Introduction: -

Diabetes mellitus is a common and very prevalent disease affecting the citizens of
both developed and developing countries. It is estimated that 25% of the world population is
affected by this disease. Diabetes mellitus is caused by the abnormality of carbohydrate
metabolism which is linked to low blood insulin level or insensitivity of target organs to
insulin [1]. Despite considerable progress in the treatment of diabetes by oral hypoglycemic
agents, search for newer drugs continues because the existing synthetic drugs have several
limitations. The herbal drugs with antidiabetic activity are yet to be commercially formulated
as modern medicines, even though they have been acclaimed for their therapeutic properties
in the traditional systems of medicine [2]. The plants provide a potential source of
hypoglycemic drugs because many plants and plant derived compounds have been used in the
treatment of diabetes. Many Indian plants have been investigated for their beneficial use in
different types of diabetes and reports occur in numerous scientific journals.

Ayurveda and other traditional medicinal system for the treatment of diabetes describe
a number of plants used as herbal drugs. Hence, they play an important role as alternative
medicine due to less side effects and low cost. 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 [3].

Hyperglycemia is involved in the etiology of development of diabetic complications.

Hypoglycemic herbs increase insulin secretion, enhance glucose uptake by adipose or muscle
tissues and inhibit glucose absorption from intestine and glucose production from liver [4].
Insulin and oral hypoglycemic agents like sulphonyl ureas and biguanides are still the major
players in the management but there is quest for the development of more effective
antidiabetic agents.

Diabetes mellitus (DM), also known simply as diabetes is a complex metabolic

disorder characterized by hyperglycemia, a physiologically abnormal condition represented
by continued elevated blood glucose levels [5]. Hyperglycemia results from anomalies in
either insulin secretion or insulin action or both and manifests in a chronic and heterogeneous
manner as carbohydrate, fat, and protein metabolic dysfunctions. Diabetes follows a
progressive pattern with complex pathogenesis and varied presentation [6].

1
History: -
The history of diabetes in modern time coincided with the establishment of the
experimental foundations of modern medicine. Two prominent milestones in the history of
medicine paved the way towards understanding the pathogenesis of diabetes. The first one
was the application of chemistry as a diagnostic tool in the 2 nd half of the 18th century. The
other milestone was the emergence of endocrinology as a formal discipline with the works of
the Claude Bernard (1813-1878) and Brown-Sequard (1817-1894). Bernard established the
concept of organs of internal secretions (glands), whereas Brown-Sequard demonstrated that
death from adrenalectomy could be delayed by infusing blood from healthy animals [7]. Four
years later, Frank classified the disease, on the basis of presence of sugar-like substance into
diabetes insipidus (tasteless urine) and diabetes vera (sweet urine). Approximately a century
later, Mathew Dobson (1735-1784), a Liverpool physician, confirmed the presence of sugar
in both urine and blood of diabetic patients in 1776. Later, in 1815, Michael Chevreal (a
French chemist) demonstrated the sugar was in fact glucose. Dobson did not establish the
origin of the excess sugar. He deduced that the excess urine sugar was not produced in the
kidney as was thought but it previously existed in the blood and the body failed to assimilate
it. Thus, diabetes from Dobson’s view was a systemic disease and not ‘kidney malady’. This
observation led the diabetes research in the right tract as a defect in carbohydrate metabolism
[8]. John Rollo, a French physician, in 1798, erroneously concluded that diabetes was a
disease of the stomach as a result of abnormal transformation of vegetable nutrients into
sugar. He suggested carbohydrate restriction as a treatment. Discovery of carbohydrate
metabolism. Claude Bernard is considered to be the founder of experimental medicine by
applying physical and chemical methods in artificial induction of diseases. Initially Bernard,
from his famous piqure experiments thought that diabetes was due to disease of the central

nervous system [9].

2
 Fig. 2.1 :Banting and Best
Insulin was discovered in 1921 by Banting and Best who demonstrated the
hypoglycemic action of an extract of pancreas prepared after degeneration of the exocrine
part due to ligation of pancreatic duct. It was first obtained in pure crystalline form in 1926
and the chemical structure was fully worked out in 1956 by Sanger.

Anatomy of pancreas:-
The pancreas has both endocrine and exocrine functions. The exocrine secretions are
mostly the digestive enzymes such as pancreatic amylase (a carbohydrate digesting enzyme),
trypsin and chymotrypsin (protein digesting enzymes) and pancreatic lipase (a triglyceride
digesting enzyme). Scattered among the exocrine portion of the pancreas are millions of tiny
clusters of endocrine tissue called pancreatic islets or islets of Langerhans, which contains
four types of cells secreting different hormones:

1. Alpha cells (α-cells) which constitute about 17% of islet mass, and secrete glucagon
that raises blood sugar levels.
2. Beta cells (β-cells) which constitute about 70% of islet mass, and secrete insulin that
lowers blood sugar levels.
3. Delta cells (δ-cells) which constitute about 7% of the islet mass and secrete growth
hormone release-inhibiting hormone or somatostatin. In pancreas it inhibits the secretions of

3
glucagon and insulin. In hypothalamus it inhibits the synthesis and release of growth
hormone while in GIT it inhibits the release of gastrin.
4. The F-cells which constitute the remainder of the islet mass, secrete pancreatic
polypeptide which regulates the release of pancreatic digestive enzymes and contraction of
gall bladder. Glucagon and insulin are two most important endocrine hormones that maintain
the glucose homeostasis [10].

Fig.3.1 Pancreas
The pancreas, a retroperitoneal gland that is about 12–15 cm (5–6 in.) long and 2.5 cm (1 in.)
gland that is about 12–15 cm (5–6 in.) long and 2.5 cm (1 in.) pancreas consists of a head, a
body, and a tail and is usually connected to the duodenum by two ducts. The head is the
expanded portion of the organ near the curve of the duodenum; superior to and to the left of
the head are the central body and the tapering tail [11].
Pancreatic juices are secreted by exocrine cells into small ducts that ultimately unite
to form two larger ducts, the pancreatic duct and the accessory duct. These in turn convey the
secretions into the small intestine. The pancreatic duct, or duct of Wirsung, is the larger of the
two ducts. In most people, the pancreatic duct joins the common bile duct from the liver and
gallbladder and enters the duodenum as a dilated common duct called the hepatopancreatic

4
ampulla, or ampulla of Vater. The ampulla opens on an elevation of the duodenal mucosa
known as the opens on an elevation of the duodenal mucosa known as the duodenum of the
small intestine is regulated by a mass of smooth muscle surrounding the ampulla known as
the sphincter of the hepatopancreatic ampulla, or sphincter of Oddi. The other major duct of
the pancreas, the accessory duct (duct of Santorini), leads from the pancreas and empties into
the duodenum about 2.5 cm (1 in.) superior to the hepatopancreatic ampulla [12].

