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.


39

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.


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


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


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


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


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


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.


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


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


48

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 %.


49

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.


50

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.


51

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


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


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


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.


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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 alloxaninduced

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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