavailability and a [27]
promising alternative for diabetes therapy

complications of diabetes mellitus remarkably. Besides optimal treatment approaches essentiality [9]. Even though there is
control of blood glucose level alone, could not prevent no cure for diabetes, the pharmacological and non-pharmaco-
complications and it promotes to hypothesize an alternative logical approaches certainly improved the prognosis and im-

Please cite this article in press as: Mohan S, Nandhakumar L, Role of various avonoids: Hypotheses on novel approach to treat
diabetes, J Med Hypotheses Ideas (2013), http://dx.doi.org/10.1016/j.jmhi.2013.06.001
Role of various avonoids: Hypotheses on novel approach to treat diabetes 3

Fig. 1 Flavonoids function in diabetes mellitus.

proved the quality of life to certain extent. However, a compli-
cation pertaining to micro and macro-vascular set up of the
body remains imperative. The role avonoids are quite impor-
tant in ghting with the complications of diabetes mellitus
than any other method of treatment [10].
In recent years various approaches have been made to
utilize the avonoids in animal model to by incorporating
few novel methods to improve its antidiabetic property, they
are categorized in Tables 1 and 2 [1127]. Nevertheless, in
this context we propose few nanoparticulate systems in ani-
mal models and other signicant role as extracts are com-
piled and given.
Hypotheses
We propose avonoid in nanoparticulate system like avo-
noids association with polymers prone to show enhanced
properties for the purpose it is intended to it (Fig. 1).
We suggest the following
(1) Flavonoids have solid potential to serve as better alter-
native for diabetic treatment. Lack of safety is a main
concern in using current system for treating diabetes
and more prone to have serious side effects. Substantial
evidences are there to prove the antidiabetic activity for
even to single avonoidal component.
(2) One of the problem associated with utilizing the avo-
noids as alternative approach is that they are poorly sol-
uble candidates. Improving the solubility of avonoids
would benet the treatment protocol for diabetes as an
alternative approach.
(3) Flavonoids are the promising alternative for diabetes
and its associated complications. However, effective
control of not only keeping the blood glucose level opti-
mum will provide better results, but compromising con-
tinued damage of human islets as well as stabilizing the
cellular components is more essential for effective dia-
betic management.
(4) Adopting novel methods to improve the solubility of
avonoids would account for enhanced bioavailability
of the fraction and dose reduction initiative. Various
methods are there to improve the component solubility.
Further, novel techniques incorporation leads to
improved utilization of avonoids.

