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INTRODUCTION
Diabetes mellitus, a current threat to world population health with its multiple disorders, is now one
of the major diseases. Diabetes is very aged disease since 1550 B.C. It was documented by
Egyptians on papyrus. Historical accounts reveal that as early as 700-200 B.C., Diabetes mellitus
was a well recognized disease in India and was even distinguished as two types; a genetically based
disorder and other one resulting from dietary indiscretion (Oubre et al., 1997).
The term diabetes, which is Greek word, means “to run through” or “a siphon” was coined by
Aretaeus of Cappadocia (81-138 A.D.), who noted that a large amount of urine “run through” the
kidneys in this disease. The Latin adjective, mellitus means ‘honey-sweet’, was added by Cullen
(1710–1790) in order to distinguish diabetes mellitus or ‘sugar diabetes’ from diabetes insipidus. In
the Sanskrit literatures of the 5th-6th century A.D., the Indian physician, Sušruta (A.D. 500) gave a
recognizable description of diabetes mellitus as “Madhu-Meha” (or Ikshu-Meha) or Honey-urine
and described the symptoms of thirst, foul breath, voracious appetite and languor.
The major breakthrough came in 1921 through isolation of blood sugar lowering hormone by
Banting and Best. Earlier insulin was extracted from the pancreas of calf, porcine. After introduction
of recombinant DNA technology, the synthetic genes for the A and B chains were cloned into
bacteria (Eli Lilly, Indianapolis) and the resultant peptide products were combined to form human
insulin.
Besides the use of insulin for the treatment of diabetes, other therapeutic approaches for the control
of hyperglycemia include the use of α- glucosidases, sulphonylureas, biguanides, and
thioazolidinediones etc. However, these drugs have many adverse effects such as causing
hypoglycaemia, liver problems, lactic acidosis, weight gain and diarrhea. Since the currently
available treatment is expensive and far from satisfactory, alternate therapeutic approaches like the
use of medicinal plants for controlling diabetes are gaining popularity among the scientific
community.
For centuries, plants with medicinal properties have been employed by traditional systems of
medicine like Ayurveda, Siddha, Unani, Traditional Chinese Medicine, Native American Medicine,
and Latin American folk systems for the treatment of various diseases including diabetes mellitus.
They are considered to be effective and non-toxic. They have a vast potential which has only partly
been explored by modern methods. Traditional plant remedies have provided modern medicine with
numerous pharmaceutical preparations. During the last two decades, there has been a sudden
resurgence of interest in medicinal plants used in traditional systems of medicine. The use of herbal
medicine as an alternative therapy is gaining considerable recognition and popularity worldwide. In
fact, the use of herbal remedies has increased approximately 380% during the last 7 years in the
United States. So there is a great need to emphasize on the use of these traditional medicines for the
cure of diabetes and other diseases.
GLOBAL PREVALENCE OF DIABETES MELLITUS
Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase
in the incidence of diabetes worldwide. Diabetes mellitus is now a major threat to human health in
the 21st century. In the past two decades there is an explosive increase in the number of people
affected with diabetes. The global prevalence of diabetes for all age group worldwide was estimated
to be 2.8% in 2000 and 4.4% in 2030. The total number of people with diabetes is projected to rise
from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than
women, but there are more women with diabetes than men. The urban population in developing
countries is projected to double between 2000 and 2030. The most important demographic change to
diabetes prevalence across the world appears to be the increase in the proportion of people >65 years
of age (Sarah et al., 2004). The Asia Pacific region is at the vanguard of the current epidemic of
diabetes (Cockram, 2000). The Indian scenario is equally alarming, with the age and gender
standardized prevalence rate of 4.3% (Sadikot et al., 2004), clearly shows that the WHO estimate of
the Indian diabetes burden of 35 million people by 2025 (King et al., 1998) has been reached more
than two decades earlier. In figure 1 you can compare the number of people at the age group of 2079 in 2007 and 2025. Figure 2 is covering the statistics of diabetic people country wise in 2007 and
in 2025. This increase in incidence of diabetes in developing countries is due to the rapid increase in
population, increased longevity and high ethnic susceptibility to diabetes coupled with rapid
urbanization and lifestyle changes.