Histology of the Pancreas

The pancreas is made up of small clusters of glandular epithelial cells. About 99% of
the clusters, called acini, constitute the exocrine portion of the organ. The cells within acini
secrete a mixture of fluid and digestive enzymes called pancreatic juice. The remaining 1% of
the clusters, called pancreatic islets (islets of Langerhans), form the endocrine portion of the
pancreas. These cells secrete the hormones glucagon, insulin, somatostatin, and pancreatic

polypeptide [10].

Composition and Functions of Pancreatic Juice

Each day the pancreas produces 1200–1500 mL (about 1.2–1.5 qt) of pancreatic juice,
a clear, colorless liquid consisting mostly of water, some salts, sodium bicarbonate, and
several enzymes. The sodium bicarbonate gives pancreatic juice a slightly alkaline pH (7.1–
8.2) that buffers acidic gastric juice in chyme, stops the action of pepsin from the stomach,
and creates the proper pH for the action of digestive enzymes in the small intestine. The
enzymes in pancreatic juice include a starch-digesting enzyme called pancreatic amylase;
several enzymes that digest proteins into peptides called trypsin, chymotrypsin,
carboxypeptidase, and elastase; the principal triglyceride–digesting enzyme in adults, called
pancreatic lipase; and nucleic acid–digesting enzymes called ribonuclease and
deoxyribonuclease that digest ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) into

nucleotides.

The protein digesting enzyme of the pancreas are produced in an inactive form just as
pepsin is produced in the stomachas pepsinogen because they are inactive, the enzyme don’t
digest cells of the pancreas itself. Trypsin is secreted in an inactive form called trypsinogen.
Pancreatic acinar cells also secrete a protein called trypsin inhibitor that combines with any

5
trypsin formed accidentally in the pancreas or in pancreatic juice and blocks its enzymatic
activity. When trypsinogen reaches the lumen of the small intestine, it encounters an
activating brush-border enzyme called enterokinase, which splits off part of the trypsinogen
molecule to form trypsin. In turn, trypsin acts on the inactive precursors to produce
chymotrypsin, carboxypeptidase, and elastase, respectively.

6
 Fig. 5.1

Fig. 5.2

Types of diabetes: - Three major types of diabetes mellitus are

1. Type 1 (insulin-dependent diabetes mellitus)

2. Type 2 (noninsulin-dependent diabetes mellitus)

3. Gestational diabetes mellitus

1. Type 1 diabetes mellitus: - It is also called "Insulin Dependent Diabetes

Mellitus (IDDM) because in such patients, due to an absolute lack of insulin, regular
injections of insulin are needed to save life. Earlier, it was called "juvenile-onset
diabetes" because it most commonly develops either before puberty or in youngsters
below 20 years of age and persists throughout their life [10]. IDDM is mainly an
autoimmune disease of the pancreatic B-cells resulting in their degeneration (type1A).
It could also be idiopathic (type1B). Viral infection such as echovirus can also
damage pancreatic B-cells (type 1B). Approximately 10% of diabetics suffer from
type-1 DM. These patients have a low degree of genetic predisposition, yet 15-20% of
patients reveal a positive family history and the incidence in homozygous twins is

7
 about 50%. The clinical features of type-1 DM include hyperglycemia with polyuria,
polydipsia, polyphagia and ketoacidosis. These patients are generally not obese.
Diabetic ketoacidosis is the end result of insulin deficiency in uncontrolled type-1
diabetes. Since insulin is not present to aid the entry of glucose in skeletal muscles
and body cells, most cells now use fatty acids to produce ATP to compensate and to
provide calories. This accelerated fat breakdown generates acetyl-CoA. But, due to
DM, this acetyl COA cannot be removed by Krebs cycle (to H 2O2, and CO2) and
therefore gets accumulated. In absence of aerobic carbohydrate metabolism, two
acetyl-CoA molecules join to form acetoacetic acid, and beta-hydroxybutyric acid,
which are collectively called ketone bodies and excreted in urine (ketonuria). The
acetoacetate (ketone body) is converted in liver to acetone which is excreted through
lungs and provides a fruity odor to the breath of these patients. These metabolic
products cause metabolic acidosis or diabetic ketoacidosis, which decreases glucose
utilization in brain and decreases pH of the blood leading to coma and death. Renal
losses of glucose (glycosuria), nitrogenous substances and ketone bodies promote
osmotic diuresis (polyuria) that can result in dehydration and thirst (polydipsia).
Ketoacidosis means state of ketosis with acidosis [13].

2. Type 2 diabetes mellitus: -Noninsulin-dependent diabetes

mellitus
(NIDDM)/maturity onset diabetes mellitus: There is no loss or moderate reduction in
β cell mass; insulin in circulation is low, normal or even high, no anti-β-cell antibody
is demonstrable; has a high degree of genetic predisposition; generally, has a late
onset (past middle age). Over 90% cases of diabetes are type 2 DM.

Causes of diabetes mellitus:

• Abnormality in gluco-receptor of β cells so that they respond at higher glucose

concentration or relative β cell deficiency. In either way, insulin secretion is impaired;
may progress to β cell failure [13].

• Reduced sensitivity of peripheral tissues to Insulin: reduction in number of insulin

receptors, ‘down regulation’ of insulin receptors. Many hypertensives are
hyperinsulinemia, but Normoglycemic; and have associated dyslipidemia,
hyperuricemia, abdominal obesity (metabolic syndrome). Thus, there is relative
8
 Insulin resistance, particularly at the level of liver, muscle and fat. Hyperinsulinemia
per Se has been implicated in causing angiopathy.

