12. CHAPTER II REVIEW OF LITERATURE -...
Transcript of 12. CHAPTER II REVIEW OF LITERATURE -...
Chapter II Literature Review
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2.0 Diabetes mellitus
Diabetes mellitus is a metabolic disease which, when not properly treated or
untreated is characterized by chronic hyperglycemia and disordered carbohydrate,
lipid and protein metabolism and is associated with the development of specific
microvascular complications and of non-specific macrovascular disease (Fowler,
2008). Diabetes is now ranked among one of the most common non-communicable
diseases in the world. Diabetes is a progressive condition initially characterized by
insulin resistance, where muscle and adipose tissue become relatively insensitive to
the effects of insulin. As the condition progresses, a decline in beta cell activity
results in relative insulin deficiency and blood glucose levels rise above normal
levels. (Hill, 2009). It is a systemic disease caused by an imbalance between insulin
supply and insulin demand in the body by pancreas.
2.1 Relationship between pancreas and diabetes
Pancreatic islets, also called islets of Langerhans, are tiny clusters of cells
scattered throughout the pancreas located behind the lower part of the stomach.
Pancreatic islets (Figure 1) contain beta cells, which produce the hormone insulin to
keep the supply and use of glucose in balance. Pancreatic cells in the islets of
Langerhans continuously monitor blood glucose levels in the body. cells in the
pancreas are the key players in glycemic homeostasis. Glucotoxicity, lipotoxicity,
endoplasmic reticulum (ER)/oxidative stress, inflammatory mediators, and incretins
were reported to modulate -cell function and survival (Leahy et al., 2010).
Pancreatic polypeptide secretion was absent in chronic pancreatitis without
endogenous insulin production. Sometimes pancreatic enzyme replacement therapy
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(PERT) may be carried out in patient with chronic diabetes. Any form of extensive
pancreatic damage may result in diabetes.
2.2 Classification of diabetes mellitus (Davidson’s, 1987, Smith, 1995 and
Kahn, 1995)
Based on etiology, there are three main categories of diabetes namely
1. Primary diabetes
2. Secondary diabetes
3. Gestational diabetes
2.2.1 Primary diabetes
Primary diabetes, in general, has been classified into two types, viz., insulin
– dependent (Type 1) and non -insulin dependent (Type 2). Type 1 diabetes
formerly called as “Juvenile onset diabetes/childhood diabetes”, generally caused by
destruction of insulin producing pancreatic beta-cell or decrease in the number of
beta cells, usually leading to absolute insulin deficiency, often occurs in children and
young adults. Type 1 diabetes people develop ketoacidosis due to insulin deficiency.
It is necessary to administer insulin exogenously.
The non-insulin-dependent type 2 DM (NIDDM) was previously called as
"adult onset diabetes/maturity-onset diabetes" (caused by aging, obesity, spiritual
stress, or other environmental factors and it may range from predominantly insulin
resistance with relative insulin deficiency to a predominantly secretory defect with
or without insulin resistance). Usually about 10 and 90% of all people with diabetes
accounts for type 1 and type 2 DM respectively.
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NIDDM is usually associated with normal -cell morphology and insulin
content. Type 2 diabetes mellitus has both genetic and environmental components
(Ezenwaka et al., 2004). It has been characterized as hepatic and peripheral (muscle
and adipose tissues) insulin resistance. Pancreas compensates by secreting more
insulin but eventually beta cells will fail to sustain this and during this stage patient
requires treatment (Cerasi, 2000). Type 2 diabetes affects many metabolic pathways
in different tissues and many of which are considered to be target for drug treatment.
Patient suffering from type 1 are therefore totally dependent on exogenous source of
insulin, whereas, patient suffering from type 2, are unable to respond to insulin and
can be treated by medications. According to Adiseshiah (2005), the high-prevalence
of type 2 diabetes resides with the age group of 45-64 years. The treatment system
for type 2 diabetes may involve lifestyle modifications, physical exercise or oral
medications (Hypoglycemic agents) or sometimes insulin injections.
2.2.2 Secondary diabetes
The factors considered for secondary diabetes includes, (i) genetic defects of
beta-cell function; (ii) genetic defects in insulin action; (iii) diseases of the exocrine
pancreas; Endocrinopathies; pancreatic dysfunction (iv) drug or chemical or
surgically induced diabetes; (v) infections like viral; (vi) uncommon forms of
immune-mediated diabetes; (vii) other genetic syndromes sometimes associated with
diabetes; (viii) diseases such as cystic fibrosis, exposure to certain drugs; (ix)
hormonal imbalances; (x) malnutirition and other unknown causes.
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2.2.3 Gestational diabetes
Other categories of diabetes include gestational diabetes (a state of
hyperglycemia which develops during pregnancy) (without previously known
diabetes) and usually (but not always) resolving within 6 weeks of delivery. Several
other diabetes subtypes beyond type 1 and 2 are Latent Autoimmune Diabetes of
Adulthood (LADA) or type 1.5 diabetes and Maturity Onset Diabetes of the Young
(MODY).
2.3 Causes
The causes of all type I diabetes include genetic factors, immunologic
factors, environmental factors and infectious agents. Age, obesity, stress, depression,
family history and ethnic group are the major cause associated with the development
of type 2 diabetes. The focus of the management and control of diabetes is
maintaining a healthy lifestyle by following the correct diet, exercising, and taking
medication as prescribed by the physician. Aspects, which are considered essential
to diabetic control, include urine and blood glucose self-monitoring, foot care, eye
care, attendance of diabetic clinics and counselling. Despite the efforts to control the
growing number of diabetes patients, yet, the number of adults with diabetes
worldwide is increasing rapidly. It is observed that human and economic costs of
diabetes are abnormally high. In every 10 seconds, diabetes causes one death and
one amputation in every 30 seconds. Despite oral administration of anti-diabetic
drugs and insulin injections, phytotherapy and metal based phytomedicine plays a
crucial role in the management of diabetes mellitus.
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2.4 Transition metal complexes in diabetes therapy
Many metal compounds play a vital role in living systems and found to elicit
potential effect in the pathogenesis and complication of the disease. The metal, its
oxidation state, the number and types of coordinated ligands, and the coordination
geometry of the complexes can provide a variety of properties. A characteristic of
metals is that they easily lose electrons to form positively charged ions, which tend
to be soluble in biological fluids. It is in this cationic form metals play their role in
biology. Metal ions are electron deficient, whereas, most biological molecules such
as proteins and DNA are electron rich. The attraction of these opposing charges
leads to a general tendency for metal ions to bind to and interact with biological
molecules and elicit pharmacological activity. These variables provide enormous
potential diversity for the design of metallodrugs (Pattan et al.,2012).
The transition metal ions are responsible for proper functioning of different
enzymes (Hariprasath et al.,2010). Chronic hyperglycemia may cause alterations in
the status of trace elements in the body and thus the essential trace elements such as
zinc, chromium and manganese are deficient in DM. Therefore, trace elements may
play an important functions for glucose and lipid metabolisms, particularly insulin
function in DM (Hiromura et al., 2008). The amount of metals present in the human
body is approximately 0.03% of the body weight ((http://www.who.int/
diabetes/publications/diagnosis_diabetes2006/en/ ) and Bharti et al., 2009).
Metal based drugs to treat diabetes with metal complexes are first studied by
Coulson and Dandona in the year 1980 and reported that ZnCl2 stimulate lipogenesis
in rat adipocytes similarly to the action of insulin (Tripathi et al., 2013). The idea of
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using metal ions for the treatment of diabetes originates from the report in 1899.
