1.

INTRODUCTION

Diabetes is defined as a state in which homeostasis of carbohydrate,

lipid and protein metabolism is improperly regulated by insulin. This

results primarily in elevated fasting and postprandial blood glucose

levels. If this imbalanced homeostasis dose not returns to normal and

continues for a prolonged period of time, it leads to hyperglycaemia that

in due course turns into a syndrome called diabetes mellitus.1 [Cited 2006
Nov 17] WHO 1999]

Diabetes mellitus is a chronic metabolic

disorder characterized by a high blood glucose concentration-

hyperglycaemia (fasting plasma glucose > 7.0 mmol/l or plasma glucose

> 11.1 mmol/l 2 h after a meal) caused by insulin deficiency, often

combined with insulin resistance. Hyperglycemia occurs because of

uncontrolled hepatic glucose output and reduced uptake of glucose spills

over into the urine (glycosuria) and causes an osmotic diuresis

(polyuria), which in turn results in dehydration, thirst and increased fluid

intake (polydipsia).2
Diabetes mellitus is also called as idiopathic diabetes mellitus.

Secondary diabetes mellitus is occurrence of hyperglycaemia associated

with some identifiable causes such choronic pancreatitis, post-

pancratectomy, hormone-producing tumours, certain drugs,

haemochromatosis and genetic endocrinologic disorder. The number of

cases of diabetes worldwide in 2000 among adults 20 years of age is

estimated to be 171 million. This figure is 11% higher than the previous

estimate of 154 million. The IDF (International Diabetes Federation) has

subsequently released estimates of the numbers of people with diabetes

for 2003 and forecasts for 2025 of 194 million and 334 million,

respectively.3 India leads the world with largest number of diabetic

subjects earning the dubious distinction of being termed the “Diabetes

capital of the world”. According to the diabetes nowhere is the diabetes

epidemic more pronounced than in India as the World Health

Organization (WHO) reports show that 32 million people had diabetes in

the year 2000. International Diabetes Federation, (2006) published the

number of people with diabetes in India currently is around 40.9 million

and is expected to rise to 69.9 million by 2025 unless urgent preventive

steps are taken.4 Figure 1 represents the statistics of diabetes. [Cited 2006
Nov 17] WHO 1999]

Figure 1: Diabetes statistics.

. Symptoms of diabetes mellitus

The classical triad of diabetes symptoms is

Polyuria,Polydipsia: increased thirst, Visual disturbances such as

blurred vision, ketoa cidosis, increased risk of cardiovascular,

peripheral and cerebrovascular disease. progressive development

of retinopathy with potential blindness, nephropathy that may lead

to renal failure and/or neuropathy with risk of foot ulcers,

amputation, charcot joints and features of autonomic dysfunction,

including sexual dysfunction. [Craig ME, Hattersley A, 2009]

Classification of diabetes mellitus:

Type 1 Diabetes mellitus

The symptoms of type-1 Diabetes often occur suddenly and can be

severe. They include:

• Increased thirst

• Increased hunger (especially after eating)

• Dry mouth

• Frequent urination

• Unexplained weight loss (even though you are eating and feel

hungry)

• Fatigue (weak, tired feeling)

• Blurred vision

• heavy breathing (Kussmaul respirations)

• Loss of consciousness
Type 2 Diabetes mellitus

The symptoms of type 2 Diabetes may be the same as type 1 diabetes

mellitus. Most often, there are no symptoms or a very gradual

development of the above symptoms. Other symptoms may include:

• Recent weight gain

• Low blood glucose levels

• Impotence or erectile dysfunction

• Slow-healing sores or cuts

3.4.1. Pathogenesis of type 1 diabetes mellitus

The basic phenomena in type 1 diabetes mellitus are destruction of β-cell

mass, usually leading to absolute insulin deficiency. Currently

pathogenesis of type 1 diabetes mellitus is explained on the basis of

three mutually-interlinked mechanisms (Fig 3).17

• Genetic susceptibility

• Autoimmune factors

• Certain environmental factors

Autoimmune factors

Studies on humans and animal models on type 1 DM have shown

several immunological abnormalities.

• Presence of islet cell antibodies against GAD (glutamic acid

decarboxylase), insulin etc,

• Occurrence of lymphocytic infiltrate in and around the

pancreatic islets termed insulitis.

• Selective destruction of β-cells while other islet cell types

(glucagon-producing α-cells, somatostatin-producing delta cells)

remain unaffected. This is mediated by T-cell mediated

cytotoxicity or by apoptosis.
 • Role of T cell-mediated autoimmunity is further supported by

transfer of type 1 DM from diseased animal by infusing T

lymphocytes to a healthy animal.

