Accepted Manuscript

Title: A Novel Strategy of Nanotized Herbal Drugs and their

Delivery in the Treatment of Diabetes: Present Status and
Future Prospects

Authors: Saima Amjad, Asif Jafri, A.K. Sharma, M.

Serajuddin

PII: S2210-8033(19)30025-9
DOI: https://doi.org/10.1016/j.hermed.2019.100279
Article Number: 100279

Reference: HERMED 100279

To appear in:

Received date: 23 November 2016

Revised date: 25 October 2017
Accepted date: 29 April 2019

Please cite this article as: Amjad S, Jafri A, Sharma AK, Serajuddin M, A
Novel Strategy of Nanotized Herbal Drugs and their Delivery in the Treatment of
Diabetes: Present Status and Future Prospects, Journal of Herbal Medicine (2019),
https://doi.org/10.1016/j.hermed.2019.100279

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A Novel Strategy of Nanotized Herbal Drugs and their Delivery in the Treatment of
Diabetes: Present Status and Future Prospects

Saima Amjad- Department of Zoology, University of Lucknow, Lucknow-226007, U.P., India

Email: saimaamjadlko@gmail.com

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Asif Jafri- Department of Zoology, University of Lucknow, Lucknow-226007, U.P., India
Email: asifjafri.jafri@rediffmail.com

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A K Sharma-Department of Zoology, University of Lucknow, Lucknow-226007, U.P., India
Email: draksharma57@gmail.com

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M Serajuddin-(Corresponding author) Department of Zoology, University of Lucknow,
Lucknow-226007, U.P., India
Email: lu.fisheries@gmail.com

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Highlights N
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 The review highlights traditional plants used in nanoform for the treatment of diabetes
and their mode of action
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 The development of nanoherbal medicine opened new vistas for the management of
diabetes.
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 The Nanoformulation of herbal drugs has enhanced the mode of action, bioavailability
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and effectiveness of herbal drugs to manage the diabetes.

 Herbal drug nanoformulation increase the possibilities to overcome the drawback of
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conventional management of glucose and to control the complications of diabetes like

delayed wound healing and the side effects of synthetic drugs.
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Abstract
It is now recognised that one of the most far reaching developments in the management of
diabetes (Diabetes mellitus) is the targeted delivery of herbal nanoparticles using nano-pumps,
smart cells, nanorobots, and nanotized herbal drugs (NHDs). The design, development and
targeted delivery of NHDs has now become a frontier research area. Previous research on nano-
herbal medicines such as the methanolic extract of Triphala churn nanoparticle, Costus pictus D.
Don (insulin plant) silver nanoparticles, and Talinum portulacifolium solid lipid nanoparticles
indicated the possibility of overcoming the drawbacks of conventional management of glucose
and controlling the complications of diabetes such as delayed wound healing and the side effects
of synthetic drugs. Curcumin loaded poly (caprolactone) nanofibers were also found to have
beneficial effects for treating diabetic ulcers; hence, the scientific data available to support the
exploration of various nanotized herbal drugs or phyto-constituents which are effective in
diabetes treatment and have wound healing capability. This paper focuses on the integration of
nanotechnology with herbal remedies for the effective management of diabetes.

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Abbreviations: DM, Diabetes mellitus; NHDs, Nanotized Herbal Drugs; T-SLN, Talinum
portulacifolium solid lipid nanoparticles; CUR, Curcumin; CSNPs, Chitosan nanoparticles; Qu-

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NP, quercetin-loaded PLGA nanoparticles; Qu-SLNs, Quercetin solid lipid nanoparticles; NEL,
Nano-emulsified ethanolic extracts of E. littorale; SLNs, Solid lipid nanosphere; PCL
Poly(caprolactone); Multiwalled carbon nanotube/dihydropyran, MWCNT/DHP; NPG,

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Nanoporous gold.

Keywords: Diabetes, Nanoparticle, Nanotized herbal drugs, Nanomedicine, Nanotechnology.

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1. Introduction
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Diabetes mellitus (DM) is a long lasting multifactorial metabolic disorder and remains one of the
most challenging unsolved health problems of the 21st century. Nanotechnology and nano-herbal
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medicine offer potentially more accurate and timely options for the diagnosis and treatment of
DM respectively. The development of nano-herbal medicine opened new vistas for the
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management of DM, because DM is a complex disease which demands multiple therapeutic

approaches. DM develops through two routes: the failure to secrete an adequate amount of
insulin by β-cells of the pancreas, or the failure of cells of the body to respond to insulin. The
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term "diabetes" was given by the Greek physician Apollonius of Memphis in the 3rd century
BCE and means “to pass through”, perhaps referring to the classic signs of increased frequency
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and volume of urination whereby DM was considered a curse in the ancient era. Sushruta and
Charaka classified DM into Type 1 and Type 2 for youth and obesity respectively in 400-500 CE
(Poretsky, 2009). The first complete clinical description was given by the physician Aretaeus of
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Cappadocia in 2nd century AD who reported the polyuria seen in this disease (Dallas, 2011). The
role of the pancreas in DM was reported by Joseph von Mering and Oskar Minkowski in 1889
who observed that dogs without a pancreas developed diabetic conditions and shortly died (Von
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and Minkowski, 1890). Insulin deficiency by the pancreas in DM was reported by Sir Edward
Albert Sharpey Schafer (1910). Banting, Best and Collip of Toronto University isolated insulin
hormone from bovine pancreas. An effective treatment was developed using insulin by
Canadians Charles Best and Frederick Banting in the year 1921 and 1922 respectively (Poretsky,
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2009). Insulin injections are given to diabetic patients in cases of the total lack of secretion of
insulin. The Biotech Company “Genentech” of the United State developed the biosynthetic
human insulin in 1980 from genetically altered bacteria.