• Excess of hyperglycemic hormone(glucagon.)/obesity: cause relative insulin

deficiency—the β cells lag behind.

3. Gestational Diabetes mellitus: - It is observed in approximately 4 -5 % of all

pregnancies. Elevated blood sugar levels are usually observed in second or last
trimester of pregnancy and usually resolved during the postpartum period. There is no
genetic predisposition. The most plausible cause is that during pregnancy, the
placental hormones promote insulin resistance [10]. This type affects females during
pregnancy. Some women have very high levels of glucose in their blood, and their
bodies are unable to produce enough insulin to transport all of the glucose into their
cells, resulting in progressively rising levels of glucose. Diagnosis of gestational
diabetes is made during pregnancy. The majority of gestational diabetes patients can
control their diabetes with exercise and diet.
Between 10 to 20 percent of them will need to take some kind of blood-
glucosecontrolling medications. Undiagnosed or uncontrolled gestational diabetes can

raise the risk of complications during childbirth [14].

Fig. 6.1

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Sign and symptoms of diabetes mellitus
• Frequent urination: -When blood sugar levels are high, the kidneys
try to remove the excess sugar by filtering it out of the blood. This can
lead to a person needing to urinate more frequently, particularly at
night.
• Increased thirst: - The frequent urination that is necessary to remove
excess sugar from the blood can result in the body losing additional
water. Over time, this can cause dehydration and lead to a person
feeling more thirsty than usual.
• Always feeling hungry: - Constant hunger or thirst can be early signs
of type 2 diabetes. People with diabetes often do not get enough
energy from the food they eat. The digestive system breaks food down
into a simple sugar called glucose, which the body uses as fuel. In
people with diabetes, not enough of this glucose moves from the
bloodstream into the body’s cells. As a result, people with type 2
diabetes often feel constantly hungry, regardless of how recently they
have eaten.
• Feeling very tired: - Type 2 diabetes can impact on a person’s energy
levels and cause them to feel very tired or fatigued. This tiredness
occurs as a result of insufficient sugar moving from the bloodstream
into the body’s cells.
• Blurry vision: - An excess of sugar in the blood can damage the tiny
blood vessels in the eyes, which can cause blurry vision. This blurry
vision can occur in one or both of the eyes and may come and go. If a
person with diabetes goes without treatment, the damage to these
blood vessels can become more severe, and permanent vision loss may
eventually occur.
• Slow healing of cuts and wounds: - High levels of sugar in the blood
can damage the body’s nerves and blood vessels, which can impair
blood circulation. As a result, even small cuts and wounds may take
weeks or months to heal. Slow wound healing also increases the risk
of infection.

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 • Tingling, numbness, or pain in the hands or feet: - High blood
sugar levels can affect blood circulation and damage the body’s
nerves. In people with type 2 diabetes, this can lead to pain or a
sensation of tingling or numbness in the hands and feet. This condition
is known as neuropathy, and it can worsen over time and lead to more
serious complications if a person does not get treatment for their
diabetes.
• Patches of dark skin: -Patches of dark skin forming on the creases of
the neck, armpit, or groin can also signify a higher risk of diabetes.
These patches may feel very soft and velvety. This skin condition is
known as acanthosis nigricans.
• Itching and yeast infections: - Excess sugar in the blood and urine
provides food for yeast, which can lead to infection. Yeast infections
tend to occur on warm, moist areas of the skin, such as the mouth,
genital areas, and armpits. The affected areas are usually itchy, but a
person may also experience burning, redness, and soreness [15].

Diagnostic tests for Diabetes Mellitus

1. Blood tests
a) Fasting glucose test: - Fasting glucose is directly proportional to the severity
of the diabetes mellitus. During this test, blood is drawn from a vein in the
patient’s arm after the patient has not eaten for at least eight hours, usually in
the morning before breakfast. The red blood cells are separated from the
sample and the amount of glucose is measured in the remaining plasma. A
plasma level of 200 mg/dL or greater strongly indicates diabetes provided that
drugs such as glucocorticoids are not being administered. The fasting glucose
test is usually repeated on another day to confirm the results [16].

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b) Postprandial Plasma Glucose Test: - Diabetes mellitus is more readily
detected when carbohydrate metabolic capacity is tested. This can be done by
stressing the system with a defined glucose load. Measurement of the rate that
the glucose load is cleared from the blood, as compared to the rate of glucose
clearance in healthy persons, detects impairment in glucose metabolism. A
meal high in carbohydrates is used as the carbohydrate load, although a 75g
glucose drink is usually preferred over a meal. Blood is drawn at 2 hours after
ingestion of the meal or glucose drink. Glucose levels above 1400mg/L are
abnormal; levels of 1200 to 1400 mg/L are ambiguous; and levels below
1200mg/L are normal [17]. Though widely used for detection of diabetes
mellitus, this test method is highly inaccurate due to several variables that are
difficult to control or adjust for. These variables include age, weight, previous
diet, activity, illness, medications, time of the day that the test is conducted
and actual size of the glucose dose. When a meal is used as the load, the
effective glucose load depends on the digestion of disaccharides and
polysaccharides and their subsequent absorption from the intestinal tract [16].
c) Oral Glucose Tolerance Test (OGTT): - The oral glucose tolerance test
evaluates clearance from the circulation after glucose loading under defined
and controlled conditions. The test has been standardized by the Committee
on Statistics of the American Diabetes Association. The patient should have
been fasting for the previous 8-14 hours. A zero-time (baseline) blood sample
is drawn. The patient is given a glucose solution, which is drunk within 5
minutes. Blood is drawn at intervals for measurement of glucose (blood
sugar), and sometimes insulin levels. The intervals and number of samples
vary according to the purpose of the test. For simple diabetes screening, the
most important sample is the 2-hour sample. The zero and 2-hour samples
may be the only ones collected. In a non-diabetic, the level of glucose in the
blood goes up immediately after the drink and then decreases gradually as
insulin is used by the body to metabolize or absorb the sugar. In a diabetic, the
glucose in the blood goes up and stays high after drinking the sweetened
liquid. A plasma glucose level of 2000 mg/L or higher at two hours after
drinking the syrup and at one other point during the two-hour test period
confirms the diagnosis of diabetes [17]. During the test, the patient must be