Insulin resistance

One of the most prominent metabolic features of type 2 DM is the lack

of responsiveness of peripheral tissues to insulin, especially of skeletal

muscle and liver. Obesity, in particular, is strongly associated with

insulin resistance and hence type 2 DM. Hyperglycemia in this cases is

due to following reasons,

• Resistance to insulin impairs glucose utilization and hence

hyperglycemia.

• There is increased hepatic synthesis of glucose.

• Hyperglycemia in obesity is related to high levels of free fatty

acids and cytokines (e.g. TNF-α and adiponectin) affect
peripheral tissue sensitivity to respond to insulin.
 • Polymorphism in various post-receptor intracellular signal
pathway molecules.

• Elevated free fatty acids seen in obesity may contribute. E.g. by

impaired glucose utilization in the skeletal muscle, by increased
hepatic synthesis of glucose and by impaired β-cell function.

Impaired insulin secretion

In type 2 DM, insulin resistance and insulin secretion are interlinked:

• Early in the course of disease, in response to insulin resistance

there is compensatory increased secretion of insulin

(hyperinsulinaemia) in an attempt to maintain normal blood

glucose level.

• Eventually, however, there is failure of β-cell function to

secret adequate insulin i.e. cases of type 2 DM have mild to

moderate deficiency of insulin but not its total absence.

The exact genetic mechanism why there is fall in insulin secretion in

these cases is unclear. Islet amyloid polypeptide (amylin) which forms

fibrillar protein deposits in pancreatic islets in long standing cases of

type 2 DM may be responsible for impaired function of β-cells islet

cells.

Etiologic classification of diabetes mellitus5[Craig ME, Hattersley A, ]

I. Type 1 diabetes (β -cell destruction, usually leading to absolute

insulin deficiency)

a. Immune mediated

b. Idiopathic

II. Type 2 diabetes (may range from predominantly insulin resistance

with relative insulin deficiency to a predominantly secretory defect with

insulin resistance)

III. Gestational diabetes mellitus (GDM)

IV. Other specific types:

a. Genetic defects of β -cell function

b. Genetic defects in insulin action

d. Drug- or chemical-induced

e. Infections

f. Uncommon forms of immune-

i. Anti–insulin receptor antibodies

ii. Others

h. Other genetic syndromes sometimes associated with diabetes.

Type 1 Diabetes mellitus

Type 1 diabetes is an autoimmune disease. An autoimmune disease

results when the body's system for fighting infection (the immune

system) turns against a part of the body. In diabetes, the immune system

attacks the insulin-producing beta cells in the pancreas and destroys

them. The pancreas then produces little or no insulin. A person who has

type 1 diabetes must take insulin daily to live.

Type 2 Diabetes mellitus

Type 2 Diabetes was also called non-insulin-dependent diabetes mellitus

(NIDDM) or adult-onset diabetes. Type 2 diabetes may account for

about 90% to 95% of all diagnosed cases of diabetes. It usually begins as

insulin resistance, a disorder in which the cells do not use insulin

properly. As the need for insulin rises, the pancreas gradually loses its

ability to produce insulin. Risk factors for Type 2 diabetes are older age,

obesity, and family history of diabetes, history of gestational diabetes,

impaired glucose metabolism, physical inactivity, and race ethnicity.

Type 2 diabetes is increasingly being diagnosed in both children and

adolescents.

Gestational diabetes mellitus (GDM) 6

GDM or carbohydrate intolerance is first diagnosed during pregnancy

through an oral glucose tolerance test. Between 5.5 and 8.8% of

pregnant women develop GDM in Australia. Risk factors for GDM

include a family history of diabetes, increasing maternal age, obesity and

being a member of a community or ethnic group with a high risk of

developing type 2 diabetes. While the carbohydrate intolerance usually

returns to normal after the birth, the mother has a significant risk of

developing permanent diabetes while the baby is more likely to develop

obesity and impaired glucose tolerance and/or diabetes later in life. Self-

care and dietary changes are essential in treatment.

Herbal treatment

Nature has provided an excellent storehouse of remedies to cure all the

aliments of mankind. In ancient days, almost all the medicine used was
from natural sources, particularly from plants and plants continue to be
an important source of new drugs even now. The importance of
biological, chemical and pharmacological evaluation of plant derived
agents used in the treatment of human aliments has been increasingly
recognized in the last decades.