Currently many drugs such as acarbose, miglitol and voglibose are used where cells are insulin
resistant. The drugs reduce glucose absorption by disturbing carbohydrate metabolism.
Biguanides, such as metformin, are used to enhance glucose uptake by peripheral cells.
Sulphonylureas like glibenclamide are insulinotropic and work as secretagogues for pancreatic
cells (Modak et al., 2007). The details of mode of the actions of drugs for DM are given in
Figure 1. Several side effects such as insulin resistance (a situation in which cells are ineffective
in their utilization of insulin occasionally combined with an absolute insulin inadequacy) brain
atrophy, anorexia nervosa and fatty liver were reported for patients on lifelong medication with
insulin therapy and allopathic diabetic drugs (Thiyagarajan et al., 2016; WHO Diabetes Fact
sheet, 2014). The complications resulting from uncontrolled DM are ketoacidosis and nonketotic

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hyperosmolar coma which may cause cardiovascular disease, kidney failure, foot ulcers and
damage to the retina of the eyes (Kitabchi et al., 2009). Increased levels of blood glucose lead to
increased levels of lipids, which contribute to cardiovascular disorders (Bindu et al., 2014).

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Currently, more than 415 million people are suffering from DM and the numbers are expected to
reach about 642 million by 2040 (IDF Update, 2015). Due to the side effects of conventional
drugs, attention is now being focused on development of nano-sized-herbal drugs and their

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precise and targeted delivery, which may help to overcome the limitations and complications of
conventional drugs used to control DM (Rahiman and Tantry, 2012). The prospects of nano
formulations of herbal medicines include “smart drugs” which only activate when needed,
engineered “nanotools” to produce human hormones and “nanorobots” to screen the body

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through blood capillaries (Nantechnology for Diabetes Treatment, 2013). Therefore, an attempt
was made to provide a brief overview on nanotized herbal drugs (NHDs) and their delivery in the
management of DM. N
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The National Nanotechnology Initiative defines nanotechnology as the manipulation of matters
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to develop devices and dosage forms with at least one dimension in the size range of 1 to 100
nm. Nanotechnology can be used for the diagnosis and monitoring of disease and treatment
through targeted delivery of drugs. The efficacy and absorption of some herbal drugs are
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considered to be low and could be increased through their nanoformulation and by incorporating
nano-carriers. Nanoforms of herbal drugs are used to overcome the drawbacks of herbal drugs
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such as poor solubility, poor permeability through the intestine, rapid removal following oral
administration and first past-pass metabolism before reaching the blood circulation (Shah et al.,
2009). Nanocarriers used for herbal drug delivery include carbon nanotubes, polymeric
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nanoparticles, dendrimers, polymer conjugate, gold nanoparticle and lipid base nanocarriers
which increase the effective herbal drug delivery for the therapy of various diseases.
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2. Materials and Methods

The authors reviewed the research works or articles in English on nanotized herbal drugs and
their delivery in the treatment of DM for a period of 126 years from 1890 to 2016 using a
number of electronic databases namely Science Direct, Elsevier, Pubmed, Google Scholar and
Springer. Patents and abstracts of symposia, conferences and congress were excluded because
they contained insufficient information. A survey of the literature was conducted using various
key words such as diabetes, conventional drugs for diabetes, nanoformulation of herbal drug,
herbal drug used in diabetes, nanocarriers and nanodevices. 9 studies were included which were
based on traditionally antidiabetic plants that were used in nanotized form along with their
possible mode of action. Discussion of some previous studies was undertaken, to understand how
the nanotized forms of herbal drugs are different from the extracts of herbal drugs in their mode
of action. Efforts were also made to increase understanding of integration of the herbal drugs
with their mode of action in both extract and nanotized forms using nano tools. Most of the
available scientific data confirmed the antidiabetic activity of traditionally used plants in

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nanoform, which included systematic studies on their efficacy, stability, toxicity and safety. The
data relating to nano carriers and nano devices used in insulin management were also discussed.
The details of the evaluated studies are summarized in Table 2.

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3. Diabetes Treatment through Natural and Synthetic Drugs
The World Health Organization has listed approximately 21,000 plants universally for medicinal

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purposes. Among these, 2500 species are found in India and of those 150 species are utilized
commercially on a large scale for the management of glucose levels in DM. India is known as
the botanical garden of the world because it produces the largest number of medicinal herbs
(Seth and Sharma, 2004). The different medicinal plants were found to have varying levels of

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hypoglycaemic and antihyperglycaemic actions in diabetic conditions. A list of antidiabetic
plants is given in Table 1.
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In ancient times, plant derived products with hypoglycaemic properties were used as folk
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remedies around the world (Yeh et al., 2003). DM and its secondary complications continued to
be a health problem in spite of the introduction of hypoglycaemic drugs from natural and other
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sources (Ravi et al., 2005). More than 1200 plants are being utilized around the world for the
control of DM and out of this only 30% of the antidiabetic plants were chemically and
pharmacologically investigated (Alarcon-Aguilar et al., 2002). A total of 800 anti-diabetic Indian
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plants were identified and reported by ethnobotanical investigations (Gupta, 1986).

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Diet control, conventional medicines and physical exercise have been recommended for the
management of DM. Insulin injection and hypoglycemic drugs such as sulphonylureas are used
for the control of type 1 and type 2 diabetes respectively. The sulphonylureas enhance insulin
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release from the pancreas through blocking ATP-sensitive potassium channels. The mode of
action of sulphonylureas is shown in Figure 2. The sulphonylureas drugs alone were found to be
ineffective for the management of blood glucose levels in 10% of diabetic patients. The
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biguanides decrease insulin production through decreasing gluconeogenesis by the liver and
delaying the absorption of carbohydrates from the gastrointestinal tract (alpha-glucosidase
inhibitors), while thizaolidinediones enhance insulin reactivity by increasing the sensitivity of
muscles and other tissues to insulin. Metiglinides α-glucodase is an inhibitor, similar to acarbose,
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which reduces glucose absorption from the intestine (Jarald et al., 2008). DM treatments using
synthetic drugs are considered to be expensive and have side effects, for example sulfonylurea
drugs may cause abdominal upset, hypersensitivity and headache with prolonged use. Some DM
experts reported that sulfonylureas should be avoided because they speed up the breakdown of β-
cells from the pancreas (Maedler et al., 2005) while metformin may cause diarrhoea, indigestion,
headache, nausea, weakness, gas and abdominal discomfort. The side effects of
thiazolidinediones are mild anaemia, headache, upper respiratory infections and sinusitis and
retention of fluid in the body which may be responsible for muscular pain and heart failure (De
Fronzo, 1999; Dey et al., 2002; Kane et al., 2005). Nanotechnology can improve drug delivery,
particularly to those areas where conditions are unfavorable. Nanotools and nanoparticles are
being explored as carriers for oral insulin formulations (Yadav et al., 2011; Roy and Barik, 2001;
Parashar et al., 2009).