12
 ambulatory, since inactivity decreases glucose tolerance. The test can also be
affected by illness, abnormalities of such hormones as thyroxine, growth
hormone, cortisol, and catecholamines, drugs and medications such as oral
contraceptives, salicylates, nicotinic acid, diuretics and hypoglycemic agents
and testing time. The glucose load should consist of glucose only [18].
d) Intravenous Glucose Tolerance Test: - The intravenous glucose tolerance
test is used for persons with malabsorptive disorders or previous gastric or
intestinal surgery. Glucose is administered intravenously over 30 minutes,
using a 20% solution. A glucose load of 0.5g/kg of body weight is used.
Nondiabetics respond with a plasma glucose level of 2000 to 2500mg/L.
Discontinuation of the glucose loading leads to a decrease in plasma levels
with fasting levels reached at about 90 minutes. Diabetics demonstrate plasma
glucose level above 2500mg/L during administration of the load. On
discontinuation of the loading, plasma glucose levels of diabetics also return
to fasting levels at about 90 minutes. An alternative procedure called the
Soskin method uses 50% glucose delivered intravenously within 3 to 5
minutes. The glucose load used is 0.3 g/kg of body weight. Non- diabetics
reestablish fasting levels in less than 60 minutes after discontinuing the
glucose infusion. In diabetics fasting levels are established significantly later
than 60 minutes [16].
e) O’Sullivan Test: - This test is used to detect gestational diabetes. A 50 g load
of glucose is given to a fasting patient. Blood is drawn at one hour.
Gestational diabetes is suggested by plasma levels above 1500mg/L [19].

2. Urine Tests
Urine tests are undertaken to analyses ketones bodies, glucose and proteins in
the urine. The colorimetric reaction that occurs between ketones and nitroprusside
(Sodium nitroferricyanide) is the method used for the rapid semi-quantitive
measurements of ketones [20].

Clinistix and Diastix are paper strips or dipsticks that change color when
dipped in urine. The test strip is compared to a chart that shows the amount of glucose
in the urine based on the change in color. The level of glucose in the urine lags behind

13
the level of glucose in the blood. Testing the urine with a test stick, paper strip, or
tablet is not as accurate as blood testing.
However, it can give a fast and simple reading. Ketones in the urine can be
detected using similar types of dipstick tests (Acetest or Ketostix). Urine samples
with a specific gravity of 1.010 to 1.020 yield the most accurate results [16].

Ketoacidosis can be a life-threatening situation in Type I diabetics, so having

a quick and simple test to detect ketones can assist in establishing a diagnosis sooner.
Another dipstick test can determine the presence of protein or albumin in the urine.
Protein in the urine can indicate problems with kidney function and can be used to
track the development of renal failure. A more sensitive test for urine protein uses
radioactively tagged chemicals to detect microalbuminuria, small amounts of protein
in the urine, which may not show up on dipstick tests [17].

3. Plasma insulin Test

Fasting plasma insulin levels in type I diabetics are low. Those of type II diabetics are
low only when fasting plasma glucose levels exceed 2500mg/L.
Otherwise, they are normal. A glucose challenge separates type I diabetics from type
II diabetics. Glucose loading elicits no significant insulin response for type I diabetics
and a delayed, exaggerated response in type II diabetics [21].

Diabetics can monitor their own blood glucose levels with home blood
glucose monitoring kits. A small needle or lancet is used to prick the finger and a
drop of blood is collected and analyzed by a monitoring device. The correct use of
such a device minimizes the wide variations of blood glucose experienced by
diabetics and, as a result, the hypoglycemic events and even the long-term
complications of diabetes mellitus. Some patients may test their blood glucose levels
several times during a day and use this information to adjust their diet or doses of
insulin [22].

In a consensus statement on blood glucose monitoring, many insulin-treated

populations have been recommended for self-monitoring programs. These include
pregnant women, patients with unstable diabetes, patients with histories of severe
ketosis or hypoglycemia especially those who do not demonstrate warning symptoms

14
of hypoglycemia, patients receiving intensive insulin therapy and patients with
abnormal renal thresholds for glucose [23].

4. Random plasma test

The simplest test and doesn’t require fasting before taking the test. If 200 or
more than 200 mg/dl of blood glucose it probably indicates diabetes but has to be
reconfirmed.

Complications of diabetes mellitus

Over time, diabetes complications can affect major organs in your body, including
heart, blood vessels, nerves, eyes and kidneys. Maintaining a normal blood sugar
level can dramatically reduce the risk of many complications. Eventually, diabetes
complications may be disabling or even life-threatening.
• Heart and blood vessel disease: -Diabetes dramatically increases
your risk of various cardiovascular problems, including coronary
artery disease with chest pain (angina), heart attack, stroke, narrowing
of the arteries (atherosclerosis) and high blood pressure.
• Nerve damage (neuropathy): - Excess sugar can injure the walls of
the tiny blood vessels (capillaries) that nourish your nerves, especially
in the legs. This can cause tingling, numbness, burning or pain that
usually begins at the tips of the toes or fingers and gradually spreads
upward. Poorly controlled blood sugar could cause you to eventually
lose all sense of feeling in the affected limbs. Damage to the nerves
that affect the gastrointestinal tract can cause problems with nausea,
vomiting, diarrhea or constipation. For men, erectile dysfunction may
be an issue.
• Kidney damage (nephropathy): - The kidneys contain millions of
tiny blood vessel clusters that filter waste from your blood. Diabetes
can damage this delicate filtering system. Severe damage can lead to
kidney failure or irreversible end-stage kidney disease, which requires
dialysis or a kidney transplant.
• Eye damage: - Diabetes can damage the blood vessels of the retina
(diabetic retinopathy), potentially causing blindness. Diabetes also
15
 increases the risk of other serious vision conditions, such as cataracts
and glaucoma.
• Foot damage: - Nerve damage in the feet or poor blood flow to the
feet increases the risk of various foot complications. Left untreated,
cuts and blisters can become serious infections that may ultimately
require toe, foot or leg amputation.
• Skin and mouth conditions: - Diabetes may leave you more
susceptible to infections of the skin and mouth, including bacterial and
fungal infections. Gum disease and dry mouth also are more likely.
• Pregnancy complications: - High blood sugar levels can be
dangerous for both the mother and the baby. The risk of miscarriage,
stillbirth and birth defects increases when diabetes isn’t wellcontrolled.
For the mother, diabetes increases the risk of diabetic ketoacidosis,
diabetic eye problems (retinopathy), pregnancy-induced high blood
pressure and preeclampsia.
• Skin conditions: - Diabetes may leave you more susceptible to skin
problems, including bacterial and fungal infections.
• Slow healing: - Left untreated, cuts and blisters can become serious
infections, which may heal poorly. Severe damage might require toe,
foot or leg amputation.
• Hearing impairment: -Hearing problems are more common in people
with diabetes.
• Sleep apnea: - Obstructive sleep apnea is common in people living
with type 2 diabetes. Obesity may be the main contributing factor to
both conditions. It’s not clear whether treating sleep apnea improves
blood sugar control.
• Dementia: -Type 2 diabetes seems to increase the risk of Alzheimer’s
disease and other disorders that cause dementia. Poor control of blood
sugar levels is linked to more-rapid decline in memory and other
thinking skills [24].