Ayurveda is recorded in ancient scripture, handed down through

generations and developed over 6000 years. This time-tested holistic
medicinal system maintains that good health exists when the body,
mind, spirit and environment are in perfect harmony. Good health is a
phenomenon rare in today’s fast moving world, where people live in a
stressful environment and follow an unplanned diet and unbalanced life
style. It has become the need of the hour that a new vibrant medical
system evolved which is devoid of any side effects and which leads
resurgence of Ayurvedic traditions. Herbal and herbal-based molecules
are expected to form the basis for such a development. Even in the era of
genetic engineering, plants account for forty percent (40%) of all the
medicinal formulation prescribed in the United States. In China about
forty percent (40%) of the total medical consumption is attributed to
traditional tribal medicines. About 1400 herbal preparation are used
widely, according to a recent survey in member states of European
Union.

Rig-Veda and Ayurveda (4500-1600 BC) reveal that

ancient Indians had a rich knowledge of the use of medicinal plants.

India unquestionably occupies the topmost position in the use of herbal

drugs since ancient times utilizing nearly 600 plant species in different

formulations. Great majorities of people in India have been depending

on crude drugs for the treatment of various diseases as evidenced from

well-documented indigenous system of medicines, Ayurveda and Unani.

The Materia Medica of these systems contains a rich heritage of

indigenous herbal drugs.8

Herbs for Diabetes

Since antiquity, diabetes has been treated with plant medicines. Recent scientific

investigation has confirmed the efficacy of many of these preparations, some of

which are remarkably effective. Only those herbs that appear most effective, are
relatively non-toxic and have substantial documentation of efficacy are covered

here.

Pterocarpus marsupium (Indian Kino, Malabar Kino, Pitasara, Venga)

The tree is the source of the Kino of the European pharmacopeas. The gum-resin
looks like dried blood (Dragon's blood), much used in Indian medicine. This herb
has a long history of use in India as a treatment for diabetes. The flavonoid, (-)-
epicatechin, extracted from the bark of this plant has been shown to prevent
alloxan-induced beta cell damage in rats.

Both epicatechin and a crude alcohol extract of Pterocarpus marsupium have

actually been shown to regenerate functional pancreatic beta cells. No other drug
or natural agent has been shown to generate this activity.

Bitter Melon (Momordica charantia)

Bitter melon, also known as balsam pear, is a tropical vegetable widely cultivated
in Asia, Africa and South America, and has been used extensively in folk medicine
as a remedy for diabetes. The blood sugar lowering action of the fresh juice or
extract of the unripe fruit has been clearly established in both experimental and
clinical studies.

Bitter melon is composed of several compounds with confirmed anti-diabetic

properties. Charantin, extracted by alcohol, is a hypoglycaemic agent composed of
mixed steroids that is more potent than the drug tolbutamide which is often used in
the treatment of diabetes. Momordica also contains an insulin-like polypeptide,
polypeptide-P, which lowers blood sugar levels when injected subcutaneously into
type 1 diabetic patients. The oral administration of 50-60 ml of the juice has shown
good results in clinical trials.

Excessively high doses of bitter melon juice can cause abdominal pain and
diarrhea. Small children or anyone with hypoglycemia should not take bitter
melon, since this herb could theoretically trigger or worsen low blood sugar, or
hypoglycemia. Furthermore, diabetics taking hypoglycemic drugs (such as
chlorpropamide, glyburide, or phenformin) or insulin should use bitter melon with
caution, as it may potentiate the effectiveness of the drugs, leading to severe
hypoglycemia.

Gymnema Sylvestre (Gurmar, Meshasringi, Cherukurinja)

Gymnema assists the pancreas in the production of insulin in Type 2 diabetes.

Gymnema also improves the ability of insulin to lower blood sugar in both Type 1
and Type 2 diabetes. It decreases cravings for sweet. This herb can be an excellent
substitute for oral blood sugar-lowering drugs in Type 2 diabetes. Some people
take 500 mg per day of gymnema extract.

Onion and Garlic ( Allium cepa and Allium sativum)

Onion and garlic have significant blood sugar lowering action. The principal active
ingredients are believed to be allyl propyl disulphide (APDS) and diallyl
disulphide oxide (allicin), although other constitutents such as flavonoids may play
a role as well.

Experimental and clinical evidence suggests that APDS lowers glucose levels by
competing with insulin for insulin-inactivating sites in the liver. This results in an
increase of free insulin. APDS administered in doses of 125 mg/ kg to fasting
humans was found to cause a marked fall in blood glucose levels and an increase in
serum insulin. Allicin doses of 100 mg/kg produced a similar effect.