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4.1. Nanotized Herbal Drugs (NHD’s) in Diabetes
Nanotechnology has offered some new forms of medication by developing targeted drug delivery
and increasing the efficacy of drugs and herbal medicines in nanotized form. A survey of the

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literature showed that NHDs have great promise in improving the treatment and management of
many diseases including DM. Some NHDs effective in DM treatment are mentioned below:

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4.1.1. Methanolic extract of Triphala churn nanoparticle
Triphala (mixture of three equal parts of herbs: Amalaki (Emblica
officinalis), Bibhitaki (Terminalia bellirica), and Haritaki (Terminalia chebula) is a traditional
herbal drug with powerful antioxidant properties, recommended for hepatitis, DM, Alzheimer’s

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disease and other inflammatory conditions (Shreedhara et al., 2014). Biologically, triphala
churna was reported as a free radical scavenger (Naik et al., 2005), radioprotective (Jagetia et al.,
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2002), antimutagenic (Kaur et al., 2002) and anticancer (Deep et al., 2007; Sandhya and Mishra
2006). Shreedhara et al. (2014) reported that the methanolic extract of triphala churn
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nanoparticle synthesized by modified solvent evaporation method using 1:3 drug polymer ratios
gave enhanced therapeutic efficacy as compared to triphala extract or triphala churn taken in
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high dose with low solubility.

4.1.2. Talinum portulacifolium (flameflower) solid lipid nanoparticles (T-SLN)

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Talinum portulacifolium Forssk. (flameflower) is the oldest herbal remedy cultivated in tropical
Africa and India for food and medicinal purposes (Ruffo et al., 2002). The methanolic extract of
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Talinum portulacifolium Forssk was shown to help in reducing blood glucose levels and serum
lipids and to decrease elevated nalondialdehyde levels but also to significantly increase the
glutathione (GSH) level. GSH levels act as a marker for detoxification, antioxidant enzymatic
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activity and protection against free radicals mediated cell death (Lu, 1999; Mandal et al., 2007).
Bindu et al. (2014) found in their research that T-SLN gave a better antidiabetic effect in
comparison to crude Talinum portulacifolium and found it highly effective in the management of
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DM complications, through prevention of defects in lipid metabolism, because increased levels

of blood glucose in turn increased lipids and raised hyperlipidaemia resulting in cardiovascular
disorders. The phytoconstituents flavonoids and tannins are present in the plant extract which are
known to possess anti hyperglycemic and hypolipidemic activity (Higdon et al., 2009).
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4.1.3. Catharanthus roseus (Rosy periwinkle) chitosan Nanoparticles

Catharanthus roseus, commonly known as the Madagascan periwinkle, rosy
periwinkle or teresita belongs to the family Apocynaceae. The fresh leaf juice of C. roseus Linn.
was found to be hypoglycaemic as reported by Nammi et al. (2003) in normal and alloxan
diabetic rabbits (Nammi et al., 2003). Barkat and Mujeeb (2013) reported the effects of C. roseus
var. alba extract loaded chitosan based nanoparticles on alloxan induced diabetic rats which
showed antidiabetic effects and antioxidant action at lower dose. The nanoformulation of C.
roseus var.alba extract loaded chitosan was also able to partly regenerate or preserve pancreatic
β-cell from alloxan-induced DM as compared to the higher dose of methanolic extract. Some
previous studies also reported that C. roseus flowers have wound healing properties along with
antimicrobial activity in Sprague Dawley rats (Nayak and Pereira, 2006)

4.1.4. Costus pictus D. Don (Insulin plant) silver nanoparticles (MECPAgNPs)

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Costus pictus D. Don (Insulin plant) is commonly known as spiral ginger, which provides an
effective treatment for DM. The leaves of this plant have a hypoglycemic effect that helps to
maintain insulin levels in the human body (Jose and Reddy, 2010; Modak et al., 2007). Many in

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vivo and in vitro researches showed very potent anti-diabetic effects of C. pictus (Jayasri et al.,
2008; Gireesh et al., 2009; Jothivel et al., 2007; Sethumathi et al., 2009; Mani et al., 2010;
Pareek et al., 2010; Al-Romaiyan et al., 2010). Methanolic leaf extracts of Costus pictus D. Don

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silver nanoparticles (MECPAgNPs) inhibits a significant α-glucosidase inhibition mechanism as
compared to acarbose (standard drug), used for the treatment of DM. The α-glucosidase
inhibitors are oral antidiabetic drugs that prevent or delay the breakdown of polysaccharide to
glucose (Aruna et al., 2014).