Please cite this article in press as: Mohan S, Nandhakumar L, Role of various avonoids: Hypotheses on novel approach to treat
diabetes, J Med Hypotheses Ideas (2013), http://dx.doi.org/10.1016/j.jmhi.2013.06.001
4 S. Mohan, L. Nandhakumar
(5) More relatively the possibility of nanoparticulate system
comprising avonoids ensures the altered pattern of
release preferably slow release will account for increased
intestinal absorption, thereby the chance of getting
affected from gastric enzymes are prevented.
(6) Profound biodegradable and biocompatible polymers
are the viable option to encounter the problem associ-
ated with solubility. As it improves the antidiabetic
property of avonoids as compared with pure isolate
of avonoids.
(7) Nanoparticulate system of avonoids will produce bet-
ter results if the component of same avonoids is used
in increased dose, if tested in animal models. The side
effect of current diabetic treatment associated with the
damaging of signaling pathways and cellular networks
can better be prevented with avonoid nanoparticulate
system.
Evaluation of hypotheses
The propositions are conrmed by following studies
(1) We put forward to evaluate the avonoid nanoparticu-
late system to that of pure drug. This is to evaluate
and conrm that the suggested nanoparticulate system
provide enhanced solubility and bioavailability over
the avonoid administration as such.
(2) Biocompatibility of avonoids and selected polymers are
done to show that there is no interaction between avo-
noid and polymer. It is proposed to conrm by Fourier
Transmission Infrared Spectroscopy (FTIR),
Differential Scanning Colorimetry (DSC) etc. to ensure
the possible interaction between the intra avonoid
nanoparticulate systems.
(3) We propose to conrm the formation of nanoparticulate
system by any of the established technique like nanopre-
cipitation, solvent evaporation method etc. Steps must be
taken to prove the efcacy of the particulate system as it is
superior in antidiabetic property as compared to pure
component. This is to conrm the formation of nanopar-
ticulates with optimum drug loading and drug entrap-
ment potential by suitable factorial designing.
(4) We suggest to utilize various groups of animal models are to
evaluate the antdiabetic property of the prepared
nanoparticles. We propose suitable analytical method evalu-
ate the blood glucose level at various intervals. It is to ensure
the bioavailability of nanoparticulates with pure drug.
(5) We propose to conrm the surface morphology and
dimension of the prepared particulate system by Trans-
mission ElectronMicroscopy (TEM), Scanning Electron
Microscopy (SEM) and particle size analysis by Zetasizer.
This is done to ensure the size distribution and surface
characteristics, which also determines the solubility of
the prepared nanoparticulates.
(6) Propositions are implied to ensure the dissolution of the
nanoparticulate system by using suitable USP model
dissolution apparatus. Samples must be withdrawn at
suitable intervals and avonoid contents are determined
at each interval. This study is to conrm the release
pattern of the avonoids from particulate system.
Please cite this article in press as: Mohan S, Nandhakumar L, Role of various avonoids: Hypotheses on novel approach to treat
diabetes, J Med Hypotheses Ideas (2013), http://dx.doi.org/10.1016/j.jmhi.2013.06.001
(7) To ensure the stability of the formulation, preparations
are stored at various temperature. This study is to pro-
vide the stability of avonoid nanoparticulates as com-
pared with the pure component.
(8) We propose to study the cell line uptake of glucose by
avonoids or insulinomimmetic activity of avonoids
as nanoparticulates are measured in insulin sensitive
cells. This study is done to ensure the antidiabetic activ-
ity of nanoparticulate avonoids with that of pure drug.
Discussion
Novel approach to treat diabetes with avonoid nanoparticu-
late system to enhance the antidiabetic activity on animal mod-
els has been discussed in this article. Diabetes is the wide
spread pandemic disease resulting in increased morbidity and
mortality. The blood glucose level of diabetics can be effec-
tively controlled by utilizing currently available antidiabetic
agents. The FDA approved anti diabetic agents is used for
the therapy to control blood glucose level [28,29]. Incorpora-
tion of natural antidiabetic preparation is given privilege to
make use of it, as it holds less toxicity and negligible side ef-
fects. Almost all the avonoids having potential for antidia-
betic activity but they are limited in usage on account of
deprived solubility and bioavailability.
Among the well known antidiabetic formulation stevioside
from the leaves of Stevia rebaudiana is reported as antidiabetic
drug [30]. The stevioside regulates the blood glucose concen-
tration by increasing insulin secretion and utilization in rats.
[3133]. Stevioside is potent antidiabetic agent but less compe-
tent because of less bioavailability, less persistence and degra-
dation in metabolism. To overcome the problem of solubility a
poly (D,L-lactic acid) nanoparticles of stevioside prepared by
nanoprecipitation method [14]. Further nanoencapsulated ste-
vioside of PLA nanoparticles have better bioavailability and
intestinal absorption than stevioside. The combination setarud
with quercetin is proved to be a viable alternative for diabetes
[34]. Based on the above fact we propose polymeric nanopar-
ticles increases the bioavailability than the avonoid alone
for safer antidiabetic treatment alternative with synergistic ac-
tion. On other hand, role of biological antioxidants like super
oxide dismutase (SOD), catalase (CAT) etc., in recent times for
pancreatic islets isolation and transplantation in animal mod-
els has been very effective [35]. This activity reveals the option
for utilizing plant biomolecules (avonoids) in transplantation
process involving pancreas with novel technology.
Conclusion
In this context, we propose a novel approach to treat diabetes
with enhanced antidiabetic activity from avonoid nanopar-
ticulate system. The proposed nanoparticulate systems with
novel biodegradable releasers are to increase the solubility
of avonoids, which in turn it increases the bioavailability
of the avonoid component. The proposed system further ex-
pected to prevent avonoid from rst pass metabolism and
intestinal absorption in the form of avonoid nanoparticulate
system. The avonoidal nanoparticulate system is expected to
have better antidiabetic potential against the isolate of pure
avonoids.
Role of various avonoids: Hypotheses on novel approach to treat diabetes
Overview box
First question: What do we already know about this sub-
ject?
Flavonoids are compounds present almost in all fruits
and vegetables. They are responsible for various activities
like antidiabetic, anticancer, anti-inammatory and so on.
Especially, antidiabetic potential properties of these avo-
noids are limited in use, because of its limited solubility,
bioavailability and subsequent undesirable metabolism
at various sites in the body.
Second question: What does your proposed theory add
to the current knowledge available, and what benets does
it have?
Nanoparticulate avonoidal system provides a viable
option to overcome the problem associated with solubil-
ity, bioavailability and biocompatibility with various
entrapping systems. With facile analytical tool and
numerous biodegradable agents available, nanoparticu-
late system is an easy word. Such fabricated nanopartic-
ulate system of potential avonoids would have better
synergistic activity against the non particulates or
isolates.
Third question: Among numerous available studies, what
special further study is proposed for the testing of idea?
We suggest evaluating avonoid nanoparticulate sys-
tem in various animal models for the antidiabetic activity
(insulinomimmetic, stimulation of pancreatic cell and
blood glucose levels). We suggest detailed examination
on release pattern of components from the nanoparticu-
late system by in vitro studies. Comparisons of prepared
system with the pure component of the same avonoids
are performed in animal models. Incorporation of cell line
study provides detailed behavioral pattern and pathway
of the avonoids.
Acknowledgement
The authors state that they do not have any conict of interest.
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Please cite this article in press as: Mohan S, Nandhakumar L, Role of various avonoids: Hypotheses on novel approach to treat
diabetes, J Med Hypotheses Ideas (2013), http://dx.doi.org/10.1016/j.jmhi.2013.06.001