Vanadium, chromium, copper, cobalt, tungsten and zinc were found to be effective
for treating diabetes in experimental animals. The orally active metal complexes
containing vanadyl oxidovanadium (IV) ion and cysteine or other ligands were first
proposed in 1990 (Sakurai et al., 2010). Many metal complexes have been
synthesized and evaluated to overcome the problems of painful insulin injection and
the side effects for type 1 or type 2 DM. So far chromium, manganese,
molybdenum, copper, cobalt, zinc and vanadium ions have been reported to exhibit
insulin-mimetic or enhancing insulin like properties under in vitro and in vivo
condition (Bharti et al.,2009).
Metal compounds induce hypoglycemia by a wide variety of mechanisms.
Possible mechanisms of antidiabetic insulin-like effects are due to the activation of
insulin receptor signaling (chromium, magnesium), antioxidant properties (cobalt,
manganese, tungstate, zinc), inhibition of phosphatases (vanadium), stimulation of
glucose uptake, glycogen and lipid synthesis in muscle, adipose and hepatic tissues
and inhibition of gluconeogenesis (chromium, cobalt) or stimulation of the activities
of the gluconeogenic enzymes: phosphoenol pyruvate carboxykinase and glucose-6
phosphatase (manganese) (Bharti et al., 2009 and Wiernsperger et al., 2010).
Table 1 depicts the metal and the complexes to induce hypoglycemia in diabetic
patients (Sakurai et al., 2002).
VANADIUM
The human body is estimated to contain 50-200 g of vanadium. In each
organ, vanadium is present at very low concentrations, 0.01-1 g, and is thought to
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play a role in a wide variety of physiological processes. So far number of vanadium
complexes have been developed; most of them have insulin-mimetic properties
(Rafique et al., 2010).
In 1985, it was discovered that a simple vanadium salt, sodium
orthovanadate, when added to drinking water, could reverse most of the diabetic
symptomatology of experimentally-diabetic rats, was exceptionally enticing.
Vanadyl complexes with maltol (3-hydroxy-2-methyl-4-pyrone) and kojic acid (3-
hydroxy-2-hydroxymethyl-4-pyrone) which possess insulin mimetic activity and
low toxicity profile, have been proposed for clinical use inhumans.
Oxovanadium(IV) with maltol/ethylmaltol has shown enhancing insulin mimetic
activity in experimental diabetic animals in recent years (Bharti et al., 2009). Since
1990, a wide class of vanadyl oxidovanadium (IV) complexes involving
bis(methylcysteinato) [VO(cysm) 2]- (1990), bis(L-tartrato) [(V2O4)(L-tart)2]-
(1990), bis(maltolato) [VO(ma)2]- (1992), bis(pyrrolidine-N-dithiocarbamato)
[VO(pdc)2]- (1994), bis(picolinato) [VO(pa)2]- (1995), and bis(1-oxy-2-
pyridinethiolato) [VO(opt)2]- (1999) have been found to improve the hyperglycemic
state in streptozotocin induced diabetes in rats (STZ-rats). In particular, studies on
VO(pa)2 with a VO(N2O2) coordination environment and bis(3-hydroxy-4-pyronato)
[VO(3hp)2]-, bis(1,4-dihydro-2-methyl-4-oxo-3-pyridinolato)- and bis(1,2-dihydro-
2-oxo-1 pyrimidinolato) oxidovanadium (IV) complexes with a VO(O4)
coordination environment have been intensively performed to find more potent
analogues than the parent complexes, leading to the discovery of the linear
relationship between in vitro insulin-mimetic activity and the partition coefficient of
these complexes (Sakurai et al., 2010).
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The discovery that modification of the vanadium core by chelation could
improve biodistribution and tolerability was found to be a crucial step in
development of vanadium compounds for treatment of diabetes. Bis(maltolato)
oxovanadium(IV) or BMOV is the first vanadium complexes shown superior
activity over other inorganic vanadium sources (e.g. VOSO4 or NaVO3) both in vivo
and/or in vitro studies (Bharti et al.,2009 and Thompson et al.,2006 ) (Figure 2)
Earlier reports have shown that VV-dipicolinato complex has more insulin
enhancing effect compared to BMOV. New orally active -diketonato complexes
such as VO(acac)2 and bis( -furancarboxylato) oxovanadium (IV) have shown
glucose lowering ability comparable to BMOV and possess high water solubility
and less toxicity, when orally administered in diabetic rats. Vanadium complex,
bis(pyridine-2-carboxylato) oxovanadium(IV) [VO(pic)2] has shown higher insulin-
mimetic activity than VOSO4 (Bharti et al.,2009 ).
ZINC
Zinc, an essential trace element is an activator for more than three hundred
enzymes in the body (Haase et al. 2008) and plays a major role in various metabolic
pathways including glucose metabolism. The antidiabetic activity of zinc is
currently thought to be its important role. In fact, zinc and diabetes interact at
several points during metabolism in a cell. In the relevance of zinc to diabetes
mellitus, zinc is known to be present in insulin, coordinated by three nitrogen atoms
from histidines and three water molecules in an irregular octahedral environment,
which is also believed to have a functional structure. Zinc is also known to keep the
structure of insulin (Sun et al., 2009), and has a role in insulin biosynthesis, storage
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and secretion (Chausmer et al.,1998). There are several zinc transporters in
pancreatic cells (Smidt et al., 2009); like zinc transporter which has a potent role
in insulin secretion (Rungby et al., 2010). Zinc promotes hepatic glycogenesis
through its actions on the insulin pathways and thus improves glucose utilization.
Surprisingly, zinc was found to have important physiological and pharmacological
functions involving an insulin-mimetic activity. Diabetes is usually accompanied by
zincuria. Higher zinc intake has also been associated with a slightly lower risk of
type 2 diabetes in women (Rafique et al.,2010). For diabetes mellitus with an
increased risk of zinc deficiency, more important clinical data would be needed
because zinc has an insulin-mimetic effect and protects against oxidative damage
associated with the disease (Yoshikawa et al.,2012).
Upon oral administration of Zinc(II) complexes containing bis(6-
methylpicolinato) [Zn(6mpa)2], bis(maltolato) [Zn(ma)2], bis(1-oxy-2-pyridonato)
[Zn(opd)2]-, and bis(1-oxy-2-pyridinethiolato) [Zn(opt)2], it has been found to
exhibit anti-diabetic activity and ameliorate hyper insulinemia and massive
hereditary obesity in experimental studies on mice. In addition, structure–activity
relationships on zinc complexes with dithiocarbamates and pyridine-2-sulfonates
made to create new potential zinc complexes such as bis(pyrrolidine-N-
dithiocarbamato) Zn [Zn(pdc)2] and bis(3-methylpyridine-2- sulfonato)Zn,
respectively under in vitro insulin mimetic activity. Oral administration of Zn(3hp)2-
related complexes with a Zn(O4) coordination environment helped to induce high
quality anti-diabetic properties and also a few complexes exhibited not only anti-
diabetic activity, but also anti-metabolic syndrome activity in respect to
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hypoglycemic effect and adiponectin secretion enhancing effect, when it was given
to Streptozotocin induced rats by daily intraperitoneal injections(Bharti et al.,2009 ).
Zinc seems to exert insulin-like effects by affecting the insulin signaling
pathway at several levels, inducing phosphorylation of the subunit of the insulin
receptor as well as of Akt and leading to inhibition of GSK-3 probably as a
consequence of Akt phosphorylation and by reducing the production of cytokines,
which lead to beta-cell death during the inflammatory process in the pancreas. Zinc
supplementation produced a significant improvement in glucose disposal (Pandey et
al., 2012).