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4.1.5. Curcumin loaded Chitosan Nanoparticles and Nanofiber
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Curcumin (CUR) is commonly used as an anti-inflammatory, anti-infectious and antioxidant
agent that helps in wound healing particularly in diabetic patients (Kant et al., 2014). A soluble
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formulation with sustained release properties is desired for CUR because of its poor
bioavailability and stability for clinical application (Sharma et al., 2005). Archana et al. (2016)
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incorporated CUR into chitosan (CS, a naturally derived polymer) nanoparticles (CSNPs) to
improve stability and controlled release in wound healing of DM and found that the CSNPs
inhibited the fast clearance of CUR from the site of inflammation (Archana et al., 2016).
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Karri et al. (2016) evaluated the wound healing efficiency of CUR loaded CSNPs with fabricated
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and incorporated collagen-alginate scaffolds and reported a reduced inflammation rate with
increasing rate of healing of diabetic wounds, due to tissue regeneration. The nanohybrid
scaffold possesses porous morphology with good biodegradability and biocompatibility
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properties. Topical application of nanohybrid scaffold accelerated cutaneous wound healing by

decreasing inflammation. Future studies should also include the potential of nanohybrid scaffold
against various microorganisms present in diabetic foot infections since infections are major
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causes of amputations in patients with diabetic wounds (Karri et al., 2016).

4.1.6. Ethanolic extracts of nano-emulsified Enicostemma littorale (Indian Gentian)

Enicostemma littorale Blume (Indian Gentian) is a traditional medicine used in Gujarat (India)
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by rural people. This herb has anti-inflammatory (Sadique et al., 1987) and anti-cancerous
properties (Kavimani and Manisenthlkumar, 2000). E. littorale showed a hypoglycemic effect on
alloxan-induced diabetic rats (Vijayvargia et al., 2000).Investigations of nano-emulsified
ethanolic extracts of E. littorale (NEL) were carried out for antidiabetic activity and found to be
100 times more effective than the oral dose of E. littorale nanocapsules in the management of
DM (Deepa et al., 2012). Nanoemulsification is advantageous because the targeted drug
contained in the inner phase of the NEL avoids direct contact with the body and tissue fluids
and so is delivered in a more sustained manner for a longer period (Friberg et al., 2004), as two
immiscible liquids dispersed as small spherical droplets into each other (Van der et al., 2005).

4.1.7. Syzygium cumini Seeds Nanoparticle

Syzygium cumini (L.) Skeels is an evergreen tropical tree of the Myrtaceae family which is
commonly known as jambolan, black plum, java plum, Indian blackberry, Portuguese plum,
Malabar plum, purple plum, Jamaica and damson plum. The seeds of the plant are used to

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control DM because of the high content of phenolic and flavonoid compounds (Ayyanar et al.,
2013). DM mediated changes in immune status may render patients more prone to infections
such as those caused by fungi (Delamaire et al., 1997; Sun et al., 2012; Fraga-Silva et al., 2015).

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Investigation of the antioxidant and antifungal activities of polymeric nanoparticles containing
aqueous extract of Syzygium cumini seeds (NPASc) was carried out by Bitencourt et al. (2016)
and found effective against fungi such as Candida guilliermondii and Candida haemulonii.

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4.1.8. Quercetin Nanoformulation
Quercetin is categorized as a flavonol, and found in many plant products used to supplement
beverages or foods as an ingredient (Gregory and Kelly, 2011). Quercetin has many medicinal

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properties but studies showed the oral bioavailability of quercetin is <17% in rats and <2% in
humans, limiting its clinical application in conventional dosage (Li et al., 2009, Gao et al., 2011).
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Several studies reported that quercetin has the potential to protect the β cell from degeneration
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and stimulates the ductal stem cells to regenerate and differentiate into pancreatic islets cells
(Rifaai et al., 2012). In in vitro studies, the poly-d,l-lactide (PLA) nanoparticles (size of 250 nm)
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with 40% encapsulation of quercetin showed a maximum level of intestinal absorption of

quercetin. Moreover, quercetin encapsulated PLA nanoparticles utilized for effective oral
quercetin administration, improved cellular uptake with suitable persistence in the systematic
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circulation (Kumari et al., 2011, 2012).

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In summary, herbal nanoformulations were found to increase solubility, stability, biological

availability, and pharmacological activity that reached to the targeted cell without physical and
chemical degradation (Ajazuddin and Saraf, 2010). Table 2 shows a summary of some NHDs
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and their modes of action.

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4.2. Nanotechnology in diabetes treatment

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4.2.1. Solid lipid Nanospheres

Medicinal plant products used for the management of DM, may remain unproven on their
potency and availability to the targeted organs. The availability, stability, quality and potency of
plant products can potentially be increased with the use of solid lipid nanosphere (SLNs) through
sustained targeted drug delivery and by preventing labile compounds from degradation by
digestive enzymes (Zhu et al., 2009). Efforts were made by many scientists to achieve
nanosphere drug delivery in colon and breast cancer treatments (Ogawara et al., 2009). Li et al.
(2009) also synthesized Qu-SLNs to increase the bioavailability of quercetin herbal drugs.

4.2.2. Gene delivery by Nanoliposomes

Transfer of genetic material by nano-vehicles gives a new possibility for treatment of various
incurable genetic disorders such as DM, cystic fibrosis and α-1 antitrypsin deficiency, caused by
the absence of enzymes due to missing or defective genes (Davis and Cooper, 2007). Gene
therapy may be replaced or supported by carrier systems for the treatment of genetic disorders

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and other diseases such as cancer metastases, heart disease and neurological diseases (Alex and
Sharma, 2013). Nanoliposomes can be used to deliver genetic materials into cells of the target
organ. The DNA pieces are encapsulated inside the nanoliposomes on DNA fragments, which

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can adhere to the cell membrane to transfer DNA into the cell and to the nucleus. The details of
the mechanism are shown in Figure 3. The nanomaterials which are used as a carrier must be
soluble, safe, biocompatible bio-available, minimally incursive and minimally toxic and not

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block the blood vessel so that it can reach the specific diseased tissue in a safe concentration
(Webster et al., 2013).