Onion extract was found to reduce blood sugar levels during oral and intravenous
glucose tolerance. The effect improved as the dosage was increased; however,
beneficial effects were observed even for low levels that used in the diet (eg., 25 to
200 grams). The effects were similar in both raw and boiled onion extracts. Onions
affect the hepatic metabolism of glucose and/or increases the release of insulin,
and/or prevent insulin's destruction.

The additional benefit of the use of garlic and onions are their beneficial
cardiovascular effects. They are found to lower lipid levels, inhibit platelet
aggregation and are antihypertensive. So, liberal use of onion and garlic are
recommended for diabetic patients.

Fenugreek (Trigonella foenum-graecum)

Experimental and clinical studies have demonstrated the antidiabetic properties of

fenugreek seeds. The active ingredient responsible for the antidiabetic properties of
fenugreek is in the defatted portion of the seed that contains the alkaloid
trogonelline, nicotinic acid and coumarin.

Blueberry leaves (Vaccinium myrtillus)

A decoction of the leaves of the blueberry has a long history of folk use in the
treatment of diabetes. The compound myrtillin (an anthocyanoside) is apparently
the most active ingredient. Upon injection it is somewhat weaker than insulin, but
is less toxic, even at 50 times the 1 g per day therapeutic dose. A single dose can
produce beneficial effects lasting several weeks.
Blueberry anthocyanosides also increase capillary integrity, inhibit free-radical
damage and improve the tone of the vascular system. In Europe, it is used as an
anti-haemorrhagic agent in the treatment of eye diseases including diabetic
retinopathy.

Asian Ginseng

Asian ginseng is commonly used in traditional Chinese medicine to treat diabetes.

It has been shown to enhance the release of insulin from the pancreas and to
increase the number of insulin receptors. It also has a direct blood sugar-lowering
effect.
A recent study found that 200 mg of ginseng extract per day improved blood sugar
control as well as energy levels in Type 2 diabetes (NIDDM).

Bilberry

Bilberry may lower the risk of some diabetic complications, such as diabetic
cataracts and retinopathy.

Stevia

Stevia has been used traditionally to treat diabetes. Early reports suggested that
stevia might have beneficial effects on glucose tolerance (and therefore potentially
help with diabetes), although not all reports have confirmed this. Even if stevia did
not have direct antidiabetic effects, its use as a sweetener could reduce intake of
sugars in such patients.
Ginkgo Biloba

Ginkgo biloba extract may prove useful for prevention and treatment of early-stage
diabetic neuropathy.

Cinnamon - Triples insulin's efficiency

Barberry - One of the mildest and best liver tonics known.

Dosage: tincture, 10-30 drops; standard decoction or 3-9 g.

Herbal Combinations

For all pancreatic problems:

1 part uva ursi
1 part goldenseal
1 part elecampane
2 parts dandelion root
2 parts cedar berries
1 part fennel part(http://www.holistic-online.com/remedies/Diabetes/diabetes_herbs.htm)

Free radicals in biological system

A free radical is any atom or group of atoms capable of independent existence that

contains one or more unpaired valence electrons. The unpaired electrons do not

contribute to intramolecular bonding. That unpaired electron/s controls the

properties of radicals.They are produced by oxidation/reduction reactions, in

which there is a transfer of only one electron at a time, or when a covalent bond is
broken and one electron from each pair remains with each group. Free radicals

can be either highly reactive species like hydrogen atom, hydroxyl radical, or

they can be stable entities like nitric oxide, DPPH radical. In biological systems

free radicals have a range of transitory existences depending upon their reactivity.

Some are stable, e.g. melanins can have a long lifetime, moderately stable ones

such as nitric oxide can have lifetimes of ~5 seconds and highly unstable ones such

as hydroxyl radicals exist for only a hundredth of a microsecondd.[ Halliwell B,

Gutteridge]

The importance of free radicals and reactive oxygen species (ROS) has

attracted increasing attention over the past decade. ROS, which include free
• •−
radicals such as hydroxyl radicals ( OH), superoxide anion radicals (O2 ) and non

free radical species such as H2O2 and singlet oxygen (1O2) are various forms of

activated oxygen. These molecules exacerbate cellular injury and aging process.21