COPPER
Copper (Cu) is an essential metallo element that is required for a variety of
molecules to maintain the normal structures and functions and for cells to live, grow
and proliferate. Copper is found in the liver, gallbladder, lungs and heart and is
needed for synthesis of hemoglobin, proper iron metabolism and maintenance of
blood vessels (Siva et al., 2013). Copper plays an important role in electron transfer
reactions (Pandey et al., 2012). Copper complexes have different pharmacological
actions such as antiulcer, anticonvulsant, anticancer, and antidiabetic activity
(Sorenson et al., 1989). Yasumatsu et al. (2007) proposed that copper (II)-picolinate
[Cu (Pic) 2] may be a potent alternative antidiabetic agent and Cu (Pic)2 complexes
by single intraperitoneal injection, exhibited a higher hypoglycemic effect on
treatment with STZ induced diabetic mice.
Copper ions are also involved in the pathogenesis of type II diabetes and
copper chelating agent exerts a beneficial effect in the treatment of type II diabetes.
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The treatment with copper chelating agent tetrathiomolybdate decreased both serum
copper ion and ROS levels and consequently ameliorate glucose and lipid
metabolism in diabetic mice (Barthel et al., 2007). Treatment with copper sulfate can
exert beneficial effects in diabetes with preservation of -cell function by reducing
free radicals or through reduction in glucose levels (Tanaka et al., 2008).
CHROMIUM
Chromium is an essential element required for normal carbohydrate and lipid
metabolism. Chromium, Cr (III) the most stable oxidation state, is considered as an
essential micronutrient for humans by many nutritionists. In 1950s, Schwarz and
Mertz conducted experiments on nutrient-deficient rats and suggested that a
biological Cr (III) compound could act as a nutritional enhancement to glucose
metabolism. The Cr (III) complexes with propionate, L-histidinate, D-
phenylalaninato and nicotinato (niacinato or 3- pyridinecarboxylato) ligands as well
as Cr (III)- enriched yeast have been proposed as safer antidiabetics (Pandey et al.,
2012). Chromium supplementation significantly improves glycemia among patients
with diabetes, but do not show any significant effect on glucose metabolism in
healthy subjects (Balk et al., 2007). Chromium picolinate (CrPic) may have a
possible antidiabetic effect in insulin-resistant 3T3-L1 adipocytes through the
involvement of p38 Mitogen-activated protein kinase (MAPK). Treatment with
Chromium picolinate (CrPic) could partially reduce hyperglycemia and insulin-
induced insulin resistance (Horvath et al.,2008).
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COBALT
Cobalt is one of the most important trace elements and has therapeutic value
in pharmacological doses. In the form of vitamin B12 (Cobalamin), this metal plays
a number of crucial roles in many biological functions. Vitamin B12 is the only
metal-containing water-soluble vitamin that is stored in the liver and must come
from the diet. Cobalamin is necessary for DNA synthesis, formation of red blood
cells, maintenance of the nervous system, growth and development of children.
Cobalt was found to boost the effects of insulin and its action. Cobalt chloride
(CoCl2) works by augmentation of GLUT-1 gene expression and found to decreases
the glycemia of diabetic rats. Treatment of STZ diabetic rats with cobalt chloride
showed significant decline in blood glucose, no effect on plasma insulin and
significant increase in liver glycogen showing no effect on muscle glycogen. Since
cobalt is toxic to patients in its single and pure form various cobalt complexes has
been suggested, which could reduce the potential toxicity of cobalt without
impacting on its effectiveness (Pandey et al., 2012). Glucosaminic acid-cobalt
chelate has been reported to be effective as an antidiabetic agent (Talba et al., 2011).
Cobalt therapy may prove effective in improving the impaired antioxidant status
during the early state of diabetes and ascorbic acid supplementation at this dose
potentiates the effectiveness of cobalt action (Yildirim et al.,2003 and 2009).
TUNGSTEN
The antidiabetic properties of sodium tungstate have been widely reported.
Sodium tungstate has shown a remarkable normoglycemic effect in several animal
models of diabetes and found to be low toxic in diabetic and healthy animals
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(Muñoz et al., 2001 and Ballester et al., 2007). Administration of this metal
enhances the insulin activity rather than increased insulin levels (Nagareddy et al.,
2005) and also treatment with this metal found to increases extra-islet -cell
replication without modifying intra islet -cell replication rates (Fernández-Alvarez
et al., 2004). Tungstate improves pancreatic function through a combination of
hyperglycemia-independent pathways and through its own direct and indirect
effects, whereas the MAPK pathway has a key role in the tungstate-induced increase
of beta cell proliferation (Altirriba et al., 2009).
MANGANESE
Manganese (Mn) seems to be particularly important for the proper
functioning of enzymes and it plays an important role in a number of physiological
processes as a constituent or activator of some enzymes needed for metabolism
process. The human body does not require much of this element, but several
biological uses of manganese for the proper functioning of the body, and it is often
included in small doses in mineral supplements. These enzymes have a variety of
different functions. Some aid in repairing damage to the body. Others are
antioxidants. Additional enzymes make use of manganese to aid in the development
of strong and healthy bones. It is an essential component of metalloenzymes such as
Se–cys containing glutathione peroxidase, Cu/Fe cytochrome C oxidase or different
types of superoxide dismutase, all of them important in intra- and extra-cellular
antioxidant defense (Pandey et al., 2012). Synthetic manganese porphyrins can be
used as potent therapeutic agent in diabetes. EUK-8 is a member of a new class of
synthetic salen-manganese compounds with low toxicity that possess catalytic
superoxide dismutase, peroxidase and catalase activity that can inactivate superoxide
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and nitrogen oxides (e.g. peroxynitrite and nitrogen dioxide). EUK-8 administration
inhibited the adoptive transfer of type II diabetes and completely inhibited
spontaneous disease progression in pre-diabetic NOD mice with established cell
autoimmunity (Olcott et al., 2004).
MOLYBDENUM
Molybdenum (Mo), an important trace element plays a key role for
participation in the active sites of metalloenzymes. It is capable of forming
complexes with many compounds of biological importance and excreted in the form
of simple molybdate ion, [MoO4]2-. Molybdenum is essential for life and is much
less toxic than many other metals of industrial importance. Most organisms
including human beings require molybdenum for their existence. Various forms of
molybdenum have shown insulin mimetic properties and being used as anti-diabetic
agent. Sodium molybdate (Na2MoO4) and its complex compounds such as cis-
MoO2L2 (L ¼ maltol (3-hydroxy-2-methyl-4 pyrone)) were found to reduce the
levels of blood glucose significantly and also free fatty acids (Lord et al.,1999).
Molybdenum/ascorbic acid complex showed some significant insulin-mimic and
cardio protective effects (MacDonald et al., 2006).
TIN
Tin is an ultra trace element in humans and generates a wide variety of
biological activities deriving from its chemical character. It has been suggested that
the amount of tin found in a healthy diet should be the value used to describe
appropriate intake. Vanga bhasma, an Ayurvedic preparation of tin is used
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traditionally for treatment of diabetes. Vanga bhasma is purified and calcinated form
of tin with additional herbs (Soni Chandan et al., 2011).
2.5 Transition metal complexes of embelin
Among all quinones, benzoquinones possess numerous biologically
significant properties and are present in several living organisms. Number of natural
products containing benzoquinones exhibited important biological properties such as
anticoagulant, antidiabetic, antioxidative, anticancer activities, etc. One such natural
benzoquinone compound is Embelin from Embelia ribes berries received great
attention in pharmaceutical and research field. However, only few literatures are
available with metal complexes of embelin.
2.6 Herbal medicines Vs diabetes
Medical plants are used to treat various diseases for number of years and this
also play a crucial role in the management of diabetes mellitus especially in
developing countries due to less side effects and low cost. The medicinal plants
provide a useful source of oral hypoglycemic compounds for the development of
new pharmaceutical leads as well as a dietary supplement to existing therapies.
Some of the plants, which are being used for the treatment of diabetes, have received
scientific or medicinal scrutiny and even the WHO expert committee on diabetes
recommends that this area warrant further attention (WHO, 1980).