4.3. Insulin management and detection of blood sugar by Nanodevices:

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Nanotechnology also plays a major role in the rapid detection of the amount of insulin and blood
sugar level by the following nanotools:

4.3.1. Nanopores
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The size of nanopores is 20 nm in diameter. The shape and design of the nanopores are based on
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biological cell membrane physiology and processes (Duan et al., 2013). Biological cells
communicate chemically and electronically with the extracellular world through ion channels
which are found to be on the surface of the cell membrane. Ion channels implement the
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physiological activities in the cell during life processes by controlling the ions flow across the
cell membrane (Tsien, 1983). Similarly, nanopores equipped with biological or synthetic
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molecules can provide a highly organized means of controlling ionic or molecular transport in
response to pH (Xia et al., 2008; Zhang et al., 2013), light (Liu et al., 2004) and temperature
(Guo et al., 2010). Nanopores consist of wafers with high density pores like cell membranes,
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which work as gating channels and allow biomolecules such as insulin, glucose, oxygen to pass
through. Nanopores can be used as a vehicle to transplant tissues (Freitas, 2005) such as β-cells
of the pancreas, which can be trapped inside the nanopore device and implanted in the recipient’s
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body. Whenever the body needs to balance glucose, it secretes insulin from the pancreatic β-
cells. Nanopores provide protection to the transplanted cells against the different type of
scavenging bodies inside the cell. It is also helpful in overcoming the drawbacks of insulin drugs
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and injections (Yadav et al., 2011). Terminalia chebula’s dried fruits and its aqueous extract
have been used for the treatment of DM in the Ayurvedic system of medicine (Rai, 1980; John,
2001; Murali et al., 2004) ). Chakraborty et al, (2012) synthesized T. chebula extract and
entrapped it in nanoporous silica gel for the treatment of DM.

4.3.2. Nanoporous Electrode

Nanoporous gold (NPG) electrode is used for the detection of non-enzymatic glucose
electrochemicals. The free-standing NPG films showed a strong and sensitive current in response
to glucose. The impact of NPG pore sizes, detecting potentials and chloride ions on glucose
oxidation were systematically studied. The highest sensitivity of NPG was obtained from film
which has the smallest pore size and possesses the largest active surface area. Moreover, the
NPG electrodes can effectively evade interference from the oxidation of common organic
interferents in body liquids. NPG make promising electrodes for applications in electrochemical
biosensors due to high sensitivity and selectivity (Chen et al., 2011).

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4.3.3. Carbon Nanotube Biosensor (Microphysiometer)
The carbon nanotube biosensor technique measures insulin production in regular time intervals,

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by collecting small samples and detecting their insulin levels and insulin concentration. Snider et
al. developed a multiwalled carbon nanotube/dihydropyran (MWCNT/DHP) composite sensor in
2008 for the electrochemical detection of insulin in a microfluidic device. The MWCNT/DHP

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sensor film was able to detect insulin concentrations as low as 1µM in the multianalyte
microphysiometer during calibration experiments. The MWCNT/DHP composite sensor has
been successfully used for the direct detection of insulin secreted by islets in the
microphysiometer (Snider et al., 2008). Different types of glucometer are used for the detection

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of blood glucose, but pricking the finger daily is quite painful and detection of many hyper and
hypoglycemia conditions may be missed. Therefore, several studies focused on developing such
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types of microtype biosensor which could be transplanted inside the human body and give a
continuous reading of blood glucose levels (Jia et al., 2008).
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4.3.4. Nanorobot and Smart Cells

Worldwide efforts are being made by scientists to design a nanorobot or nano-artificial pancreas
with a glucosensor that detects sugar level and insulin chamber in order to supply insulin in
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hyperglycemic conditions (Freitas, 2006). Efforts are being made by researchers to imitate the
function of β-cells as these insulin secreting cells do not function correctly in DM patients and
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insulin injections provide a painful and often imperfect alternative. Transplants of normal β-cells
risk rejection or side effects from immuno-suppressive therapies. At present, researchers have
devised another option, natural β-cells filled in a synthetic patch that can secrete insulin to
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control blood sugar levels on requirement with no risk of inducing hypoglycemia (Ye et al.,
2016). In 1998, Desai et al., and Ferrari collaborated to create one of the earliest therapeutically
useful nanomedical devices which was applicable to DM care. It consisted of a nano, bio-
compatible silicon box composed of micromachined nanopores measuring 20 nm in diameter.
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The internal structure had been assembled to hold healthy pancreatic β -cells to replace those not
functioning properly in the host organism. To conquer the rejection of foreign material by the
body, Ferrari constructed a nanotechnological membrane placed between the transplanting cells
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and the host organism (Desai et al, 1998).

Smart-cell technology is another development in the management of DM where glucose attacks
the smart cell in hyperglycaemia by eating away its insulin-containing structure. The damage to
the cell membrane structure disintegrates the protein matrix to release insulin and normalize
blood glucose levels (Aaron, 2003).

4.3.5. Nanofibers
Nanofiber matrices are attracting attention for a variety of biomedical applications as they
closely mimic the diameter of collagen fibrils in the natural extracellular matrix (Laurencin and
Nair, 2008). The large surface area of the fiber matrix allows for increased interaction with the
tissue to serves as a substrate for the sustained delivery of bioactive molecules and to regulate
cellular functions during regeneration of tissue (Kumbar et al., 2008). Merrell et al. (2009)
developed curcumin loaded PCL (poly(caprolactone) nanofibers by the method of
electrospinning and found beneficial effects for treating diabetic wounds characterized by
persistent inflammation. The low concentration of curcumin released from the curcumin-loaded

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PCL nanofibres maintained the biological activity of curcumin and was found to be efficient in
accelerating the closure rate of punch wounds in STZ-diabetic mice compared with PCL
nanofibres (Merrell et al., 2009).