16
Prevention and management
Prevention
Healthy lifestyle choices can help prevent type 2 diabetes, and that's true even if you
have biological relatives living with diabetes. If you've received a diagnosis of prediabetes,

lifestyle changes may slow or stop the progression to diabetes A healthy lifestyle

includes:

Eating healthy foods. Choose foods lower in fat and calories and higher in fiber. Focus
on fruits, vegetables and whole grains.

Getting active. Aim for 150 or more minutes a week of moderate to vigorous aerobic
activity, such as a brisk walk, bicycling, running or swimming.

Losing weight. Losing a modest amount of weight and keeping it off can delay the
progression from prediabetes to type 2 diabetes. If you have prediabetes, losing 7% to 10% of
your body weight can reduce the risk of diabetes.

Avoiding inactivity for long periods. Sitting still for long periods can increase your
risk of type 2 diabetes. Try to get up every 30 minutes and move around for at least a few
minutes.
Management of diabetes
Insulin:-
Unless insulin is present to facilitate the uptake of glucose, it penetrates most
tissues only slowly. Glucose play the dominant roll in the regulation of insulin secretion.
Maintainance of blood glucose level within the normal physiological limits is primarily
accomplished by insulin and glucagon. Any excess in the regulation of insulin or glucagon
can lead to hypoglycemia or hyperglycemia, respectively [21].

17
Structure of insulin

Fig. 10 .1

Oral hypoglycaemic drugs

These drugs lower blood glucose levels and are effective orally. The chief draw back
of insulin is—it must be given by injection. Orally active drugs have always been saught.
The early sulfonamides tested in 1940s produced hypoglycaemia as side effect.
Taking this lead, the first clinically acceptable sulfonylurea tolbutamide was introduced in
1957. Others followed soon after. In the 1970s many so called ‘second generation’
sulfonylureas were developed which are 20–100 times more potent. Clinically useful
biguanide phenformin was produced parallel to sulfonylureas in 1957. Newer approaches
have constantly been explored and have lately yielded thiazolidinediones, meglitinide

18
analogues, α-glucosidase inhibitors and the latest are dipeptidyl peptidase-4 (DPP-4)
inhibitors [22].

Classification
A. Enhance of Insulin secretion
1. Sulfonylureas (K+ATP Channel blockers):

• First generation: Tolbutamide

• Second generation: Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride

2. Meglitinide/phenylalanine analogues: Repaglinide, Nateglinide

3. Glucagon-like peptide-1 (GLP-1) receptor agonists (Injectable drugs): Exenatide,
Liraglutide
4. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, Vildagliptin, Saxagliptin,
Alogliptin, Linagliptin.
B. Overcome Insulin resistance
1. Biguanide (AMPK activator): Metformin
2. Thiazolidinediones (PPAR γ activator): Pioglitazone
C. Miscellaneous antidiabetic drugs
1. α-Glucosidase inhibitors: Acarbose, Miglitol, Voglibose
2. Amylin analogue: Pramlintide
3. Dopamine-D2 receptor agonist: Bromocriptin
4. Sodium-glucose cotransport-2 (SGLT-2) inhibitor: Dapagliflozin [13].

A. Enhance of insulin secretion

1. Sulfonylureas (K+ATP Channel blockers) The
generic formula of sulfonylureas (SUs) is—

19
All SUs have similar pharmacological profile, their sole significant action being lowering of
blood glucose level in normal subjects and in type 2 diabetics, but not in type 1 diabetics.
Being more potent and clinically superior, only the second-generation SUs are employed
now. All first-generation compounds have been discontinued except tolbutamide which is
infrequently used.

Mechanism of action:

Fig. 10.2: Mechanism of action of insulin secretagogues

Sulfonylureas provoke a brisk release of insulin from pancreas. The rate of insulin secretion
at any glucose concentration is increased, i.e. insulin release is provoked even at low-glucose
concentration risking production of severe and unpredictable hypoglycaemia. In type 2 DM
the kinetics of insulin release in response to glucose or meals is delayed and subdued. The
SUs primarily augment the 2nd phase insulin secretion with little effect on the 1st phase. That
they do not cause hypoglycaemia in pancreatectomised animals and in type 1 diabetics
(presence of at least 30% functional β cells is essential for their action), confirms their
indirect action through pancreas.
A minor action reducing glucagon secretion, probably by increasing insulin and somatostatin
release has been demonstrated. Hepatic degradation of insulin is also slowed.

Adverse effects: Incidence of adverse effects is quite low (3–7%).

1. Hypoglycaemia: It is the commonest problem, may occasionally be severe and
rarely fatal. It is more common in elderly, liver and kidney disease patients and when

20
potentiating drugs are added. Tolbutamide carries lowest risk due to its low potency and short
duration of action.
Treatment of hypoglycaemic episode is to give glucose, may be for a few days because
hypoglycaemia may recur.