Plants containing alkaloids, flavonoids, indoles, phenolic compounds and
terpenes in small amount can serve as a phytonutrient, which is needed for the body
in small amounts. This phytonutrients may have antioxidant properties and helps to
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enhance the metabolism. Plant containing active constituents have demonstrated
biological activity and may reduce the risks of chronic disease.
In Ayurveda and other traditional system of medicine of India, a large
number of herbal drugs have shown anti-diabetic activity. The active principles
present in medicinal plants have been reported to possess pancreatic beta cells re-
generating, insulin releasing and fighting the problem of insulin resistance. Many
modern medicines have been extracted from natural sources. Even the discovery of
widely used anti-diabetic drug, Metformin is derived from the plant Galega
officinalis. Indian plants widely used to lower the blood sugar level are mentioned in
the introduction chapter (Chapter I). The effects of these phytomedicine may delay
the development of diabetic complications and correct the metabolic abnormalities.
People are greatly concerned about the efficacy and side effects of many synthetic
drugs, and hence choose herbal medicines for providing a safe and natural
alternative treatment for diabetes. With a view to explore traditional medicines and
to investigate their scientific application, an endemic medicinal plant Embelia ribes
was selected for the present study.
2.7 Botanical source of embelin
Embelia ribes Burm .f. belongs to the family Myrsinaceae
2.7.1 Geographical distribution
It is a large shrub, which is found in the hilly parts of India from the central
and lower Himalayas down to Sri Lanka and Singapore. In India, from the central
and lower Himalayas to Konkan, Deccan, Western Ghats and South India.
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2.7.2 Vernacular Names/ Nomenclature of Embelia ribes Burm. f.
Used locally by different regions of Indian people are listed below:
Latin name : Embelia ribes
English name : False Pepper, False Black Pepper
Assam : Vidang
Bengali : Vidang, Biranga, Bhai-birrung
Gujarati : Vavading, Vayavadang,Vyvirang
Hindi : Vayavidanga, Baberang, Bhabhiranga, Wawrung,
Vayvidamg
Kannada : Vayuvilanga,Vayuvidanga
Kashmiri : Babading
Malayalam : Vizhalari,Vilal
Marathi : Vavding,Karkannie
Oriya : Bidanga, Vidanga, Baibidanga
Punjabi : Babrung,Vavaring
Sanskrit : Krimighna, Tandula
Tamil : Vayuvilangam, Vayuvidangam ,Vellal, Vidanga
Telugu : Vayuvidangamu, Vayuvidangalu ,Vayuvilamgam, Vidanga
2.7.3 Botanical description
A large, scandent climber with long slender, flexible, terete branches bark
studded with lenticles. Leaves are simple (Figure 3), alternate, elliptic-lanceolate,
gland dotted, short and obtusely acuminate, entire, shiny above. Flowers are small,
white or greenish, in both terminal and axillary panicles. Fruits are globose,
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wrinkled or warty, dull red to nearly black, a short pedicel often present usually one
seeded and the seeds are globose. On drying, the colour of the fruit changes to dark
brown.
2.7.4 Parts used
Fruits (Berries), Leaves and Root-bar are used to cure various diseases.
2.7.5 Active constituents
Embelin (2, 5 dihydroxy-3-undecyl-1, 4 benzoquinone), an orange pigment
was extracted from the plant in the year 1900 by Heffter and Feurstein and then by
Du and Wie (1963). In addition to a quinone derivative embelin, an alkaloid
christembine, a volatile oil and vilangin (Rao and Venkateswarlu,1961). Other phyto
constituents include fatty ingredients (linoleic acid and palmitic acid), gallic acid,
simple carbohydrates (glucose and fructose), quercitol, a resinoid, tannins and
glycerol (Ibrahim Khan et al., 2010 and Lakshmanan,1990). Followed by its
potential use, chemical synthesis of embelin was attempted by (Hasan &
Stedman,1931, Fieser & Chamberlin,1948, and Dallacker & Lohnert,1972).
2.7.6 Traditional uses
In olden days, dried fruits were considered for anthelmintic, astringent,
carminative and used as an alternative and stimulant. The fruit is bitter in taste, good
appetizer, cures tumors, ascites, bronchitis, jaundice and mental disorders It was also
effective for the treatment of ascariasis better than santonin and as good as oil of
Chenopodium (Anonymus,1952).
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2.7.7 Physicochemical properties of embelin
Structure:
CAS Registry number: 550-24-3
Chemical name: 2,5-dihydroxy-3-undecyl-2,5-cyclohexadiene-1,4-dione
Molecular formula: C17H26O4
Molecular weight: 294.391g/mol
Melting point: 142°C (Chem ID plus)
Log p (octanol-water): 4.34 (Chem ID plus)
Solubility: Insoluble in water but soluble in organic solvents like
DMSO and ether
Appearance: Orange solid
3DMET number: B03757
3D structure:
Purity: 95%
max: 289 nm
Stability: 2 years
Storage: -20°C
2.7.8 Derivatives of embelin
Other than embelin, research on derivatives of embelin has been carried out
globally. Spectral, thermal and magnetic studies complexes of embelin with Mn(II),
Ni(II), Cu(II) and Zn(II) have been prepared and characterized by Rasheed et al.
(1983). Dhar and Onkar Singh (1986) reported various metal complexes of embelin.
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According to Dhar et al. (1989), embelin with some metal ions gives colour
reactions. Synthesis and characterization of copper (II) complexes of embelin in the
cavities of zeolite Y attempted by Abrahmn and Yusuff (2003) displayed catalytic
activity. Cherutoi et al. (2005) prepared Cu (II) embelin and Zn (II) embelin
complexes. Pyrano embelin derivatives were also available in the literatures
(Jimenez-Alonso et al., 2008). Further, the following complexes potassium
embelate, 5-Methyl embelin, Embelin-5-O-Alkyl ethers (2-hydroxy -5-methoxy-3-
undecylcyclohexa -2,5-diene-1,4-dione,5-ethoxy-2-hydroxy-3- undecylcyclohexa-
2,5-diene-1,4-dione,2-hydroxy-5-propoxy-3- undecylcyclohexa -2,5-diene-1,4-
dione,5-butaoxy-2- hydroxy -3-undecyl benzo-1,4 –quinone,5- allyloxy-2- hydroxy
-3-undecyl benzo-1,4 –quinone,5-benzyloxy-2- hydroxy -3-undecyl benzo-1,4 –
quinone) were prepared by Kantham Srinivas (2010). According to Rani et al.
(2010), the metal ions (Co, Ni, Cu and Zn ) form octahedral complexes with
bidentate embelin molecules based on their stability constant values. Recently,
Viault et al. (2011) reported synthesis of new derivatives of embelin by Suzuki-
Miyaura reaction which lead to second generation of embelin. Synthesis and
bioprofiling of Embelin, Embelin metal complexes and azo-metal complexes were
studied by Aravindhan et al. (2014). In this study, metal complexes were prepared
using pure embelin and d-block transition elements, namely Mn, Fe, Co, Ni, Cu, and
Zn. Results of antioxidant profile studies suggested that upon complexation with
metals, the free radical scavenging activity of embelin reduced significantly.
Chapter II Literature Review
40
2.7.9 Biological and Pharmacological studies
Quinones and their substituted derivatives have long been known to possess
numerous chemically and biologically significant properties with many important
applications in several areas. Biological studies on embelin and its metal have
received considerable amount of attention in recent years.
Antioxidant activity
In general, an antioxidant is a molecule or agent capable of inhibiting the
oxidation of other molecules. Oxidation reactions generate free radicals and these
radicals triggered the biochemical reactions, which finally damage cells.