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4.3.6. Implantable Sensor, Smart Tatoo and Nanopump
Polyethylene glycol beads coated with fluorescent molecules are considered to be a very

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effective tool to monitor blood sugar levels in diabetic patient, where beads are injected under
the skin of the DM patient and remain inside the interstitial fluid to indicate glucose level by
generating a glow with fluorescent molecules, which can be seen on a tattoo placed on the arm
(Gordon and Sagman, 2003). Similarly, sensor microchips are also being developed to monitor

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blood glucose level continuously along with other parameters such as pulse rate and body
temperature (Heo and Takeuchi, 2013). The Nanopump is a powerful device for insulin delivery
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in the patient's body in an unchanging manner to balance the level of sugars in the blood. The
pumps can also be used to deliver small doses of NHDs to control the blood glucose level
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(Anhalt and Bohannon, 2010).
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5. Toxicity caused during Drug Delivery

Assessments of toxicity of herbal nanoparticles together with nanotools to deliver the herbal
D

medicines are at the infancy stage. Studies showed that many herbal-nanoparticles are
biodegradable in nature, normally decomposed and their waste products xcreted out (Yih and
TE

Wei, 2005) but studies on the side effects of nanoparticles are considered to be essential. It has
been suggested that herbal-nanomedicines have the potential to transform clinical medicine and
change the treatment of patients.
EP

Non-biodegradable nanoparticles are accumulated inside the liver and blood vessels after their
delivery, which risks inducing toxicity and can generate inflammatory responses (Hett, 2004;
Hampton, 2005). Sometimes nanoparticles have travelled up to the olfactory nerves, inside the
CC

brain and damaged the blood vessels of the brain (Oberdörster et al., 2004). Issues of toxicity and
side effects of nanomedicines were raised by representatives of government agencies of The
United States, Europe and Japan during a workshop held in the month of September 2010 hosted
by the European Medicines Agency in London (Kelly, 2010).
A

6. Conclusion
Herbal remedies are finding their place alongside modern medicine and nanotechnology. The
herbs are rich resources of phytoconstituents which were found to be useful for the management
of DM as well as wound healing. Plant derived drugs may be considered to be safe in their
traditional form, but when they come in nanoform or with nanocarriers may induce toxicity.
More studies are therefore needed to evaluate the potential side effects, mechanism and mode of
action of NHDs for anti-diabetic and insulin mimetic activities. The ongoing clinical studies of
NHDs have shown the potential to achieve therapeutic effects in controlling DM at a lesser dose.
The applications of nanotechnology in the formulation of nano-herbal drugs have shown promise
in addressing the challenges and improving the safety and efficacy of plant products for treating
DM.

Declaration of Interest

PT
The authors state no conflicts of interest

Acknowledgements

RI
The authors are thankful for Head, Department of Zoology for the facilities and administrative
support. The first author is also thankful to Department of Science and Technology (INSPIRE
Fellow Code-IF140412) for funding the scholarship.

SC
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Figure1. Diagrammatic representation of mode of actions of some diabetic drugs

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D
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Figure2. Mechanism of action of Sulphonylureas drug

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Figure3. Schematic representation of gene delivery
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 Table 1. List of commonly used herbs in India for Diabetes Treatment and their

mechanism of action.

Table 1. List of common herbs used in India for the treatment of diabetes and their
mechanism of action.

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Sr. Common Scientific Part of Active Mechanism of References

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No. Name Name components action
plant
used

SC
1. Aloevera Aloe Leaf Alloin and Stimulates Jafri et al.
barbadensis Barbaloin synthesis and/ or (2011)

U
release of insulin
from the β cells of
N the pancreatic
A
islets of
Langerhans and
M

also acts on
hepatic
gluconeogenesis/
D

glucogenolysis.
TE

2. Alpha-alpha Medicago Flower Phytoestroge Stimulates insulin Tripathi et

sativa n, release from
al. (2011)
EP

spinosterol pancreatic β cells.

3. Ashwagandha/ Withania Root and Flavonoids Decreases blood Udayakuma

CC

Indian ginseng leaf glucose levels and r et al.

Somnifera increases liver (2009)
glycogen.
A

4. Avaram Senna Cassia Flower Sennoside A It stimulates the Pari et al.

Auriculata and no. of islets and β (2002),
cells
Sennosede B Pari et al.
in the pancreas, it
 also (2007)

increases the
activity of hepatic

hexokinase, and

phosphofructokin

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ase enzymes,

and represses

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glucose-6-

phosphatase and

SC
fructose-l, 6-

bisphosphatase
enzymes.

U
5. Banana Musa Flower Flavonoids, Shows insulin- Pari et al.
sapientum N
Steroid like action. (2000)
A
and
M
Glycoside

6. Banyan tree Ficus Bark Leucodelphi Shows Nikhil et al.

bengalensis nidin and antihyperglycemi (2009)
D

Leucopelarg c, insulin-
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onidin releasing and

insulin-like
activity.
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7. Bhringraj Eclipta alba Leaf and Stigmasterol, Decreases the Ananthi et

activities of al. (2003)
Root a-
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terthienylmet glucose-6-
hanol, phosphatase and
A

Wedelolacto fructose-1,6-
ne, bisphosphatase.

Demethylwe
delolactone.
8. Bitter apple Citrullus Seed Myristic , Increases insulin Dallak et al.
Palmitic, release and (2009),
colocynthis Bashir et
Stearic, reduces plasma al.( 2009)
Oleic, glucose levels.
Linoleic and

Linolenic

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acid

9. Bitter melon Momordica Leaf Charantin, Increases β cell Savula et al.

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Sterol production in the (2012),
charantia pancreas or may Garau et al.

SC
encourage the (2003)
recovery of
partially

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destroyed cells. It
also stimulates
N insulin secretion
from the β cells.
A
10. Candy leaf Stevia Whole Rebaudioside It stimulates Jeppesen et
M

rebaudiana and insulin secretion

plant via the direct al. (2000),
Stevioside action on β cells Jeppesen et
D

of pancreatic al. (2002)

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islets.

11. Castor Ricinus Seed Ricinolic Increases insulin Rao et al.

communis acid levels and (2010)
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improves lipid
profile.
CC

12. Chirayata Swertia Whole Methyl Stimulates insulin Singh et al.

chirata swertianin release from the (2012)
plant islets of
A

and Langerhans.
bellidifolin

13. Coconut Cocos Fruit Neutral Increases intake Sindurani et

nucifera detergent of neutral al. (2000)
 fiber, fatty detergent fibers
acids, which cause a

Tannins, significant
Alkaloids reduction in
glycemic and
serum insulin
level.