The frequency of type 1 diabetes is low, relative to type 2 diabetes, which accounts for over 90% of
cases globally. The diabetes epidemic is affecting particularly to people with type 2 diabetes, and is
taking place both in developed and developing nations, which is strongly associated with a sedentary
lifestyle and obesity (Zimmet, 1999). This trend of increasing prevalence of diabetes and obesity has
already imposed a huge burden on health-care systems and this will continue to increase in the
future (Zimmet, 2000; American Diabetes Association, 1998). Although type 2 diabetes is
numerically more prevalent in the general population, type 1 diabetes is the most common chronic
disease of children. But with the increasing prevalence of type 2 diabetes in children and
adolescents, the order may be reversed within one to two decades (Fagot-Campagna et. al., 2000;
Fagot-Campagna and Narayan, 2001). Epidemiological studies among migrant Asian Indians in
many countries showed higher prevalence of type 2 diabetes compared with the host populations
and other migrant ethnic groups (Zimmet, 1999). Studies conducted in India in the last decade have
highlighted that not only is the prevalence of type 2 diabetes high, but also that it is increasing
rapidly in the urban population (Mohan et al., 2001; Misra et al., 2001).
[[Image:]]
Fig. 1. Global prevalence of Diabetes mellitus
[[Image:]]
Fig. 2. Country wise frequency of diabetic people in world (Source: Diabetes Atlas Third Edition, ©
Internaitonal Diabetes Federation 2006)
CLASSIFICATION OF DIABETES MELLITUS
The classification and diagnostic criteria used for the diagnosis of diabetes and disorders of glucose
homeostasis has been the subject of much debate (Albert and Zimmet, 1998; Expert Committee,
1997). Currently, there are five major clinical categories of disordered glucose homeostasis:
1.
2.
3.
4.
5.
Type 1 Diabetes
Type 2 Diabetes
Impaired glucose tolerance/impaired fasting glucose
Gestational Diabetes
Other rare form include maturity-onset diabetes of the young (MODY), pancreatic diabetes.
Several types of diabetes have been reported and are enlisted below. Of these, Type 1 diabetes
mellitus (T1DM) and Type 2 diabetes mellitus (T2DM) are the two major types of diabetes that
affect majority of the population.
Contents


1 OTHER TYPES OF DIABETES MELLITUS
o 1.1 -Chronic or recurrent pancreatitis
2 ALTERNATIVE THERAPY: USE OF PLANT PRODUCTS AS POTENTIAL ANTIDIABETIC AGENTS
o 2.1 Butler, A. E., Janson, J., Bonner-Weir, S., Ritzel, R. A., and Butler, P. C. (2003)
Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes.
Diabetes, Jan;52(1):102-110.
o 2.2 Kahn, S. E. (2001) Importance of ß-Cell Failure in the Development and
Progression of Type 2 Diabetes. The Journal of Clinical Endocrinology &
Metabolism, Vol. 86, No. 9, 4047-4058.