2. Nonspecific side effects: Majority of diabetics started on SUs tend to gain 1–3 kg
weight. This may be a consequence of their insulinaemic action. Nausea, vomiting,
flatulence, diarrhoea or constipation, headache and paresthesias are generally mild and
infrequent.

3. Hypersensitivity: Rashes, photosensitivity, purpura, transient leukopenia, rarely

agranulocytosis.
Flushing and a disulfiram-like reaction after alcohol is reported to occur in some individuals
taking SUs.
Tolbutamide reduces iodide uptake by thyroid but hypothyroidism does not occur.
Safety of SUs during pregnancy is not established. Change over to insulin is advised.
Sulfonylureas are secreted in milk: should not be given to nursing mothers.

2. Meglitinide / D-phenylalanine analogues (K+ATP Channel blockers)

These are K+ATP channel blockers with a quick and short lasting insulinemic action.
Repaglinide: This meglitinide analogue oral hypoglycaemic is designed to normalise
mealtime glucose excursions. Though not a sulfonylurea, it acts in an analogous manner by
binding to SUR → closure of ATP dependent K+ channels → depolarisation → insulin
release.
Repaglinide is quickly absorbed and rapidly metabolized. It induces fast onset
shortlasting insulin release. Because of this characteristic its pattern of use is different from
that of SUs. It is administered before each major meal to control postprandial
hyperglycaemia; the dose should be omitted if a meal is missed. Because of short lasting
action it may have a lower risk of serious hypoglycaemia. Side effects are mild headache,
dyspepsia, arthralgia and weight gain.
Repaglinide is indicated only in selected type 2 diabetics who suffer pronounced post
prandial hyperglycaemia, or to supplement metformin/long-acting insulin. It should be
avoided in liver disease.

21
Nate-glinide: It is a D-phenylalanine derivative which principally stimulates the 1st phase
insulin secretion by closing β cell K+ATP channels resulting in faster onset and shorter lasting
hypoglycaemia than repaglinide. Ingested 10 min before meal, it limits postprandial
hyperglycaemia in type 2 diabetics without producing late phase hypoglycaemia. There is
little effect on fasting blood glucose level. Episodes of hypoglycaemia are less frequent than
with SUs. Side effects are dizziness, nausea, flu like symptoms and joint pain. It is used in
type 2 DM along with other antidiabetics, to control postprandial rise in blood glucose [22].

3. Glucagon-like peptide-1 (GLP-1) receptor agonists:

GLP-1 is an important incretin released from the gut in response to ingested glucose.
It induces insulin release from pancreatic β cells, inhibits glucagon release from α cells, slows
gastric emptying and suppresses appetite by activating specific GLP-1 receptors, which are
cell surface GPCRs expressed on β and α cells, central and peripheral neurones,
gastrointestinal mucosa, etc. Characteristically GLP-1 induces insulin release only at high
glucose concentration. The incretin system appears to promote β cell health as well. Failure
of incretins has been implicated in the pathogenesis of β cell dysfunction of type 2 DM,
particularly progression of the disease. GLP-1 based therapy appears to be the most effective
measure for preserving β cell function in type 2 DM.
GLP-1 itself is not suitable for clinical use because of rapid degradation by the
enzyme dipeptidyl peptidase-4 (DPP-4) which is expressed on the luminal membrane of
capillary endothelial cells, kidney, liver gut mucosa and immune cells. Another incretin
glucose-dependent insulinotropic peptide (GIP) also induces insulin release, but in human
beings GLP-1 is the more important incretin and GIP has poor action in type 2 diabetics. The
GIP receptor is distinct from GLP-1 receptor, but mediates mostly similar responses. Some
more stable analogues of GLP-1 have been produced for clinical use in type-2 DM.
Exenatide: It is a synthetic DPP-4 resistant analogue which activates GLP-1 receptors and
produces the same responses. Being a peptide, it is inactive orally. After s.c. injection its
plasma t½ is ~ 3 hours and duration of action 6–10 hours. It is marketed in USA, UK, Europe
for use mainly as add-on drug to metformin/SU or a combination of these or pioglitazone in
poorly controlled type 2 diabetics. Benefits noted are lowering of postprandial as well as
fasting blood glucose, HbA1c and body weight. The most important side effect is nausea and
vomiting occurring in ~ 50% recipients, but tolerance develops later.

22
Liraglutide: This recently developed long-acting GLP-1 agonist is closely related to the
native peptide but its tight binding to plasma proteins extends t½ to > 12 hours and duration
of action to > 24 hours. Injected s.c. once daily, alone or added to oral metformin ± SU or
pioglitazone, it has achieved improved glycaemic control in type 2 diabetics. Nausea and
diarrhoea are the frequent side effects, but decrease in incidence over time. Use of liraglutide
is attended by weight loss, and it is being evaluated as an antiobesity drug even for
nondiabetics.
Hypoglycaemia is rare with exenatide/liraglutide monotherapy, but can occur when
combined with SUs/metformin [13].

4. Dipeptidyl peptidase-4 (DPP-4) inhibitors:

Realizing the key role of the enzyme DPP-4 in rapid degradation of endogenous GLP-1,
orally active inhibitors of this enzyme have been developed as indirectly acting insulin
secretagogues. In the past few years, DPP-4 inhibitors have emerged as important adjunctive
drugs in type 2 DM.
Sitagliptin: This is the first DPP-4 inhibitor introduced in USA in 2006 and now available
world-wide. It is a competitive and selective DPP-4 inhibitor which potentiates the action of
GLP-1 and GIP, boosts post prandial insulin release, decreases glucagon secretion and lowers
meal-time as well as fasting blood glucose in type 2 diabetics. No effect on gastric emptying
and appetite have been noted. It is body weight neutral and carries low risk of hypoglycaemia
unless combined with SUs or insulin. The HbA1c lowering caused by sitagliptin is equivalent
to that with metformin. Further lowering of HbA1c occurs when it is added to
pioglitazone/SUs/insulin with or without metformin. However, sitagliptin monotherapy is
recommended only when metformin cannot be used. Most professional guidelines
recommend DPP-4 inhibitors primarily as adjuvant drugs in type 2 diabetics not well
controlled by metformin/SUs/pioglitazone or insulin. Though clinical efficacy of all DPP-4
inhibitors is comparable, one meta-analysis has found sitagliptin to cause greater reduction of
fasting blood glucose than vildagliptin.
Sitagliptin is well absorbed orally, is little metabolized and is largely excreted
unchanged in urine with a t½ averaging 12 hours. Dose reduction is needed in renal
impairment, but not in liver disease. Sitagliptin is well tolerated, side effects are nausea, loose
stools, headache, rashes, allergic reactions and edema. Nasopharyngitis and cough occurs in

23
some patients, which has been ascribed to prevention of substance P degradation. Pancreatitis
is rare.