In living organisms, various ROS can be formed in different ways. Normal aerobic

respiration and the stimulation of polymorphonuclear leukocytes, macrophages and

peroxisomes constitute prominent sources of ROS. These are major endogenous

sources of cellular oxidants. Exogenous sources of ROS include tobacco smoke,

certain pollutants, organic solvents and pesticides.22

Antioxidant

Antioxidants can be defined as “any substance which significantly delays or

inhibits oxidative damage to a target molecule.” Antioxidants are the first line of

defense against free radical damage, and are critical for maintaining optimum

health. The need for antioxidants becomes even more critical with increased

exposure to free radicals. As part of a healthy lifestyle and a well-balanced,

wholesome diet, antioxidant supplementation

Oxidation is a chemical reaction that transfers electrons from a

substance to anoxidizing agent. Oxidation reactions can produce free radicals. In

turn, these radicals can start chain reactions that damage cells. Antioxidants

terminate these chain reactions by removing free radical intermediates, and inhibit

other oxidation reactions. They do this by being oxidized themselves, so

antioxidants are often reducing agents such as thiols, ascorbic

acid or polyphenols.[1]

Although oxidation reactions are crucial for life, they can also be damaging;

hence,plants and animals maintain complex systems of multiple types of

antioxidants, such as glutathione, vitamin C, and vitamin E as well

as enzymes such as catalase,superoxide dismutase and various peroxidases. Low

levels of antioxidants, or inhibition of the antioxidant enzymes, cause oxidative

stress and may damage or kill cells.

As oxidative stress might be an important part of many human diseases, the use of
antioxidants in pharmacology is intensively studied, particularly as treatments
for stroke and neurodegenerative diseases. However, it is unknown whether
oxidative stress is the cause or the consequence of disease.

Antioxidants are widely used as ingredients in dietary supplements in the hope of

maintaining health and preventing diseases such as cancer, coronary heart

disease and even altitude sickness. Although initial studies suggested that

antioxidant supplements might promote health, later large clinical trials did not

detect any benefit and suggested instead that excess supplementation may be

harmful. In addition to these uses of natural antioxidants in medicine, these

compounds have many industrial uses, such as preservatives in food and cosmetics

and preventing the degradation of rubber and gasoline.

Antioxidants can also be extracted from fruits,

vegetables, seeds, nuts, meats, and oil. There are two

lines of antioxidant defence within the cell. The first line,

found in the fat-soluble cellular membrane consists of

vitamin E, beta-carotene etc Of these, vitamin E is

considered the most potent chain breaking antioxidant

within the membrane of the cell. Inside the cell water

soluble antioxidant scavengers are present. These

include vitamin C, glutathione peroxidase, superoxide

dismutase, and catalase.20

3.5.3 Classification of Antioxidants

The antioxidant systems are classified into two major groups, enzymatic

antioxidants and non enzymatic antioxidants.

• Enzymatic antioxidants

Enzyme antioxidants are produced in the body and they act as body’s

first line of defense against free radicals. They convert reactive free

radicals into less reactive or inert species. Enzymatic antioxidant present

in the body includes superoxide dismutase (SOD), catalase (CAT), and

glutathione peroxidase (GPx).

 Defense mechanism

• Catalase

Catalase is an enzyme, which can function either in the catabolism of

H2O2 or in the peroxidase oxidation of small substrates such as ethanol,

methanol, and quinine.Most of the aerobic cells have catalyse activity. It

was first crystallized from beef liver by Sumner and Dounce.30 Catalase

is present in all major body organs, especially in liver

The catalyse activity of animal and plant is largely located in sub

cellular organelles known as peroxisome.31 Peroxisomes in animal cells

are involved in the oxidation of fatty acids, synthesis of cholesterol and

bile acids. Hydrogen peroxide is a byproduct of fatty acid oxidation.

Catalase present in the peroxisomes serves to protect the cell from the
toxic effects of hydrogen peroxide. It promotes the conversion of

hydrogen peroxide into molecular oxygen and water without the

production of free radicals.32

Non-enzymatic antioxidants

Endogenous non-enzymatic antioxidants such as GSH and total thiol

were playing an important role in scavenging ROS. Low molecular

weight non-enzymatic antioxidants such as carotenoids, and dietary

phenolic compounds are not manufactured by cell itself so they are

required to supplement through food and diet.

ANTIOXIDANTS IN BIOLOGICAL SYSTEM

Antioxida Mechanisms ref’s.
nts

(a) Enzymatic

Superoxide + 1e (Mitchell RN, et al ,2003)

dismutase
(SOD) O2. – →+ 2H → H2O2 (Vivekananthan,et al,
SOD 2003)

(detoxifies superoxide anion) (Reilly PM,et al, 1993)

2H2O2 → Catalase → 2H2O + O2 (Mitchell RN, et al ,2003)

 (detoxifies hydrogen peroxide) (Rangan U et al 1993)
Catalase
(Reilly PM,et al, 1993)

2GSH + H2O2 → GPX → GSSG + 2H2O (Mitchell RN, et al ,2003)