OTHER TYPES OF DIABETES MELLITUS
1.Diabetes due to pancreatic disease
-Chronic or recurrent pancreatitis
-Hemochromatosis
2.Diabetes due to other endocrine disease
-Cushing’s syndrome
-Hyperaldosteronism
-Acromegaly
-Thyrotoxicosis
-Phaerochromocytoma
-Glucagonoma
3.Diabetes due to drugs and toxins
-Glucocorticoids and ACTH
-Diazoxide
-Diuretics
-Phenytoin
-Pentamidine
-Vacor
4.Diabetes due to abnormalities of insulin or its receptor
-Insulinopathies
-Receptor defects
-Circulating antireceptor antibodies
5.Diabetes associated with genetic syndromes
-DIDMOAD (Diabetes Insipidus, Diabetes mellitus, Optic Atrophy, and Deafness) syndrome
-Myotonic dystrophy and other muscle disorders
-Lipoatrophy
-Type 1 glycogen storage disease
-Cystic fibrosis
Type 1 Diabetes Mellitus (T1DM)
Type 1 indicates the processes of beta–cell destruction that may ultimately lead to diabetes mellitus
in which “insulin is required for survival” to prevent the development of ketoacidosis, coma and
death. An individual with a Type 1 process may be metabolically normal before the disease is
clinically manifest, but the process of beta–cell destruction can be detected (fig. 3) Type 1 is usually
characterized by the presence of anti–GAD (Glutamic acid decarboxylase), islet cell or insulin
antibodies which identify the autoimmune processes that lead to beta–cell destruction. In some
subjects with this clinical form of diabetes, particularly non–Caucasians, no evidence of an
autoimmune disorder is demonstrable and these are classified as “Type 1 idiopathic”. Aetiological
classification may be possible in some circumstances and not in others. Thus, the aetiological Type
1 process can be identified and sub–categorized if appropriate antibody determinations are
performed. It is recognized that such measurements may be available only in certain centres at the
present time. If these measurements are performed, then the classification of individual patients
should reflect this. Type 1 Diabetes is autoimmune disease that affects 0.3% on average.
Researchers believe that some of the Etiology and Risk factors which may trigger type 1 diabetes
may be genetic, poor diet (malnutrition) and environment (virus affecting pancreas). Secondly, in
most of the cases diabetes occurs because there is abnormal secretion of some hormones in blood
which act as antagonists to insulin. Example- Adrenocortical hormone, Adrenaline hormone and
Thyroid hormone.
[[Image:]]
Fig. 3. Histopathology of Islets of Langerhans
Type 2 Diabetes Mellitus (T2DM)
Concurrent with obesity epidemic, the incidence of type 2 diabetes is increasing at an alarming rate.
Type 2 diabetes arises when the endocrine pancreas fails to secrete sufficient insulin to cope with
the metabolic demand (Donath and Halban, 2004), because of acquired β-cell secretory dysfunction
and/or decreased β -cell mass. Insulin secretory dysfunction in type 2 diabetes is well documented
and has been reviewed elsewhere (Kahn, 2001). Whether insulin secretory dysfunction is a cause or
consequence of the disease is still debated, but there is mounting evidence that it may be
symptomatic of changes in β -cell mass. Although proposed nearly 50 years ago, the hypothesis that
β -cell loss plays an important role in the pathogenesis of type 2 diabetes has only recently come to
the fore. β -cell mass in the adult is plastic, and adjustments in β -cell growth and survival maintain a
balance between insulin supply and metabolic demand. For example, obese individuals who do not
develop diabetes exhibit an increase in β -cell mass that appears to compensate for the increased
metabolic load and obesity-associated insulin resistance. However, this β -cell adaptation eventually
fails in the subset of obese individuals who develop type 2 diabetes (Weir et al., 2004). Indeed, most
individuals with type 2 diabetes, whether obese or lean, show a net decrease in β -cell mass (Butler
et al., 2003). Thus, type 2 diabetes is a disease of relative insulin deficiency.
SYMPTOMS
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by
chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting
from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include
long–term damage, dysfunction and failure of various organs. Diabetes mellitus may present with
characteristic symptoms such as polydipsia (thrist), polyuria (excretion), polyphagy (eating),
blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non–ketotic
hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment,
death. Often symptoms are not severe, or may be absent, and consequently hyperglycaemia
sufficient to cause pathological and functional changes may be present for a long time before the
diagnosis is made. The long–term effects of diabetes mellitus include progressive development of
the specific complications 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. People with diabetes are at increased risk of
cardiovascular, peripheral vascular and cerebrovascular disease (WHO report, 1999).