Antioxidants terminate these chain reactions by neutralizing free radicals
intermediates and inhibit other oxidation reactions. Sumino et al. (2002) reported,
embelin exhibited free radical scavenging activities towards diphenyl-picrylhydrazyl
(DPPH) radicals with 50% inhibitory concentration of 23.3 ± 0.5 µM. Joshi (2007)
studied free radical scavenging reactions and antioxidant activity of embelin and
suggested that embelin can act as a competitive antioxidant effect in physiological
conditions. Surveswaran et al. (2007) reported crude Embelia ribes displayed free
radical scavenging activities when tested using DPPH assay. Uma et al. (2008a)
reported aqueous extract of E.ribes berries administered orally showed antioxidant
activity in streptozotocin induced diabetic rats and Venkateshwar rao et al. (2008)
substantiates the antioxidant activity of embelin. Dharmendra Singh et al. (2009)
reported the hepatic antioxidant capacity of embelin (from Embelia ribes) using
different antioxidant tests and in that reports embelin exhibited a natural antioxidant
activity at concentration of 25mg/kg body weight. The antioxidant potential of
Chapter II Literature Review
41
embelin in streptozotocin-induced diabetes studied by Gupta et al. (2012) at the dose
levels of 15, 25, and 30 mg/kg/day for 21 days. He has shown treatment with
embelin proved that the potent antioxidant activity of this compound helps in the
management of diabetes.
Anti-inflammatory activity
Anti-inflammatory refers to a substance that reduces inflammation. Most of
commercially available anti-inflammatory agents have side effects and embelin finds
use as anti-inflammatory drug in traditional medicine. Kapoor et al. (1983) reported
the whole E.ribes plant as anti-inflammatory drug. Embelin and its 2,5-isobutylmine
salts have been reported to possess anti-inflammatory effect in carrageenan-
induced paw edema (Handa et al., 1992). Chitra et al.(1994) reported embelin as
anti-inflammatory agent using rat model. Quinn et al. (2002) reported embelin
inhibits binding of MIP-1 to HEK cell membranes expressing human CCR1
receptor.
Anthelmintic activity
Anthelmintics or antihelminthics are drugs that expel parasitic
worms (helminths) from the body by either stunning or killing them and without
causing significant damage to the host. Honiberger (1852) reported Embelia ribes as
a vermifuge and then Watt (1972) suggested powdered seeds of E.ribes in curdled
milk in combination with castor oil was found to be effective in expelling
tapeworms. In the year 1987, Ved Prakash and Mehrotra, E.ribes is one out of the 52
Indian medicinal plants identified for anthelmintic activity. Further, Embelin is
effective against tapeworms and not round/hookworms according to herbal
Chapter II Literature Review
42
monographs (Anonymous 2002). Jalalpure et al. (2007) reported E.ribes seed oil had
shown effective activity against Pheretima posthuma compared to standard
piperazine citrate.
Antiandrogenic activity
Antiandrogenic are agents to counteract the effects of androgens (male sex
hormones) on various body organs and tissue. Agarwal and co-authors reported
antiandrogenic property of embelin during the year 1986 and after this report, no
reports were available till today.
Antiulcer activity
Antiulcer drugs are class of drugs, exclusive of the antibacterial agents, used
to treat ulcers in the stomach and the upper part of the small intestine. Vyawahare et
al. (2009) reported E.ribes as one of the important ingredient of amlant (capsule)
which cures ulcer. The protective effect of embelin against acetic acid induced
ulcerative colitis in rats may be due to its antioxidant and anti-inflammatory
activities was reported by Thippeswamy et al. (2011).
Antimicrobial activity
Antimicrobial drugs are an agent that kills microorganisms or inhibits their
growth. In vitro antibacterial activity fruits extract of Embelia ribes was reported by
Khan et al. (2010). Chitra et al. (2003) reported antibacterial activity of embelin
against three strains of the 12 bacterial species tested using disc diffusion method.
Feresin et al. (2003) reported embelin inhibited methicillin-sensitive and methicillin-
resistant strains of Staphylococcus aureus with minimal MIC value of 250, 62 µg/ml
Chapter II Literature Review
43
respectively. According to Rathi et al. (2009), petroleum ether extract of Embelia
ribes showed lowest MIC value against Candida parapsilosis and 360 µg/ml against
Candida laurinitis. Suthar et al. (2009) reported antifungal activity of Embelia ribes
against A. flavus and A. fumigatus. In addition to this report, Tambekar et al. (2009)
reported acetone fraction of Embelia ribes showed antibacterial activity against
Enterobacter and Klebsiella pathogens. Radhakrishnan et al. (2011a) bacteriostatic
and bactericidal activity against Gram-ve and +ve organisms. Rani et al. (2011)
indicated that the seeds of Embelia ribes has potential antimicrobial constituents
when tested against 4 different bacteria. According to Aravindhan et al. (2014),
results of antimicrobial activity studies suggested that upon complexation with
metals like Co and Ni, >80% growth inhibition were observed in comparison with
embelin alone.
Antihyperlipidemic activity
Antihyperlipidemic agents lower abnormally elevated levels of lipids in the
blood. They are also called as lipid lowering agents. Uma et al. (2008a) reported the
antihyperlipidemic activity of aqueous extract of E.ribes berries in rats. Jagadeesh et
al. (2009) reported that embelin exhibited antihyperlipidemic activity towards
chemically induced hepatocarcinogenesis in wistar rats.
Antispermatazoal activity
Antispermatazoal compounds interfere with spermatogenesis process.
Purandare et al. (1979) reported powdered berries of Embelia ribes administered
orally 3 months at a dose of 100mg/day shown reduction in quantity and quality of
semen. Seth et al. (1982) reported embelin significantly reduce the sperm count and
Chapter II Literature Review
44
motility in all the tested albino rats. Gupta et al. (1989) reported significant
reduction in the sperm count with embelin.
Anticonvulsant activity
Anticonvulsant agents are used to treat convulsions and/or epileptic seizures.
Mahendran et al. (2011) reported embelin significantly inhibited seizures induced by
electric shock and shown effective against both grandma and petit mal epilepsy.
Anticancer activity
Anticancer drugs are an agent that inhibits or prevents the formation or
growth of tumor. Chitra et al. (1994) reported anti tumor activity of embelin in
albino rats. Nikolovska-Coleska et al. (2004) reported embelin as a lead compound
for anticancer drugs that target the BIR3 domain of XIAP. Dai et al. (2011) reported
embelin inhibits chemical carcinogen-induced colon carcinogenesis.
Antidiabetic activity
Antidiabetic drugs are used to lower blood glucose levels. They are also
called as hypoglycemic or antihyperglycemic agents. Tripathi (1979) reported,
antihyperglycemic activity of decoction of E.ribes berries in glucose-fed albino rats.
Uma et al. (2008) reported the hypoglycemic activity of ethanolic extract of E.ribes
berries in streptozotocin induced diabetic rats. And added that E.ribes treated rats
showed 68% reduced blood glucose level versus control group. Mahendran et al.
(2011) reported antihyperglycemic activity of embelin against alloxan induced
diabetic rats at concentration of 25 and 50 mg/kg body weight administered orally
and had shown reduction in blood glucose levels with a body weight gain. Gandhi et
Chapter II Literature Review
45
al. (2013) showed that embelin could improve adipose tissue insulin sensitivity
without increasing weight gain, enhance glycemic control, protect -cell from
damage and maintain glucose homeostasis in adipose tissue.
Toxicity
According to OSHA 29 CFR 1910.1200 as reported in (M/S Santa Cruz
Company, USA) material safety data sheet (sc-2015555, 2010) embelin is not a
hazardous agent. Despite this information, number of experimental studies have
been undertaken to understand the nature of embelin using animal models and the
results substantiate with the material safety data sheet. Gupta et al. (1991) observed
no change in food intake, behavior, appearance and clinical signs in the
experimental animals (rats) administered with embelin (subcutaneous) at a dose of
20mg/kg body weight /day for 30 days. Similarly, Prakash (1994) also observed no
significant physical and morphological changes after the administration of embelin
at a dose of 120 mg/kg body weight, except an increase in weight of the adrenals.