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14. Coffee Coffea Seed Caffeine, Increases the Park et al.
Arabica Tannin number of

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pancreatic (2007)

β cells and

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stimulates the

release of insulin.

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15. Coriander Coriandrum Seed Coriandrol, Significantly Eidi et al.

Sativam
N
Coriendryl
increases the (2009),
Gray et al.
A
acetate, activity of the β (1999)
cells and insulin
M

Geraniol and release.

Pinene
D

16. Cumin Cuminum Seed Cuminaldehy Reduces blood Jagtap et al.

cyminum de, (2010)
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glucose,
Phellandrene, glycosylated

Hydrocumin hemoglobin,
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e creatinine, blood,

urea, nitrogen.
CC

17. Curry leaves Murraya Leaf Carbazole Shows Vinuthan et

koenigii alkaloids hypoglycemic al. (2004)
A

effect

coupled with
increased hepatic

glycogen content
 due to increased

glycogenesis and
decreased

glycogenolysis
and

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gluconeogenesis.

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SC
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N
A
M
D
TE
EP
CC
A
18. Custard apple, Annona Fruit Liriodenine, Promotes the Kaleem et
squamosa release of insulin al. (2008)
sugar apple Moupinamid from the
e pancreatic β cells,

Increases the

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utilization of
glucose in the
muscles

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and prevents the

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glucose output
from the liver.

19. Dhavanam Artemisia Leaf and Germacranol Increases Donga et al.

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pallens ide peripheral (2011)
flower glucose
N utilization or
A
inhibits the
reabsorption of
M

glucose in the
proximal tubule.
D

20. Fenugreek Trigonella Leaf and 4-hydroxy Stimulates the Ali et al.
foenum- isoleucine glucose induced (1995),
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Seed
graecum insulin release Abdel-Barry
from pancreatic et al.
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(1997),
β cells. Bawadi
CC

et al. (2009)

21. Garlic Allium Bulb Allyl propyl Regulates blood Thomson et

sativum glucose and lipids al. (2007)
A

disulphide, in serum as well

Allicin as in tissues and
alters the
activities of liver
hexokinase,
 glucose 6-

phosphatase and
HMG CoA

reductase.

22. Golden Aegle Leaf Marmelosin Increases either Arumugama

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marmelos the glucose , et al.
Apple (2008),
utilization or Yaheya et

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directly al. (2009)
stimulates insulin
release from

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pancreatic β cells.

23. Green tea Camellia Leaf Caffeine and Shows Islam et al.

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sinensis insulinotropic (2007)
Catechins activity and
N curative effects of
oxidative damage.
A
24. Heart-leaved Tinospora Root Tinosporone, Inhibits α- Gupta et al.
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moonseed glycosidase (2012)

cordifolia Tinosporic
acid activity.
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25. Hellebore Picrorrhiza Rhizome Picroside I Reduces serum Joy et al.

kurrao and II glucose levels (1999)
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along with anti-

oxidant activity.

26. Holy Basil Ocimum Whole Eugenol Reduces uronic Agrawal

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sanctum acid, total

plant cholesterol, et al.
(1996), Rai
A

triglyceride and et al. (1997)

total lipids which

indicate its
hypoglycemic
 and

hypolipidemic
effects.

27. Horehound Marrubium Aerial Flavonoids, Antihyperglycemi Elberry et

vulgare part Tannins, and c with al. (2015)
sterols and/or antidyslipidemic

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terpenoids effect

28. Indian Gentian Enicostemma Flower Gentianin , Induces insulin Rajamani et

RI
Tannins release through al. (2012),
littorale
K+-ATP channel Vishwakar

SC
dependent ma et al.
(2010)
pathway.

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29. Indian Gum Acacia Seed and Polyphenols, Induced Wadood et
arabica
bark N
Tannins
hypoglycemic
effect by
al. (1989),
A
Patil et al.
initiating release (2011)
M

of insulin from
pancreatic β cells.
D

30. Indian screw Helicteres Stem Phytosterol, Shows insulin- Kumar et al.
tree isora bark, sensitizing (2009)
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Saponins, activity.
root and
Sugars,
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seed phlobatannin
s

and Lignin
CC

α-amyrin, β-
amyrin,
A

Lupeol

31. Ivy Gourd Coccinia Leaf Resins, Inhibits the key Jose et al.
indica Starch, gluconeogenic (2010),
Deokate et
Glucose, enzyme glucose-
 Fatty acid 6-phosphatase. al. (2011)

and Carbonic
acid

32. Jamun Syzygium Fruit and Ellagic acid, Shows insulin Nahar et al.
cumini stimulatory (2010)
Leaf Polyphenols activity.

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34. Mango Mangifera Leaf Mangiferin Reduces the Aderibigbe

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indica intestinal et al.
absorption (1999),
Martinez et

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of glucose. al. (2000)

5. Marking Nut Salacia Root bark Salacinol Inhibitory activity Vasi et al.

U
Tree, Salacia reticulata against sucrose (2009)
and decreases the
N elevation of the
plasma glucose
A
level and
M

intestinal α-
glucosidase
D

activities in type
1 diabetes.
TE

36. Mustard Brassica Whole Isorhamnetin Glycogen Anand et al.

nigra (2009)
Plant diglucoside. Synthetase
EP

activity increases,
Isothiocynate
, Sinigrin glycogenolysis
CC

decreases and
gluconeogenesis
by reducing
A

the activity of
glycogen

phosphorylase
and
 gluconeogenic

enzymes.

37. Neem Azadirachta Leaf, Azadirachtin Regenerates the Khosla et al.

indica and pancreas β cells. (2000)
flower &
Nimbin
seed

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38. Nilgiri, Eucalyptus Leaf Cineole, Enhances Gray et al.
Pinene, peripheral (1998)

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Dinkum Globulas glucose
Camphene,
Citronella, uptake.