Apart from all these symptoms there are major skin and other complications as cataract and
glaucoma. Diabetes affects different body parts of a person including skin. The skin disorders can be
seen in normal individual too, but diabetics are more frequently prone to it. Some of the specific
skin infections frequently seen in the diabetes patients are bacterial and fungal infections,
dermopathy, necrobiosis lipoidica, diabeticorum, xanthomatosis, disseminated granuloma annulare
and blisters and others as albuminiuria, Diabetes myonecrosis, diabetic mastopathy
(http://diabetesinformationhub.com).
Several pathogenetic processes are involved in the development of diabetes. These include processes
which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that
result in resistance to insulin action. The abnormalities of carbohydrate, fat and protein metabolism
are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.
DIAGNOSIS
If a diagnosis of diabetes is made, the clinician must feel confident that the diagnosis is fully
established since the consequences for the individual are considerable and lifelong. The
requirements for diagnostic confirmation for a person presenting with severe symptoms and gross
hyperglycaemia differ from those for the asymptomatic person with blood glucose values found to
be just above the diagnostic cut–off value. Severe hyperglycaemia detected under conditions of
acute infective, traumatic, circulatory or other stress may be transitory and should not in itself be
regarded as diagnostic of diabetes. The diagnosis of diabetes in an asymptomatic subject should
never be made on the basis of a single abnormal blood glucose value. For the asymptomatic person,
at least one additional plasma/blood glucose test result with a value in the diabetic range is essential,
either fasting, from a random (casual) sample, or from the oral glucose tolerance test (OGTT). If
such samples fail to confirm the diagnosis of diabetes mellitus, it will usually be advisable to
maintain surveillance with periodic re–testing until the diagnostic situation becomes clear. In these
circumstances, the clinician should take into consideration such additional factors as ethnicity,
family history, age, adiposity, and concomitant disorders, before deciding on a diagnostic or
therapeutic course of action. An alternative to blood glucose estimation or the OGTT has long been
sought to simplify the diagnosis of diabetes. Glycated haemoglobin, reflecting average glycaemia
over a period of weeks, was thought to provide such a test. Although in certain cases it gives equal
or almost equal sensitivity and specificity to glucose measurement (McCance et al., 1994), it is not
available in many parts of the world and is not well enough standardized for its use to be
recommended at this time. Another criterion for the diagnosis is the glycosylated haemoglobin
(HbA1c). If the HbA1c level is >6%, the person will be diabetic.
The clinical diagnosis of diabetes is often prompted by symptoms such as increased thirst and urine
volume, recurrent infections, unexplained weight loss and, in severe cases, drowsiness and coma;
high levels of glycosuria are usually present.
A fasting blood sugar level less than 100 milligrams of glucose per deciliter of blood (mg/dL) is
considered normal. If your blood sugar level is 100 to 125mg/dL, you have prediabetes - also called
impaired fasting glucose (IFG). If you are suffering from prediabetes then the fasting blood sugar as
well as post postprandial blood sugar will fluctuate easily. After fasting for at least eight hours, FBS
(fasting blood sugar) is checked and then an oral dose of 75 g glucose (Oral glucose tolerance test
OGTT) is administered. For children the oral glucose load is related to body weight: 1.75 g per kg.
The blood glucose level is checked after one hour and if it reaches 144-199 mg/dl after two hours,
you have impaired glucose tolerance. Currently, type 2 diabetes mellitus is diagnosed when the
underlying metabolic abnormalities consisting of insulin resistance and decreased β-cell function
cause elevation of plasma glucose above 126 mg/dl (7 mmol/liter) in the fasting state and/or above
200 mg/dl (11.1 mmol/liter) 120 min after a 75-g glucose load (Report of the Expert Committee,
1999). The requirements for individual diagnosis differ from those of population studies. The
diagnosis should not be based on a single glucose determination but requires confirmatory
symptoms or blood/plasma determination. Diagnosis requires the identification of people at risk for
development of complications in whom early preventive strategies are indicated. Ideally therefore
both the 2–h and the fasting value should be used. However, the fact that many newly diagnosed
type 2 diabetic subjects already suffer from so called “late complications of diabetes” at the time of
diagnosis (Beck et al., 1994) indicates that the diagnosis may have been delayed and, in addition,
that the prediabetic condition is harmful to human health and requires increased awareness by
physicians and the general public. Thus, type 2 diabetes mellitus represents only the “tip of the
iceberg” (Fig. 4) of long existing metabolic disturbances with deleterious effects on the vascular
system, tissues, and organs.