2.8 Nanoparticles: An effective approach for the management of diabetes
Literature survey reveals that so far no formulation is available using
embelin and its metal complexes from Embelia ribes berries. Moreover, only pure
active compound of embelin and its crude extract were reported for antidiabetic
activity. In order to improve the efficacy of embelin and also to reduce the dose
related side effects, a nanopreparation is designed, which can have a therapeutic
value in human diabetics. However, few literatures on the preparation of metal
nanoparticles have been reported. The present research study focuses mainly on
metal-based nanoparticles and its therapeutic applications as an antidiabetic drug.
Chapter II Literature Review
46
Nanotechnology can be defined as the science and engineering involved in
the design, synthesis, characterization and application of materials and devices
whose smallest functional organization in at least one dimension is on the nanometer
scale (one-billionth of a meter) (Emerich et al., 2003 and Sahoo et al., 2003). When
this science is applied specifically to the problems of medicine, it is called
‘Nanomedicine’ (Freitas, 2005 and Moghimi et al., 2005). Nanomedicine is a field
with continuous progress, introducing novel applications in many health care areas.
The underlying motivation is improvement of quality of life with economic and
social benefits. Some of the most promising areas are the following (Jain, 2008 and
Surendiran et al., 2009).
Nanodiagnostics (molecular diagnostics, imaging using NP- based
contrast materials, nanobiosensors)
Nanopharmaceuticals (targeted drug delivery, nanotechnology- based
drugs, implanted nanopumps, nanocoated stents)
Reconstructive surgery (tissue engineering, implantation of rejection
resistant artificial tissues and organs)
Nanorobotics (vascular surgery, detection and destruction of cancer)
Nanosurgery (nanolasers, nanosensors implanted in catheters)
Regenerative medicine (tissue repair)
Ultrafast DNA sequencing
To overcome the patient compliance, better and safer route of administration
of herbal medicine is by nanoparticles. In this regard, application of nanotechnology
in medicine revealed a solution to overcome the side effects of already existing
Chapter II Literature Review
47
therapy. Nanomedicine shows great potential for the future diabetic management
and at the moment, the suggested benefits in diabetic health care outweigh the
possible dangers of nanoparticles use in medicine. Nanoparticles have the following
characteristics:
1. High capacity for transporting drugs
2. Very large active surface for the reaction
3. Suitable small body to cross the blood levels
4. Ability of accumulation in the target tissue
5. And low toxicity
It has been expected that this technology effectively create a ‘closed-loop’
system that mimics the activity of the pancreas in a healthy person, and with respect
to the present study on the release of embelin and its metal complexes in response to
glucose level changes. All of this systems will improve stability, adsorption and
drug therapy concentration in target tissue, in addition to those long-term
redistribution and release of drug facilitated at the target site. The frequency drug
administration is also reduced and improves patient comfort.
The design of nanoparticle-based drug delivery systems is tremendously
increasing in research field due to their great therapeutic potential. Different types of
materials have been explored as drug delivery carriers that include polymers, lipids,
polysaccharides, and proteins. The selection of nanoparticle materials depends on
many factors like (a) the size of nanoparticles, (b) properties such as aqueous
solubility and stability of drugs, (c) drug release profile desired, (d) surface charge
Chapter II Literature Review
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and hydrophobicity of nanoparticles, (e) biocompatibility and biodegradability of
nanomaterials,, and (f) antigenicity and toxicity of the product (Kreuter,1994).
2.9 Chitosan as a carrier for drug delivery system
Most of the pharmaceutical drugs have problems of poor stability, water
insolubility, low selectivity, high toxicity, side effects, and so on. Good drug carriers
play a significant role in resolving these problems. Among all the carriers used in
therapy, Chitosan has been widely used as a polymer carrier in most of the novel
drug delivery system. Chitosan ( -(1 4)-2-amino-2-deoxy-D-glucose (Figure 4)) is
a modified natural carbohydrate polymer prepared by partial N- deacetylation of
chitin, a natural biopolymer. It is widely distributed in nature as a principal
component of crustacean’s shells and insects (Chandra et al., 1998) and it is the
second most abundant biodegradable polymer produced in nature after cellulose. It
appears in nature as semi- crystalline powder. It is used in a variety of
pharmaceutical applications because it has a low/tolerable level of toxicity,
physicochemical stability, providing versatile route of administration,
biodegradability and biocompatibility. Moreover, chitosan is lack of irritant and
allergic effects (Dodane et al., 1998). Furthermore, it has the advantage of
slow/controlled drug release and improves the drug solubility (Wang et al., 2011).
The chitosan is characterized by its acetylation degree and by its molecular weight.
These parameters also influence its viscosity and solubility. Depending on the
source (shrimp, crab, mushrooms…), industrial chitosan has molecular weight
varying from 5,000 to 1,000,000 g/mol-1 and acetylating degrees from 2 to 60 %.
Chapter II Literature Review
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Drug-loaded chitosan nanoparticles are decomposed into free chitosan and
drug in vivo and as soon as the drugs enter into the cell and reaches the targeted
tissues to exert therapeutic effects. Chitosan is mainly degraded by catalysis of
lysozyme and bacterial enzyme in the colon. The kidney clears the chitosan
absorbed into blood and the rest is discharged through other excretion process.
Degree of deacetylation as well as molecular weight also influence degradation rate
and degree of chitosan in vivo (Xu et al., 1996 and Yang et al., 2007).
2.9.1 In vivo metabolic process of chitosan nanoaparticles
Usually any carrier enters into the body system will be recognized as a
foreign matter and are absorbed by antibodies generated in the human body. Most of
the proteins in plasma are also adsorbed onto the carrier (eg. Nanoparticles),
accelerating the reorganization of the reticuloendothelial system. Carrier system is
engulfed by macrophage and cleared from the body’s circulation (Mei et al., 2002).
The bridge between nanoparticles and macrophage is formed because of plasma
protein adsorbed on the nanoparticle surface, mainly due to the surface charge of the
nanoparticles (Redhead et al., 2001). Nanoparticles with polarity and high surface
potential as well as amphipathic or hydrophilic nanoparticles are engulfed less and
have a longer circulating time in vivo. Nam et al. (2009) found that glycol–chitosan
nanoparticles after hydrophobic modification is more distributed in all cells
compared with unmodified nanoparticles. Yuan et al. (2010) reported chitosan–
alumino-silicate nanoparticles has shown significant sustained/controlled-release
effects.
Chapter II Literature Review
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2.9.2 Chitosan as carrier for different types of drugs
Literature has shown that chitosan nanoparticles can carry many numbers of
drugs, which includes gene drugs, protein drugs, anticancer chemical drugs, and
antibiotics. This carrier can be administered into the body system via different routes
of administration including oral, nasal, intravenous, topical and ocular.
With regard to gene delivery, the main challenge for gene therapy is to find
safe and effective vectors that are able to deliver genes to the specific cells and get
them to express inside the cells. The carrier must enhance their physicochemical
properties, improving transfection efficiency, reducing cytotoxicity as well as
incorporating functional groups that offer better target ability and should have higher
cellular uptake. Chitosan has been reported widely for gene delivery because of their
availability, excellent non-cytotoxicity profile, biodegradability and ease of
modification (Xu et al., 2010). It has been reported by Köping-Höggård et al. (2001)
that chitosan is a nontoxic alternative to other cationic polymers and it forms a
platform for further studies of chitosan-based gene delivery systems.
Chitosan was considered to be the most effective carriers with low
cytotoxicity and good transfection activities at low charge ratios (N/P). It has also
been identified as a safe and promising polycation vector for gene delivery (Oliveira
et al., 2013).