Glutathion (detoxifies hydrogen peroxide & xenobiotics (Murray RK, et al, 2000)
e biotransformation)
Peroxidase
(GPX)

Glutathion GSSG + NADPH + H+ → GRD → 2GSH + (Mitchell RN, et al ,2003)

e NADP+
Reductase (Murray RK, et al, 2000)
(GRD) (regeneration of reduced glutathione and
xenobiotic biotransformation)

Glucose – ·G6PD+NADP+→NADPH+H+
6 +6Phosphoglucolactone (Murray RK, et al, 2000)
Phosphate ·NADPH + H+ + Oxidised (GSSG)→ NADP+
ehydrogena +Reduced (GSH)
se (G6PD)
Oxidatively →Reduced (GSH)→ Healthy RBC
damaged membrane
R.B.C membrane (prevents oxidative
damage to RBC membrane)

Cytochrom detoxifies 95-99% of O2 in cell. (Rangan U, et al .1993)

e Oxidase
System

Peroxidase detoxifies hydrogen peroxide (Rangan U, et al ,1993)

O2. –(superoxide anion), H2O2(hydrogen peroxide), GSH (reduced glutathione),

GSSG (oxidised glutathione)
TABLE – 2 : ANTIOXIDANTS IN BIOLOGICAL SYSTEM
 Antioxidants Mechanisms ref’s.
(b) Non-
enzymatic

(i) Nutrient

Carotenoid (β- · Chain breaking antioxidant prevents propagation of lipid (Murray

Carotene) peroxidation by trapping peroxide free radicals at low RK, et al,
partial pressure in its conjugated alkyl structure. 2000)
· Scavenger of singlet oxygen and superoxide free radical.
· Also complements Vitamin-E, which is effective at
higher O2concentration.

α-Tocoferol · Prevents lipid peroxidation. (Murray

LOO.+ α-tocopherol-OHÕLOOH+α-tocopherol-O. RK, et al,
2000)
which is relatively safe and stable.
· Stabilizes cell membrane.
· Major natural protective agent against ROS.
· Requires Vitamin-C and selenium for complete reaction.

Ascorbic acid · Prevents lipid peroxidation both in plasma and inside the (Murray
cell. RK, et al,
TOCO.+Vit.C(GSH)ÕRegeneratedTOCOH+Vit.C(GSSG) 2000)
· Protects LDL against peroxidative damage.
· Inactivates OH., O2.-& 1O2.
(ii)
METABOLIC

Glutathione · Metabolism of xenobiotics. (Rangan

· H2O2 detoxification U, et al .
 1993)

Uric acid · Scavenger of 1O2 & OH.. (Rangan

· Binds Fe & Cu ion in the form that they do not U, et al .
accelerate free radical reactions 1993)

Albumin ·Inhibits lipid peroxidation. (Rangan

U, et al .
1993)

Transferrin/ ·Binds to circulating Fe & Cu and therefore prevent Fe & (Rangan

lactoferrin/ Cu dependent lipid peroxidation. U, et al .
ceruloplasmin 1993)

Ferritin · Binds tissue Fe. (Rangan

U, et al .
1993)

Hepatoglobin · Binds free Hb/heme, therefore prevents release of Fe and (Rangan

indirectly prevents Fe dependent lipid peroxidation. U, et al .
1993)

Cysteine · Scavenger of O2.-& OH. (Rangan

U, et al .
1993)

Bilurubin · Scavenger of O2.-& OH. (Rangan

U, et al .
1993)
LOO.(lipid peroxyl radical), α-tocopherol-O.(tocopheroxyl radical),α-tocopherol-

OH(hydroxyl tocopherol), LOOH (lipid hydroperoxide), TOCO. (tocopheroxyl

radical), Vit.C-GSH(reduced),
Hyperlipidemia

In diabetes mellitus apart from raise blood glucose levels, disturbances in the

metabolism of number of other biomolecules such as glucose, lipids proteins &

gylcoprotiens have also been reported.(Dhawan)

Globally diabetes has shadowed the spread of modern lifestyle and it can be linked

to an increase overweight and sedentary population (Vats et al., 2005).

Hyperglycemia and hyperlipidemia are two important charactersof diabetes

mellitus, an endocrine based disease. Diabetic patients experience various vascular

complications, such as atherosclerosis, diabetic nephropathy and neuropathy

(Sheetz, 2002).

It is now well established that the hyperlipidemia represents

a major risk factor for the premature development of atherosclerosis and its

cardiovascular complications (Goldtein et al., 1973; Kaur et al., 2002). A logical

strategy to prevent or treat atherosclerosis and reduce the incidence of

cardiovascular disease events is to target the hyperlipidemia by diets and/or lipid

lowering drugs (Simons, 2002).