[[Image:]]
Fig. 4. Diabetes mellitus type 2: the tip of the iceberg.
TREATMENT OF TYPE 1 DIABETES MELLITUS
Type 1 Diabetes is treated with insulin and diet and has no place for the use of oral hypoglycemic
agents.
DIET
The selection of right type of food is extremely important at this stage. One should restrict to food
with low fat and low calories, and on the other side, fresh fruits and vegetables with lots of
antioxidant should be the preferred choice.
INSULIN THERAPY
Insulin is synthesized as a preprohormone in the beta cells of the islets of Langerhans. In normal
individual, insulin is produced by the body in response to the rise in blood glucose level. Apart from
it, spurts of insulin are produced throughout the day and night, to look after the body's resting needs
for insulin and ensure that cells can take up glucose. In other words function of insulin is to counter
the concerted action of a number of hyperglycemia generating hormones, and to sustain low blood
glucose levels. In people with type 1 diabetes, the pancreas no longer makes insulin as the beta cells
have been destroyed and they need insulin shots to use glucose from meals.
Insulin cannot be taken as a pill as it will be break down during digestion just like the protein in
food. Insulin must be injected into the fat under your skin, to make it get into your blood. By
reducing the concentration of glucose in the blood, insulin is thought to prevent or reduce the longterm complications of diabetes, including damage to the blood vessels, eyes, kidneys, and nerves. In
general, the insulins in common use can be considered in four groups based on their action profiles.
They are-
Types of Insulin Examples
Rapid Acting
Humalog (lispro)(Eli Lilly)
NovoLog
(aspart)(Novo
Nordisk)
15 minutes
Onset of
action
Peak of
action
30-90
15 minutes
minutes
40-50
minutes
3-5 hours
Duration of
action
3-5 hours
Short Acting
(Regular)
Humulin N (Eli
Lilly)Novolin N
(Novo Nordisk)
Intermediate
Acting
Mixed Acting
Humulin R (Eli Lilly)Novolin R(Novo
Nordisk)
30-60
minutes
50-120
minutes
1-3 hours
8 hours
20 hours
Humulin L (Eli Lilly)Novolin L (Novo
Nordisk)
1-2.5
7-15 hours 18-24 hours
hours
The onset, peak, and duration of
action of these mixtures would
reflect a composite of the
intermediate and short- or rapidacting components, with one peak of
action.
4-8 hours 8-12 hours 36 hours
Humulin 50/50, 70/30 Humalog Mix
75/25Humalog Mix 50/50(Eli
Lilly)Novolin 70/30Novolog Mix
70/30(Novo Nordisk)
5-8 hours
Long Acting
Ultralente (Eli Lilly)
Lantus (glargine)
1 hour
None
24 hours
(Aventis)
TREATMENT OF TYPE 2 DIABETES MELLITUS
PHYSICAL EXERCISE
Endurance exercise increases the rate of utilization of all metabolic fuels. Hence, it decreases the
glycogen content in muscle. The latter may result in an increase in the activity of glycogen synthase
and, consequently, may decrease the requirement for insulin in the stimulation of glycogen synthesis
after a carbohydrate meal. In addition, it has been shown that, in normal subjects, endurance training
markedly increase insulin sensitivity, so that very much lower concentrations of insulin are required
to control blood glucose concentration after an oral glucose load. It has also been shown that, in
diabetic subjects who were exercised to deplete muscle glycogen stores (by 80%), the rate of
glycogen synthesis in the muscles for 4-hour post -exercise, after a carbohydrate-rich meal, was the
same whether the subjects took their normal insulin or were deprived of it.