Mansouri et al. (2006) used folic acid to modify chitosan for improving gene
transfection efficiency. The results showed that folic acid-modified chitosan
nanoparticles have lower cytotoxicity and help them as a nonvirus gene carrier with
a good application potential.
Chapter II Literature Review
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2.9.3 Carrier of other drugs
Chitosan nanoparticles can able to load most categories of drugs including
antivirus drugs, antiallergic drugs, hormone drug, and other classes of drugs either to
increase the bioavailability, encapsulation efficiency or to have prolonged release.
Different methods for preparing chitosan-based nanoparticles were
summarized in Table 2.
2.10 Emulsification and cross-linking method
This method is widely used for the preparation chitosan based nanoparticles
and involves the preparation of a W/O emulsion using non-ionic surfactant. After the
formation of emulsion, to cross link and separate the nanoparticles, subsequent
addition of a cross-linking agent was carried out that has the function of hardening
the formed droplets. The reactive amino groups of chitosan undergo a covalent
cross-linking with the carboxylic groups of glutaric acid, which is added after the
emulsion formation, and, consequently lead to the production of nanoparticle.
Earlier chitosan nanoparticles were prepared with glutaraldehyde. To
overcome the problems of toxicity that are presented by glutaraldehyde, some
biocompatible cross-linkers, such as natural di- and tricarboxylic acids, including
succinic acid, malic acid, tartaric acid and citric acid, are used for intermolecular
cross-linking of chitosan nanoparticles (Bodnar et al., 2005). By this method, the
pendant amino groups of chitosan react in aqueous media with carboxylic groups of
natural acids which were previously activated by a water-soluble carbodiimide,
obtaining polycations, polyanions, and polyampholyte nanoparticles with an average
Chapter II Literature Review
52
size in the range of 270–370 nm depending on the pH. Since this method is versatile
and is followed in the present study to prepare embelin and its metal complexes
nanopartilces for antidiabetic efficacy.
2.11 Antidiabetic efficacy
2.11.1 In silico models - Docking studies
Few of the drugs have been tested for the antidiabetic efficacy under in
silico models; however, computer aided docking studies on compounds from plants
Vs proteins that mediate diabetes were even very less. This method of screening will
help to reduce the cost and time of drug discovery. Moreover, docking studies are
helpful to understand the interaction of ligand molecules with receptors with
reasonable accuracy and speed (Akhila et al., 2012). Drug design is mainly based on
protein-ligand interactions and the active site residues. The major driving force
between protein-ligand interactions for binding appears to be hydrophobic
interaction. In silico techniques helps identifying drug target via bioinformatics
tools. They can also be used to explore the target structures for possible active sites,
generate candidate molecules, dock these molecules with the target, rank them
according to the binding affinities, and further optimize the molecules to improve
binding characteristics.
The molecular modeling will show an energy binding affinity of the tested
compound. There are several targets available to lower the glucose level in the body
such as glucokinase (Angadi et al., 2013), pancreatic alpha amylase, aldose
reductase, alpha glucosidase, etc. Among this enzymes, -Amylase and -
glucosidase are significant enzymes, which cleave carbohydrates responsible for
Chapter II Literature Review
53
absorption of glucose in the blood stream. Pancreatic -amylase inhibitors offer an
effective strategy to lower the levels of post-prandial hyperglycemia via the control
of starch breakdown. According to Sivakumari et al. (2010) aldose reductase (AR) is
an enzyme associated with retinopathy of both type 1 and type 2 diabetic patients.
Hence in the present study, the docking studies were performed using two
receptors namely HPAA and HAR by using Discovery studio version 3.0. Discovery
studio has the ability to predict the interaction energy of small molecule with
molecular targets.
2.11.2 In vivo studies – Animal model
Experimental induction of diabetes mellitus in animal models is essential for
understanding its pathogenesis. Several methods have been used to induce diabetes
mellitus in laboratory animals with variable success and many difficulties. Surgical
removal of the pancreas is an effective method; however, to induce diabetes, at least
90-95% of the pancreas has to be removed (Akbarzadeh et al., 2007). Since it is
tedious and costly, alloxan or streptozotocin has been used usually to induce
diabetes in the animal studies than other diabetogenic agents. Both the drugs, causes
destruction of the beta cells of pancreas and thus gives permanent diabetes
responsible for final observed rise in blood sugar level. These drug are toxic and
affects other tissues than liver and pancreas. Alloxan is a uric acid derivative and is
highly unstable in water. The hypoglycaemic phase may be quite severe and
therefore alloxan should not be given to fasted animals. Because of this reason,
alloxan is now replaced by Streptozocin. Streptozotocin (STZ; N-nitro derivative of
glucosamine) is a naturally occurring, broad spectrum antibiotic and cytotoxic
Chapter II Literature Review
54
chemical that is particularly toxic to the pancreatic, insulin producing beta cells in
mammals (Szkudelski et al., 2001 & Hayashi et al., 2006). Induction of experimental
diabetes in the rat and mice using streptozotocin is very convenient and simple to
use (Brosky et al., 1969 & Ito et al., 1999). Streptozotocin can be injected either
intravenously or intraperitoneally. In rats, it has been reported that a dose ranging
from 25 to 100 mg/kg of streptozotocin injected intravenously was successful in
inducing diabetes (Hayashi et al., 2006). Severity and onset of diabetes symptoms
depend on the dose of streptozotocin. Clinically, symptoms of diabetes are clearly
seen in rats within 2-4 days following single intravenous or intraperitoneal injection
of 60 mg/kg STZ. In the present study, Streptozotocin was used to induce diabetes in
Sprague-dawley rats.
In this chapter, diabetes mellitus and its treatment, transition metals in
diabetic mellitus, embelin, nanoparticles and polymeric nanoparticles (chitosan)
have been described briefly along with antidiabetic efficacy. Diabetes has many
remaining problems; nanomedicine is likely to be a key technology for solving many
of them and will be a core technology in diabetic research. With the advancement of
science, the role of transition metal complexes as therapeutic compounds is
becoming increasingly important and used in various therapies. Development of
transition metal complexes as drugs is not an easy task; much effort is required to
get a compound of interest. Besides all these limitations and side effects, transition
metal complexes are still the most widely used therapeutic agents and make a large
contribution to medical field. Based on the literature, structure of the present thesis
is designed.
Chapter II Literature Review
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Yasumatsu, N., Yoshikawa, Y., Adachi, Y., & Sakurai, H. 2007. Antidiabetic copper
(II)-picolinate: Impact of the first transition metal in the metallopicolinate
complexes. Bioorganic & medicinal chemistry, 15(14): 4917-4922.
Chapter II Literature Review
xxvii
Yeh, M. K., Cheng, K. M., Hu, C. S., Huang, Y. C., & Young, J. J. 2011. Novel
protein-loaded chondroitin sulfate–chitosan nanoparticles: Preparation and
characterization. Acta biomaterialia, 7(10): 3804-3812.
Yoshikawa, Y., & Yasui, H. 2012. Zinc Complexes Developed as
Metallopharmaceutics for Treating Diabetes Mellitus based on the Bio-
Medicinal Inorganic Chemistry. Current topics in medicinal
chemistry, 12(3): 210-218.
Yildirim, Ö., & Büyükbingöl, Z. 2003. Effect of cobalt on the oxidative status in
heart and aorta of streptozotocin-induced diabetic rats. Cell biochemistry and
function, 21(1): 27-33.
Yildirim, Ö. 2009. The effect of vitamin C and cobalt supplementation on
antioxidant status in healthy and diabetic rats. African Journal of
Biotechnology,8(19): 5053-5058.