Vildagliptin: This is the second DPP-4 inhibitor available in Europe and India which binds
to the enzyme covalently. The complex dissociates very slowly resulting in persistent DPP-4
inhibition even after the free drug has been cleared from circulation. This explains the longer
duration of action (12–24 hours) despite short plasma t½ (2–4 hours). The major route of
elemination is by hepatic metabolism; only 20–25% is excreted unchanged in urine. Dose
reduction is needed in moderately severe liver and kidney disease. No significant drug
interactions have been reported. Vildagliptin is less selective than sitagliptin for DPP-4;
causes some inhibition of DPP-8, DPP-9 as well, but the clinical significance of this feature is
not known. The tolerability of vildagliptin is similar to that of sitagliptin, but hepatotoxicity
has been reported. Vildagliptin may require twice daily dosing; though single daily dose
suffices in most cases when combined with another hypoglycaemic.

Saxagliptin: It has been available in USA since 2009, and is recently marketed in India. Like
vildagliptin, it binds covalently with DPP-4 and acts for 24 hours despite a plasma t½ of 2–4
hours. It is metabolized by CYP3A4 and generates an active metabolite that has a t½ of 3–7
hours. Drug interactions with CYP3A4 inhibitors are possible.

B. Overcome insulin resistence:

1.Biguanide (AMPK activator)
Two biguanide antidiabetics, phenformin and metformin were introduced in the 1950s.
Because of higher risk of lactic acidosis, phenformin was withdrawn and has been banned in
India since 2003 [20].

24
Metformin: It differs markedly from SUs: causes little or no hypoglycaemia in nondiabetic
subjects, and even in diabetics, episodes of hypoglycaemia are rare. It does not stimulate
pancreatic β cells. Metformin is reported to improve lipid profile as well in type 2 diabetics.

Mechanism of action: Biguanides do not cause insulin release, but presence of insulin is
essential for their action. Metformin is not effective in pancreatectomized animals and in type
1 diabetics. Though the details are not clear, recent studies have recognized activation of
AMP dependent protein kinase (AMPK) to play a crucial role in mediating the actions of
metformin, the key features of which are:
1. Suppresses hepatic gluconeogenesis and glucose output from liver. This is the major
action responsible for lowering of blood glucose in diabetics.
2. Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat.
Insulin resistance exhibited by type-2 diabetics is thus overcome. This translates into—
• glycogen storage in skeletal muscle
• reduced lipogenesis in adipose tissue and enhanced fatty acid oxidation.
3. Interferes with mitochondrial respiratory chain and promotes peripheral glucose
utilization through anaerobic glycolysis.
AMPK activation by metformin appears to be an indirect consequence of interference with
cellular respiration and lowering of intracellular ATP and other energy sources. Metformin
also retards intestinal absorption of glucose, other hexoses, amino acids and Vit B12.

Pharmacokinetics: The important features of metformin pharmacokinetics are given in

Clearance of metformin approximates G.F.R. It accumulates in renal failure and increases the
risk of lactic acidosis.

Adverse effects: Side effects with metformin are frequent, but generally not serious.
Abdominal pain, anorexia, bloating, nausea, metallic taste, mild diarrhoea and tiredness are
the usual complaints, which tend to subside with time. Metformin does not cause
hypoglycaemia except in overdose.
Vit B12 deficiency due to interference with its absorption can occur with high dose of
metformin.

25
 In addition to general restrictions for use of oral hypoglycaemics, metformin is
contraindicated in hypotensive states, heart failure, severe respiratory, hepatic and renal
disease, as well as in alcoholics because of increased risk of lactic acidosis.
Drugs like cimetidine, furosemide may compete with metformin excretion and enhance its
toxicity.

Uses: Metformin is now established as a first choice drug for all type 2 DM patients, except
when not tolerated or contraindicated.
Advantages of metformin are:
• nonhypoglycaemic
• weight loss promoting
• has potential to prevent macrovascular as well as microvascular complications of diabetes
• no acceleration of β cell exhaustion/ failure in type 2 DM.
• antihyperglycaemic efficacy (HbA1c reduction by 0.8–1.2%) equivalent to other oral drugs.
• can be combined with any other oral or injectable antidiabetic, if one drug is not adequate.
The limiting feature is g.i. intolerance, especially at higher doses, but lack of serious
toxicity is well established by decades of use.

2.Thiazolidinedione (PPARγ agonist):

Pioglitazone: Only one thiazolidinedione Pioglitazone is currently available. Rosiglitazone,
the other member, is banned in India since 2010 and has been withdrawn in Europe due to
unacceptable increase in risk of myocardial infarction, CHF, stroke and death. This class of
oral antidiabetic drugs are selective agonists for the nuclear peroxisome proliferator-activated
receptor γ (PPARγ) which is expressed mainly in fat cells, but also in muscle and some other
cells. It enhances the transcription of several insulin responsive genes. Glitazones tend to
reverse insulin resistance by enhancing GLUT4 expression and translocation. Entry of
glucose into muscle and fat is improved. Hepatic gluconeogenesis is also suppressed.
Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue
contributes to the insulin sensitizing action. Lipolysis and plasma fatty acid levels are
reduced. Adipocyte turnover and differentiation is accelerated by glitazones. Thus, fatty
tissue is a major site of their action. The magnitude of blood glucose reduction is somewhat