ORAL HYPOGLYCEMIC AGENTS
Current therapeutic approaches were largely developed in the absence of defined molecular targets
or even a solid understanding of disease pathogenesis. Within the past few years, our understanding
of biochemical pathways related to the development of metabolic syndrome has expanded. There is
an unprecedented range of molecular drug targets within these pathways. They have been identified
on the basis of predicted roles in modulating one or more key aspects of the pathogenesis of diabetes
and metabolic syndrome. Several mechanistic categories for new therapeutic approaches can be
considered. First are approaches aimed at reducing excessive glucose production by the liver;
second, mechanisms to augment glucose-stimulated insulin secretion; third, specific molecular
targets in the insulin signalling pathway; and fourth, new approaches to obesity and altered lipid
metabolism, which offer the prospect of net improvements in insulin action (or secretion) (Fig. 5)
(David, 2001).
[[Image:]]
Fig. 5. A better understanding of defects involving several key organ systems has led to new drug
targets for type 2
diabetes.
When diet, exercise and ideal body weight aren’t enough to maintain normal blood sugar level, there
may be need to start medication. Medications used to treat diabetes include insulin too. Usually,
people with Type 1 diabetes don't use oral medications. Diabetes Medications work best in people
with Type 2 diabetes who have had high blood sugar for less than ten years with normal weight or
obesity. Some people who begin treatment with oral medications eventually need to take insulin.
Insulin and oral diabetes medications deliberately work to lower your blood sugar. In certain cases
medications taken for other conditions may affect glucose levels. Number of drug options exists in
market for treating type 2 diabetes (Table 1), includes:
Sulfonylureas
Since 1994, sulfonylureas were the only drug used for diabetes in United States. It stimulates your
pancreas for the production of more insulin to lower down your blood sugar. It can be effective
when your pancreas can make some insulin of its own. Sulfonylureas such as glipizide (Glucotrol,
Glucotrol XL), glyburide (DiaBeta, Glynase PresTab, Micronase) and glimepiride (Amaryl) are
prescribed more often. If your body is sensitive to sulfa drug then you must avoid sulfonylureas.
Side Effects:




Low blood sugar.
Stomach upset.
Skin rash and itching.
Weight gain.
Biguanides
Metformin (Glucophage, Glucophage XR) is the generic name of this drug. It works by inhibiting,
the production and release of glucose from your liver. It also lowers down the insulin secretion. One
good thing about biguanides drug is that it tends to slow down weight gain than do others. It can
also improve blood cholesterol level, which is generally high if you are type 2 diabetic.
Side Effects:



If you already have a kidney problem, metformin may build up in your body. Inform your
doctor when you are placed on this medication regarding your kidney problem.
If you are vomiting, have diarrhea, and can't drink enough fluids, you may need to stop
taking this diabetes medication for a few days.
You may feel metallic taste.

If you are going for medical test using dye, or planning to opt for any surgery, then inform
your doctor about your metformin intake. He will instruct you to stop taking metformin for
some specific period.
α -glucosidase Inhibitors
α -glucosidase inhibitors are of two types, acarbose and miglitol. They block the enzymes of
digestive system which are responsible to break down the starches you eat. The sugar produced is
absorbed slowly and helps prevent the rise of blood sugar level throughout the day, but usually right
after meals. Drugs under this class are acarbose (Precose) and miglitol (Glyset).
Side Effects:


Stomach problems such as gas, bloating and diarrhea, that is temporary.
High dosages may cause permanent changes in liver.
Thiazolidinediones
The generic names for these drugs are pioglitazone (Actos) and Troglitazone (Rezulin),
Rosiglitazone (Avandia). Troglitzeone (Rezulin) was banned in March 2000 as it causes liver
failure. Thiazolidinediones drug makes your body tissue more sensitive to insulin. The insulin can
then move glucose from your blood into your cells for the production of energy.Side Effects:





It may affect your liver function and lead to nausea, vomiting, stomach pain, lack of appetite,
tiredness, yellowing of the skin or whiteness in the eyes, or dark-colored urine.