Yuan, Q., Shah, J., Hein, S., & Misra, R. D. K. 2010. Controlled and extended drug
release behavior of chitosan-based nanoparticle carrier. Acta biomaterialia,
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Web source
http://www.who.int/diabetes/publications/diagnosis_diabetes2006/en/
http://faculty.virginia.edu/metals/cases/houck1.html
http://prospect.rsc.org/metalsandlife/9.13.pdf
Arumugam et al.Int J Pharm Pharm Sci, Vol 6, Issue 7, 40-44
43
compound could act as a nutritional enhancement particularly
essential for glucose metabolism. The Cr (III) complexes had better
bioavailability and more beneficial influences on the improvement
of controlling blood glucose and proposed to act as safer
antidiabetics [2]. Supplementation of chromium significantly
improves glucose level among patients with diabetes but fails to
show any significant effect on glucose metabolism in healthy
volunteers [21]. Treatment with Chromium picolinate (CrPic)
improves glycemic control in diabetic patients [22]. Chromium
picolinate is more bioavailable than other supplemental forms of
chromium and therefore may be more efficacious.
Cobalt
Cobalt is one of the most important trace elements in the world of
animals and humans and finds therapeutic application in
pharmacological fields. In the form of vitamin B12 (cobalamin), this
metal plays a number of crucial roles in many biological functions.
Vitamin B12 is the only metal-containing water-soluble vitamin that
is stored in the liver and must come from the diet. Cobalamin is
necessary for DNA synthesis, formation of red blood cells and
maintenance of the nervous system, growth and development of
children. Cobalt is used to treat anaemia with pregnant women,
because it stimulates the production of red blood cells.Cobalt was
found to boost the effects of insulin and its action. Treartment with
cobalt chloride (CoCl2
Tungsten
) decreases the glycemia of diabetic rats which
may be mediated by gene expression of GLUT-1 mRNA. Treatment
with cobalt chloride showed significant decline in blood glucose in
STZ induced diabetic rats but no observed change in plasma/serum
insulin levels of normal or diabetic rats. Cobalt is the most important
contributor to metal ion toxicityin patients both in single and pure
form. Different forms of cobalt complexes have been reported to
reduce the potential toxicity of cobalt without modifying its
therapeutic effect[2]. The glycemic lowering effect of glucosaminic
acid-cobalt chelate has been reported to be effectiveagent for
diabetes [23]. Cobalt therapy may prove effective in improving the
impaired antioxidant status during the early state of diabetes and
ascorbic acid supplementation at this dose potentiates the
effectiveness of cobalt action [24,25].
Tungstate counteracts diabetes in the form of sodium tungstate.
Studies in several animal models of diabetes have shown sodium
tungstate to be an effective anti-diabetic agent and found to be less
toxic both in diabetic and healthy animals [26, 27]. Administration of
this metal enhances the insulin activity rather than increased insulin
levels [28] and also treatment with this metal found to rise extra-
- -cell replication
rates [29]. Tungstate improves pancreatic function through a
combination of hyperglycemia-independent pathways and through
its own direct and indirect effects, whereas the MAPK pathway has a
key role in the tungstate-induced increase of beta cell proliferation
[30].
Manganese
Manganese (Mn) plays a key role in a number of physiologic
processes and is considered tobe essential for the carbohydrate,
amino acid and cholesterol metabolism. The human body does not
require much of this element, but several biological uses of
manganese are critical to the proper functioning of the body, and it
is often included in small doses in mineral supplements. Manganese
seems to be particularly important for the proper functioning of
enzymes. These enzymes have a variety of different functions. Some
aid in repairing damage to the body. Others are antioxidants.
Additional enzymes make use of manganese to aid in the
development of strong and healthy bones. It is considered to be a
key component of metalloenzymes such as Se–Cyscontaining
glutathione peroxidase, Cu/Fe cytochrome C oxidase or different
types of superoxide dismutase, which are in turn important for
intra- and extra-cellular antioxidant defense mechanism[2].
Synthetic derivative of manganese found to be used as potent
therapeutic agent in diabetes. Two newly classified antioxidants
namely EUK-8 and EUK-134 reported to reduce the serum levels of
glucose [31].
Molybdenum
Molybdenum (Mo), an important trace element plays a major role
for participation in the active sites of metalloenzymes. Molybdenum
is capable of forming complexes with many compounds of biological
importance: carbohydrates, amino acids, flavins, porphyrins; but is
probably taken up, transported, and excreted in animals as the
simple molybdate ion, [MoO4]2-. Molybdenum is essential for life and
is much less toxic than many other metals of industrial
importance.Most organisms including human beings require
molybdenum for their existence. Molybdenum alongwith tungstate
helps in the key transformations in the metabolism of nitrogen,
sulphur, carbon, arsenic, selenium and chlorine compounds. This
element plays a crucialrole in the structure of certain enzymes
involving redox reactions [32]. Molybdenum in different forms have
shown to possess insulin mimetic properties and hence it used in the
treatment of diabetes. Sodium molybdate (Na2MoO4) and its
complex compounds such as cis-MoO2L2
Tin
(L ¼ maltol (3-hydroxy-2-
methyl-4 pyrone)) were found to reduce the levels of blood glucose
significantly and also free fatty acids [33]. Combination of
molybdenum and ascorbic acid exhibited significant insulin-like
activites and also shown cardio protective effects [34].
Tin generates a wide variety of biological activities deriving from its
chemical character. Tin is an ultra-trace element in humans. It has
been suggested that the amount of tin found in a healthy diet should
be the value used to describe appropriate intake. Vangabhasma, an
Ayurvedic preparation of tin is used tradionally for treatment of
diabetes. Vangabhasma is purified and calcinated form of tin with
additional herbs[35].
Siddha System Of Medicine
Siddha system of medicine, one of the ancient medical systems has
the great potential of treating many disease ailments. Siddha system
of Medicine, many single and poyherbal formulations and higher
medicines like Parpam, Chendooramand Chunnamhave been
practiced to cure or control diabetes mellitus from time immemorial.
The familiar Siddha medicines prescribed for diabetes are
AvaraiKudineer(decoction), MadhumegaChooranam(Fine powder),
ThetranChooranam, SeenthilChooranam, NaavalChooranam, AbragaParpam,Vangaparpam etc. In Siddha, the management of a
disease not only depends on the medicine but the modification of
food, habits, and lifestyle also. In addition to this, yoga and exercise
therapy also plays a key role for themanagement of
diabetes.SidhhaKudineer, a polyherbal formulations equally referred
to Khashayasin Ayurveda are more useful to prevent the diabetes
and their associated complications.
Oral administration of Siddha formulation (Madhumegachuranam)
ameliorated the plasma glucose and lipid levels in alloxan- induced
diabetic rats reported by Vadivelanet al.Anbu et al. studied
thatAavaraiyathichurnamis one of the herbal based Siddha anti
diabetic formulation for Type II maturity onset diabetes mellitus
possess significant hypoglycemic effect when compared with non-
treated diabetic rats.KovaiKizhanguChooranamfound to possess
remarkable anti-diabetic action in alloxan induced diabetic rats was
reported by Parthiban et al. [36-40].
CONCLUSION
Metal complexes offer a platform for the design of novel therapeutic
compounds. The metal compounds offer new properties that cannot
be found amongst purely organic agents. Treatment of diabetes
mellitus with metal complexes is a new therapeutic strategy.
Although various metals like chromium, manganese, molybdenum,
tungsten, copper, cobalt, zinc andvanadium were reported to exhibit
insulin mimetic activity out of these a wide class of vanadium,
copper and zinc complexes was found to be effective for treating
diabetes in experimental animals. Since metallotherapy overcome
the problems ofpainful insulin injection and side effects for type 1 or
type 2 DM; the encouraging results of preclinical and clinical studies
with metal compounds form the basis for further investigations
towards the development of metallodrugs for better healthcare.
Arumugam et al.Int J Pharm Pharm Sci, Vol 6, Issue 7, 40-44
44
CONFLICT OF INTERESTS
Declared None
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