Moreover, although glucose levels may be well controlled,

high lipid profiles in serum increase free radical levels, and cause endothelial

damage. The American Heart Association has identified the primary risk factor
associated with progression of atherosclerosis lesions as elevated levels of

cholesterol and triglycerides in serum.

Therefore therapies consider the treatment of hyperlipidemia to be one of the major

approaches towards decelerating the atherogenesis risk (Rhoads et al., 1986).

Lowering of serum lipid levels through dietary or drugs

therapy seems to be associated with a decrease in the risk of vascular disease.

Many investigations suggested that improvement in defective lipid level, glucose,

anti-oxidant levels should be useful in the prevention of diabetes-associated

cardiovascular risk (West, 2000).

In diabetes mellitus Hypertriglyceridemia and low levels of high-

density lipoprotein are the most common lipid abnormalities. In type 1 diabetes

mellitus, these abnormalities can usually be reversed with glycemic control. In

contrast, in type 2 diabetes mellitus, although lipid values improve, abnormalities

commonly persist even after optimal glycemic control has been achieved. (O’Brien

T, et al, 1998)

Major lipids found in blood stream are triglycerides,

phospholipids, cholesterol and cholesterol esters and free fatty acids. The function

of cholesterol is to help carry fat in the body, because fat being insoluble in water
cannot travel on its own in the blood stream. Cholesterol associates with fat and

protein and comes out of the liver as lipoprotein. There are several types of

lipoproteins for the transport of fatty material in the body such as chylomicrons,

very low density lipoproteins (VLDL), low density lipoproteins (LDL),

intermediate density lipoproteins (IDL) and high density lipoproteins (HDL). Each

has a different function in the transport system. VLDL are responsible to carry

endogenous triglycerides from the liver into the blood stream and to other parts of

the body. Lipoprotein lipase catalyses triglycerides degradation to generate VLDL

remnants which are further degraded by hepatic glyceride hydrolase to generate

LDL. It easily adheres along the walls of the arteries and, therefore, called as bad

cholesterol. There are different types of HDL like HDL1, HDL2 and HDL3. It is

called good cholesterol as it finds and removes stuck LDL of peripheral cells and

bring them back to liver. Hyperlipidemia, the elevation of lipid concentration in

plasma, is the manifestation of a disorder in the synthesis and degradation of

plasma lipoproteins (Joel, G.H, et al, (2001), ( Sharma, et al, 1997).

Primary type hyperlipidemia can be treated with drugs but the secondary type

originating from diabetes, renal lipid neprosis or hypothyrodism demands the

treatment of original disease rather than hyperlipidemia.

Classification of hyperlipidemia

Type I hyperlipidemia: It is characterised by high concentration of blood

chylomicrons. Currently there are no drugs available for treating this type.

Type II hyperlipidemia: It is subdivided into Type II A hyperlipidemia and

TypeII B hyperlipidemia. Type II A hyperlipidemia is characterized by high LDL

and cholesterol levels with a slight increase in blood triglycerides. Type II B

hyperlipidemia is characterized by the elevation of triglycerides, serum cholesterol,

LDL and VLDL.

Type III hyperlipidemia: It shows elevated levels of triglycerides and IDL. A

blockade in the normal conversion of VLDL to LDL results in accumulation of

IDL. Controlled diet is the treatment of this type of hyperlipidemia.

Type IV hyperlipidemia: It is the sequel to high concentration of triglycerides

and VLDL and often faulty carbohydrate metabolism. Both diet and drug therapy

is recommended for this type of hyperlipidemia.

Type V hyperlipidemia: It shows elevated levels of chylomicrons, VLDL and

triglycerides resulting from faulty carbohydrate metabolism.

A major concern in patients with hyperlipidemia is the increased risk of

atherosclerosis resulting in heart diseases. The aim of treating the patients with

hyperlipidemia is to reduce serum cholesterol and/or improve the HDL cholesterol

by maintaining a high ratio of HDL to LDL cholesterol level there by reducing the

risk of developing heart disease or the occurrence of further cardiovascular or

cerebrovascular events.

Hesperidin:

Hesperidin is a flavanone glycoside (flavonoid) (C28H34O15) found abundantly

in citrus fruits. Its aglycone form is called hesperetin. Hesperidin is a flavanone
glycoside consisting of the flavone hesperitin bound to the disaccharide rutinose.
The sugar cause hesperidin to be more soluble than hesperitin. [
Garg A, Garg S, Zaneveld LJ, Singla AK. 2001. Chemistry and pharmacology of the Citrus
bioflavonoid hesperidin. Phytother Res 2001 Dec; 15(8): 655-69.]