If you take birth control pills, this drug may decrease its effectiveness in preventing
pregnancy.
Unusual weight gain.
Loss of appetite may develop risk of anemia which will make you feel tired.
Swelling in the legs or ankles.
Meglitinides
Meglitinides is available with the generic name Repaglinide (Prandin). It helps your pancreas make
more insulin right after meals which lowers blood sugar. This effect is much similar to short acting
sulfonylureas. Meglitinides works quickly, and the results fade rapidly, so your doctor might
prescribe Repaglinide only or with Metformin.
Side Effects:


weight gain
low blood sugar
TABLE 1
Current therapeutic agents for type 2 diabetes
Drug Class
Molecular
Target
Insulin
Insulin receptor
Sulhponylureas (e.g. glibenclamide
plus nateglinide and repagnilide)
SU receptor/K+
ATP channel
Metformin-biguanides
Unknown
Acarbose
α- glucosidase
Pioglitazone, rosaglitazone
(thioazolidinediones)
PPARγ
Site(s) of
Adverse Events
Action
Liver, fat,
Hypoglycemia, weight
muscle
gain
Pancreatic β- Hypoglycemia, weight
cell
gain
Gastrointestinal
Liver
disturbances, lactic
(muscle)
acidosis
Gastrointestinal
Intestine
disturbances
Fat, muscle, Weight gain, Oedema,
liver
Anaemia
COMBINATORIAL THERAPY
Insulin resistance is routinely present; a treatment that improves insulin sensitivity of muscle,
adipose tissue, liver, or a combination of these should also benefit nearly all patients. Also, neither
insulin secretion nor insulin action is a simple process, and single-agent regimens may not
adequately restore either of these two functions. Moreover, changes of insulin resistance at various
sites may not always be the same and a treatment targeting hepatic sensitivity may have more effect
on fasting hyperglycemia.
Given these complexities, therapy of Type 2 diabetes should strive to do several things at once. Both
insulin deficiency and insulin resistance should be treated, and both basal and postprandial
hyperglycemia should be addressed. Since no single agent can do all this, combinations will
routinely be needed.
Evidence is accumulating that the longer-acting agents have less tendency to cause hypoglycemia
than the others, especially glibenclamide, Repaglinide and nateglinide are insulin secretagogues
which, like sulfonylureas, act by binding to the KATP –channel complex on beta cells, but they have
more rapid onset and shorter duration of action than the sulfonyl ureas. Due to this difference, they
may have slightly more effect on postprandial hyperglycemia than sulfonylureas.
The α-glucosidase inhibitors acarbose and miglitol delay absorption of dietary carbohydrate by
blocking digestion of starches in the upper small intestine, and thereby reduce the postprandial
glycemic peaks.
ALTERNATIVE THERAPY: USE OF PLANT
PRODUCTS AS POTENTIAL ANTIDIABETIC AGENTS
Type 2 diabetes has become a global epidemic. Modern medicines, despite offering a variety of
effective treatment options, can have several adverse effects. Ayurveda, a science that uses herbal
medicines extensively, originated in India. Of considerable interest is the adoption of Ayurveda by
the mainstream medical system in some European countries (e.g., Hungary), emphasizing this
modality is increasing worldwide recognition. From ancient times, some of these herbal preparations
have been used in the treatment of diabetes (Saxena et al., 2004). World Health Organization
(WHO) recommendations (WHO, 1980) on the use of alternative medicines for treating diabetes
mellitus provide an impetus for research in this area. Currently, the focus of research in diabetes
includes discovering newer antidiabetic agents as well as isolating the active compounds from
herbal sources that have been documented to have antidiabetic properties as have been described in
ancient texts (Tripathi, 1998).
More than 800 plants are used as traditional remedies in some form or another for the treatment of
diabetes according to ethnobotanical information (Ajgaonkar, 1979; Alarcon- Aguilara et al., 1998).
However, only a few herbs have been evaluated scientifically.