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Geranyl
acetate

U
39 Olive Oleo Fruit Olein, Potentiates Gonzalez et
europoea N
Palmmitin,
and
glucose-induced al. (1992)
A
insulin release
Linolein and increases
M

peripheral uptake
of glucose.
D

40. Onion Allium cepa Bulb Allyl propyl Activation of Ozougwu et

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insulin secretion al. (2011)

disulphide, and also increases
S- methyl HMG CoA
EP

cysteine reductase activity

and liver
Sulphoxide hexokinase
CC

activity.

41. Pomegranate Punica Fruit Punicalagin, Reduces blood Jafri et al.

A

granatum glucose, lipid (2000)

Punicalin
parameters and
oxidative stress.

42. Punarnava Boerhavia Whole Punarnavine Improves glucose Patel et al.

 diffusa Plant and tolerance. (2012)

ursolic acid

43. Saptrangi Casearia Root Flabetanin, Reduces blood Prakasam et

esculenta dulcitol, glucose levels and al. (2005)
the activities of
glycosaides glucose-6-

PT
tannin phosphatase and
fructose-1,6-
bisphosphatase

RI
and also increases
the activity of

SC
liver hexokinase.

44. Sikerpud Biophytum Whole Unknown Stimulates the Ananda et

U
synthesis/release al. (2012)
sensitivum Plant

N of insulin from
the β cells.
A
45. Soya Glycin max Bark 3-O-methyl- Directly acts on Liu et al.
M

D- pancreatic β cells, (2006)

chiroinositol that leads to the
activation of the
D

(D-pinitol), cAMP/PKA
signaling cascade
TE

Genestein,
Daidzein for insulin
release.
EP
CC

46. Sugar Gymnema Leaf Gymnemic Stimulates Shanmugas

destroyer sylvestre acid and pancreatic beta- undaram et
A

cell function,
Gymnema elevates the al. (1981)
saponins number of β cells
and insulin
release by
increasing cell
 permeability of
insulin.

47. Sweet potato Ipomoea Root Beta- Produces a Li et al.

batatas carotene, regranulation of (2009),
fiber Miyazaki et
pancreatic islet of al.

PT
Langerhans β
cells. (2005)

RI
48. Tartar root Panax Root Ginsenosides Stimulates insulin Vladimir et
ginseng , release and al. (2005),
Kim et

SC
Panaxosides decreases liver
glycogen levels. al. (2008)

U
49. Velvet bean Mucuna Shrub, l-dopa, Shows a direct Eze et al.
prureins Dopamine insulin-like action (2012),
flower,

and seed
N due to the
presence of trace
Akhtar et al.
(1990)
A
elements such as
Manganese and
M

zinc.

50. Vinca Catharanthu Leaf and Vincristein Stimulates insulin Ahmed et

D

s and release al. (2010)

Twing
TE

roseus Veinblastin from the β cells

and was also
found to be useful
EP

against the
damage caused by
oxygen free
CC

radicals.

51. White Morus alba Leaf Mulberoside Mulberry leaf Andallu et

A

, extract al. (2001),

mulberry significantly Sadako et
vitamins, reduces a rise in al. (2011),
fibers total blood Lown et al,
glucose levels, 2017
followed by a
 reduction in
serum cholesterol,
triglycerides, free
fatty acids, LDL-
and VLDL-
cholesterols, lipid
peroxides,

PT
erythrocyte
membrane lipids
and membrane

RI
lipid peroxidation

SC
U
N
A
M
D
TE
EP
CC
A
 Table 2. Summary and Characteristics of Nanotized Antidiabetic Herbal Drugs

Table.2. Summary and Characteristics of Nanotized Antidiabetic Herbal Medicines

S. No. Name of Herbs/ Nanoform Mode of Action Study outcome References

Phytochemicals

PT
1. Catharanthus Nanoparticles Hypoglycaemic, Antidiabetic and Barkat and
roseus partly regenerate Antioxidant Mujeeb (2013)

RI
or preserved
pancreatic β-cell

SC
2. Costus pictus D. Nanoparticles α-glucosidase Antidiabetic and Aruna et al.
Don inhibition Antioxidant (2014)
activity

U
3. Curcumin Nanoparticles Increasing the Anti-inflammatory, Kant et al.
infused
collagen-
into
healing
N
rate of wound Anti-infectious and
in Antioxidant
(2014), Karri et
al. (2016)
A
alginate diabetes as well
scaffolds as tissue
M

regeneration.

4. Enicostemma Nanocapsules Act as a Antidiabetic Deepa et al.

D

littorale Blume secretagogue(s) , (2012)

TE

work in
hyperglycemic
condition,
EP

release insulin

5. Talinum Solid lipid Reducing blood Antihyperglycemic Bindu et al.

CC

portulacifolium Nanoparticles glucose level, and antioxidant (2014), Babu et

serum lipids and activites al. (2009)
antioxidant
enzymes.
A

6. Triphala Churna Nanoparticles Immune system Anticancerous and The Ayurvedic

stimulation, antioxidant pharmacopoeia
improvement of committee,
digestion, relief (2003), Juss
 of constipation, (1997),
gastrointestinal Nadkarni (1976)
tract cleansing,
relief of gas
(carminative),
treatment
of diabetes,

PT
treatment of eye
disease
7. Syzygium cumini Polymeric Antifungal Antioxidant and Bitencourt et al.

RI
Seeds nanoparticles activity against Antifungal activity (2016)
containing fungi such as

SC
aqueous seed Candida
extract. guilliermondii
and Candida

U
haemulonii.
8. Quercetin Nanoparticles, Increased oral Antidiabetic Chitkara et al.
Solid N
lipid bioavailability,
Nanoparticles decrease blood
(2012), Li et al.
(2009)
A
glucose level
M
D
TE
EP
CC
A