26
less than SUs and metformin. Improved glycaemic control results in lowering of circulating
HbA1C and insulin levels in type 2 DM patients.
Pioglitazone, in addition, lowers serum triglyceride level and raises HDL level
without much change in LDL level, probably because it acts on PPARα as well to induce
expression of reverse cholesterol transporter and some apoproteins.
Pioglitazone is well tolerated; adverse effects are plasma volume expansion, edema,
weight gain, headache, myalgia and mild anaemia. Monotherapy with glitazones is not
associated with hypoglycaemic episodes. Few cases of hepatic dysfunction have been
reported; CHF may be precipitated or worsened. Monitoring of liver function is advised. It is
contraindicated in liver disease and in CHF. Glitazones increase the risk of fractures,
especially in elderly women.
Pioglitazone is metabolized by both CYP2C8 and CYP3A4. Failure of oral contraception
may occur during pioglitazone therapy. Ketoconazole inhibits and rifampin induces
metabolism of pioglitazone.
Pioglitazone is indicated in type 2 DM, but not in type 1 DM. It reduces blood glucose
and HbA1c (by 0.5–1.2%) without increasing circulating insulin. About 25% patients may
not respond (nonresponders), probably due to low baseline insulin levels. It should be stopped
if HbA1c reduction is < 0.5% at 6 months. Pioglitazone is primarily used to supplement
SUs/metformin and in case of insulin resistance. However, it is not likely to be effective
when β cell failure has set in, which may be the cause of loss of efficacy to a combination of
SUs + metformin. It may also be used as monotherapy (along with diet and exercise) in mild
cases.
Several reports describe greater fluid retention, weight gain and precipitation of CHF
after combined use of glitazones with insulin. Experts advise avoiding such combination.
Pioglitazone should not be used during pregnancy. The Diabetes Prevention Programme
(2005) has shown that glitazones have the potential to delay progression of prediabetics to
overt type 2 DM. They may help to conserve β cell function in diabetics.

C. Miscellaneous antidiabetic drugs

1. α Glucosidase inhibitors:
Acarbose It is a complex oligosaccharide which reversibly inhibits α-glucosidases, the final
enzymes for the digestion of carbohydrates in the brush border of small intestine mucosa. It
slows down and decreases digestion and absorption of polysaccharides (starch, etc.) and
27
sucrose. In addition, GLP-1 release is promoted which may contribute to the effect.
Postprandial glycaemia is reduced without significant increase in insulin levels. Regular use
lowers HbA1c modestly (by 0.4–0.8%), but change in body weight and lipid levels is
minimal. The stop-NIDDM trial (2002) has shown that long-term acarbose treatment in
prediabetics reduces occurrence of type 2 DM as well as hypertension and cardiac disease. In
diabetics, it reduces cardiovascular events.
Acarbose is a mild antihyperglycaemic and not a hypoglycaemic; may be used as an
adjuvant to diet (with or without metformin/SU) in obese diabetics. Dose 50–100 mg TDS is
taken at the beginning of each major meal. Only a small fraction of the dose is absorbed.
Flatulence, abdominal discomfort and loose stool are produced in about 50% patients due to
fermentation of unabsorbed carbohydrates. Patient acceptability of α-glucosidase inhibitors is
poor due to uncomfortable g.i. symptoms. Hepatic transaminases may rise, but liver damage
is rare.
Miglitol: It has a smaller molecule than acarbose, and it is a stronger inhibitor of sucrase.
Potency for other α-glucosidases is equivalent to acarbose. Absorption of miglitol is
substantial, but variable. The absorbed drug is excreted by the kidney. No systemic toxicity is
known.
Voglibose: Has properties, use and side effects similar to that of acarbose.

2. Amylin analogue:
Amylin, also called ‘islet amyloid polypeptide’ (IAP), is produced by pancreatic β cells and
acts in the brain to reduce glucagon secretion from α cells, delay gastric emptying, retard
glucose absorption and promote satiety.
Pramlintide: It is a synthetic amylin analogue which on s.c. injection before meal attenuates
postprandial glycaemia and exerts a centrally mediated anorectic action. The duration of
action is 2–3 hours. It has been used as an adjuvant to meal time insulin injection to suppress
the glycaemic peak in both type 1 and type 2 diabetics. Reduction in body weight is an
additional benefit.

3. Dopamine D2 agonist:
Bromocriptine: Recently (2009) a quick release oral formulation of bromocriptine has been
approved by US-FDA for adjunctive treatment of type 2 DM. Taken early in the morning it is
thought to act on the hypothalamic dopaminergic control of the circadian rhythm of hormone

28
(GH, prolactin, ACTH, etc.) release and reset it to reduce insulin resistance. Bromocriptin can
be taken alone to supplement diet + exercise or added to metformin or SU or both. Started at
0.8 mg OD and increased upto 4.8 mg OD (as needed) it has been shown to marginally
improve glycaemic control and lower HbA1c by upto 0.5%.

4. Sodium-glucose co-transport-2 (SGLT-2) inhibitor:

Practically all the glucose filtered at the glomerulus is reabsorbed in the proximal tubules.
The major transporter which accomplishes this is SGLT-2, whose inhibition induces
glucosuria and lowers blood glucose in type 2 DM, as well as causes weight loss.
Dapagliflozin: This SGLT-2 inhibitor has been recently tested in type 2 DM patients. After
single daily dose it produces round-the-clock glucosuria and lowers blood glucose levels. The
concerns which appear inbuilt due to its mechanism of action are—glycosuria which can
predispose to urinary and genital infections, electrolyte imbalance and increased urinary
frequency. Tolerability and safety of this drug is yet to be established.

29
Fig. 10.3

30
Conclusion
Diabetes is a slow killer with no known curable treatments. However, its complications can
be reduced through proper awareness and timely treatment. Three major complications are
related to blindness, kidney damage and heart attack. It is important to keep the blood
glucose levels of patients under strict control for avoiding the complications. One of the
difficulties with tight control of glucose levels in the blood is that such attempts may lead to
hypoglycemia that creates much severe complications than an increased level of blood
glucose. Researchers now look for alternative methods for diabetes treatment. The goal of
this paper is to give a general idea of the current status of diabetes research. The author
believes that diabetes is one of the highly demanding research topics of the new century
and wants to encourage new researchers to take up the challenges.

31
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