Azadirachta indica, Aloe vera, Eucalyptus globulus, Phaseolus vulgaris, Salvia lavandufolia,
Syzygium jambolana, Lavandula stoechas, Cuminum nigrum, Coriandrum sativum, Melia
azadirachta, Amanita phalloides, Opuntia streptacantha are some of the traditional anti-diabetic
plants with scientific and/or medical support for the hypoglycemic effect, although the active
principles are unestablished.
A wide array of active principles from plants, particularly disulfides, alkaloids, glycosides, and
polysaccharides, peptidoglycans and diguanides have demonstrated hypoglycemic activity
consistent with their possible use in the treatment of diabetes mellitus. Raw onion bulbs (Allium
cepa) and garlic cloves (Allium sativum) have long been used as dietary supplements for the
traditional treatment of diabetes in Asia, Europe, and the Middle East. Several plants are deemed to
contain hypoglycemic alkaloids. Leaf infusions and decoctions of Catharanthus roseus (periwinkle)
are widely used as a traditional treatment for NIDDM (Non insulin dependent diabetes mellitus).
The seeds of Trigonella foenumgraecum (fenugreek) are more widely recommended for NIDDM
patients. Various glycoside containing fractions have been implicated as hypoglycemic constituents
of traditional antidiabetic plants. Gymnema sylvestre (gurmar) is used extensively as a treatment for
NIDDM patients, in Asia and has been studied in healthy and alloxan-induced diabetic rabbits
(Ajgaonkar et al., 1979). Leaves of Vaccinium myrtillus (bilberry) were widely used as a treatment
for diabetes before the availability of insulin, and an active glycoside principle, neomyrtillin was
extracted. Cyamopsis tetragonolobus (Indian cluster bean) is recognized in Asian folklore as a
useful aid for the diabetic subject. Another group of hypoglycemic principles is the hypoglycins
(aminopropylpropionic acid derivatives isolated from the unripe fruits of Blighia sapida (ackee
fruit), a traditional treatment for diabetes in Central America and Africa.
Of all these plants described earlier for the treatment of diabetes Momordica charantia (Fig. 6) has
great importance in current scenario for the same. M. charantia, a climber belonging to family
Cucurbitaceae, is commonly known as bitter gourd, bitter melon and karela has shown promising
effects in prevention as well as delay in progression of diabetic complications (nephropathy,
neuropathy, gastro- paresis, cataract and insulin resistance) in experimental animals. The
hypoglycemic chemicals of M. charantia are a mixture of steroidal saponins known as charantins,
insulin-like peptides and alkaloids and these chemicals are concentrated in fruits of M. charantia
(Grover et al., 2004). The mechanisms proposed for the hypoglycemic effect of M. charantia have
been attributed to an inhibitory effect on glucose absorption in the intestine (Meir and Yaniv, 1985),
enhanced insulin release from beta cells (Higashino et al.,1992), an extra pancreatic effect via
increased glucose uptake by tissues in vitro (Welihinda et al., 1986), and due to inhibition of
glucose-6-phosphatase and fructose-1,6-bisphosphatase in the liver and stimulation of red-cell and
hepatic glucose-6-phosphate dehydrogenase activities ( Shibib et al., 1993).
[[Image:]] [[Image:]]
[[Image:]]
Fig. 6. Momordica charantia and its part used for treatment of diabetes.
CONCLUSION
Due to economic constraints, providing modern medical healthcare in developing countries such as
India is still a far-reaching goal. Despite the choice of pharmacologic agents, physicians must stress
the non-pharmacologic approaches of diet modification, weight control and regular exercise.
Pharmacologic approaches must be based on patient characteristics, level of glucose control and cost
considerations. Combinations of different oral agents may be useful for controlling hyperglycemia
before insulin therapy becomes necessary. Apart from all these therapies for the treatment of
diabetes discussed above, in present world, people are looking forward for herbal medicines with
very less side effects. Plants like Momordica charantia, Trigonella foenum-graecum, Curcuma
longa, Tinospora cordifolia, and Azadirechta indica getting a great attention for the treatment of this
incurable and worldwide disease.
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