Hesperidin
MW: 610
Formula: C28H34O15
 Distribution

The phytochemical hesperidin is mainly found in citrus fruits such as lemons and

oranges. The highest concentration of hesperidin can be found in the white parts

and pulps of the citrus peels. Hesperidin can also be found in green vegetables.

Properties

Hesperidin has antioxidant, anti-inflammatory, hypolipidemic, vasoprotective and

anticarcinogenic and cholesterol lowering actions. Hesperdin can inhibit following

enzymes: phospholipase A2, lipoxygenase, HMG-CoA reductase and cyclo-

oxygenase.

Hesperidin improves the health of capillaries by reducing the capillary

permeability.

Hesperidin is used to reduce hay fever and other allergic conditions by inhibiting

the release of histamine from mast cells. The possible anti-cancer activity of

hesperidin could be explained by the inhibition of polyamine synthesis.

A study 'Hesperidin, a citrus flavonoids, inhibits bone loss and decreases serum
and hepatic lipids in ovariectomized mice' by Hiroshige Chiba et al (J. Nutrition,

June 2003) showed that hesperidin added to the died not only lowered serum and

hepatic cholesterol, but also inhibited bone loss by decreasing osteoclast number in

ovariectomized mice. The molecular mechanism of the inhibitory effect of

hesperidin on bone resorption is not clear.

Synonyms

Hesperetin 7-rhamnoglucoside, hesperetin-7-rutinoside

Properties
 Molecular formula C28H34O15

Molar mass 610.56 g mol−1

Exact mass 610.18977

Hesperidin as a Component of 'Vitamin P':

Citrus bioflavonoids were first identified by Albert Szent-Gyorgyi in 1936, winner of

The Nobel Prize for the discovery of vitamin C. He reported that citrus bioflavonoids

strengthened blood vessel walls and prevented capillary permeability in ways that

vitamin C did not. Indeed, he called these bioflavonoids 'vitamin P' after the

Permeability factor because they prevented the permeability of capillaries. It was in

the course of isolating vitamin C that he came across the bioflavonoids. Certain

vitamin C deficiency symptoms (i.e. easy bruising, bleeding gums) were found in

early studies to be relieved by crude vitamin C extract but not by purified vitamin

C. Szent-Gyorgyi had a friend with bleeding gums and thought this condition might

have something to do with a vitamin C deficiency. He gave the man some raw,

impure vitamin C, and sure enough the bleeding gums cleared up. Later on,

confronted by a recurrence of bleeding gums, he decided to try again; this time

with pure vitamin C. He expected to observe an even more dramatic result but it

did not occur. The man's gums went right on bleeding. Szent-Gyorgyi re-examined

his earlier preparation and decided that the effective impurity was bioflavonoids. He

then tried these by themselves, and reported that they worked. He named these

substances "vitamin P." Bioflavonoids thus first came into use as protectors of
capillaries, the tiniest blood vessels in the body. Later studies disputed his findings

because a deficiency state could not be identified and so these compounds

(including hesperidin) never actually attained full vitamin status. This is because

there are over 4,000 different flavonoids with different properties and biological

activities. Later studies done by Dr. Jacques Masquelier of France found that certain

bioflavonoids called oligomeric proanthocyanidins (concentrated in grape seeds,

grape skins, red wine, pine bark and many tree leaves) are the most effective

components of the 'vitamin P' mixture that Szent-Gyorgyi spoke of. Clinical studies

now confirm that hesperidin also has significant 'vitamin P' activity.

Therapeutic
Uses:

- Allergies
- Anti-aging
- Anti-inflammatory
- Antioxidant
- Bruises
- Cancer
- Capillary Fragility
- Cellular Regeneration
- Chronic Venous Insufficiency
- Circulatory Disorders
- Cramps (legs)
- Diabetic Complications
- Free Radical Related Diseases
- Hay Fever
- Hemorrhoids
- Immune System
- Leg Vein Health
- Lower LDL Cholesterol
- Menopausal Symptoms
- Nocturnal Leg Cramps
- Non-healing Ulcers
- Pain (lower extremities)
- Prevention of abnormal growths
- Skin Ulcers
- Vascular Disorders
- Ulcers (external skin ulcers)
- Venous Insufficiency
- Wounds

Drug
Interactions:
Hesperidin and other bioflavonoids tend to
reduce blood platelet stickiness in a beneficial
way and therefore may reduce the dosage
required for blood thinners.