History

The term diabetes. It was derived from the Greek verb diabaínein, the verb
diabeinein meant "to stride, walk, or stand with legs asunder"; hence, its
derivative diabētēs meant "one that straddles," or specifically "a compass,
siphon." The sense "siphon" gave rise to the use of diabētēs as the name for
a disease involving the discharge of excessive amounts of urine. Diabetes is
first recorded in English, in the form diabetes, in a medical text written
around 1425. In 1675, Thomas Willis added the word mellitus, from the
Latin meaning "honey", a reference to the sweet taste of the urine. This
sweet taste had been noticed in urine by the ancient Greeks, Chinese,
Egyptians, Indians, and Persians. In 1910, Sir Edward Albert Sharpey-
Schafer suggested that people with diabetes were deficient in a single
chemical that was normally produced by the pancreas—he proposed calling
this substance insulin, from the Latin insula, meaning island, in reference to
the insulin-producing islets of Langerhans in the pancreas

The endocrine role of the pancreas in metabolism, and indeed the existence
of insulin, was not further clarified until 1921, when Sir Frederick Grant
Banting and Charles Herbert Best repeated the work of Von Mering and
Minkowski, and went further to demonstrate they could reverse induced
diabetes in dogs by giving them an extract from the pancreatic islets of
Langerhans of healthy dogs.Banting, Best, and colleagues (especially the
chemist Collip) went on to purify the hormone insulin from bovine
pancreases at the University of Toronto. This led to the availability of an
effective treatment—insulin injections—and the first patient was treated in
1922. For this, Banting and laboratory director MacLeod received the Nobel
Prize in Physiology or Medicine in 1923; both shared their Prize money with
others in the team who were not recognized, in particular Best and Collip.
Banting and Best made the patent available without charge and did not
attempt to control commercial production. Insulin production and therapy
rapidly spread around the world, largely as a result of this decision. Banting
is honored by World Diabetes Day which is held on his birthday, November
14.hodgkin and coworkersdetermined three dimensional model of insulin

The distinction between what is now known as type 1 diabetes and type 2
Diabetes was first clearly made by Sir Harold Percival (Harry) Himsworth,
and published in January 1936
Many types of diabetes are recognized. The principal three are:

• Type 1.
• Type 2.
• Gestational diabetes:

• Many other forms of diabetes mellitus are categorized separately from

these. Examples include
• congenital diabetes due to genetic defects of insulin secretion, cystic
fibrosis-related diabetes, steroid diabetes induced by high doses of
glucocorticoids, and several forms of monogenic diabetes

Type 1 diabetes

Type 1 diabetes mellitus is characterized by loss of the insulin-producing

beta cells of the islets of Langerhans in the pancreas leading to a deficiency
of insulin. With out insulin bodies’ primary source of energy and brains only
source of energy glucose is unable to enter cells. This type of diabetes can be
further classified as immune-mediated or idiopathic. The majority of type 1
diabetes is of the immune-mediated nature, where beta cell loss is a T-cell
mediated autoimmune attack. Type 1 diabetes can affect children or adults
but was traditionally termed "juvenile diabetes" because it represents a
majority of the diabetes cases in children. , administration of exogenous
insulin can revolve the problem to some extent Type 1 diabetes is fatal
unless treated with exogenous insulin. Injection is the traditional and still
most common method for administering insulin; jet injection, indwelling
catheters, and inhaled insulin has also been available at various times, and
there are several experimental methods as well. All replace the missing
hormone formerly produced by the now non-functional beta cells in the
pancreas. In recent years, pancreas transplants have also been used to treat
type 1 diabetes. Islet cell transplant is also being investigated and has been
achieved in mice and rats, and in experimental trials in humans as well. Use
of stem cells to produce a new population of functioning beta cells seems to
be a future possibility, but has yet to be demonstrated even in laboratories as
of 2008
Type 1 diabetes was previously known as juvenile diabetes because it is one
of the most frequent chronic diseases in children; however, the majority of
new-onset type 1 diabetes is seen in adults. Scientific studies that use
antibody testing (glutamic acid decarboxylase antibodies (GADA), islet cell
antibodies (ICA), and insulinoma-associated (IA-2) auto antibodies) to
distinguish between type 1 and type 2 diabetes demonstrate that most new-
onset type 1 diabetes is seen in adults. A 2008 book, “Type 1 Diabetes in
Adults: Principles and Practice” (Informa Healthcare, 2008) says that adult-
onset type 1 autoimmune diabetes is two to three times more common than
classic childhood-onset autoimmune diabetes (p. 27). In type 1 diabetes, the
body does not produce insulin. Insulin is a hormone that is needed to convert
sugar (glucose), starches and other food into energy needed for daily life.
Some chemicals and drugs preferentially destroy pancreatic cells. Pyrinuron
(Vacor, N-3-pyridylmethyl-N'-p-nitrophenyl urea), a rodenticide introduced
in the United States in 1976, selectively destroys pancreatic beta cells,
resulting in type 1 diabetes after accidental or intentional ingestion. Vacor
was withdrawn from the U.S. market in 1979, but is still used in some
countries. Zanosar is the trade name for streptozotocin, an antibiotic and
antineoplastic agent used in chemotherapy for pancreatic cancer; it also kills
beta cells, resulting in loss of insulin production. Other pancreatic problems,
including trauma, pancreatitis or tumors (either malignant or benign), can
also lead to loss of insulin production.

Diagnosis test
The most definite laboratory test to distinguish type 1 from type 2 diabetes is
the C-peptide assay, which is a measure of endogenous insulin production
since external insulin has not (to date) included C-peptide. The presence of
anti-islet antibodies (to Glutamic Acid Decarboxylase, Insulinoma
Associated Peptide-2 or insulin), or lack of insulin resistance, determined by
a glucose tolerance test, would also be suggestive of type 1. Many type 2
diabetics continue to produce insulin internally, and all have some degree of
insulin resistance.

Type 2 diabetes

Type 2 diabetes mellitus is characterized differently and is due to insulin

resistance or reduced insulin sensitivity, combined with relatively reduced
insulin secretion which in some cases becomes absolute. The defective
responsiveness of body tissues to insulin almost certainly involves the
insulin receptor in cell membranes. However, the specific defects are not
known. Diabetes mellitus due to a known specific defect are classified
separately. Type 2 diabetes is the most common type. There are numerous
theories as to the exact cause and mechanism in type 2 diabetes. Central
obesity (fat concentrated around the waist in relation to abdominal organs,
but not subcutaneous fat) is known to predispose individuals to insulin
resistance. Abdominal fat is especially active hormonally, secreting a group
of hormones called adipokines that may possibly impair glucose tolerance.
Obesity is found in approximately 55% of patients diagnosed with type 2
diabetes. Other factors include aging (about 20% of elderly patients in North
America have diabetes) and family history (type 2 is much more common in
those with close relatives who have had it). In the last decade, type 2
diabetes has increasingly begun to affect children and adolescents Type 2
diabetes is usually first treated by increasing physical activity, decreasing
carbohydrate intake, and losing weight. The usual next step, if necessary, is
treatment with oral antidiabetic drugs.

Gestational diabetes

Pregnant women who have never had diabetes before but who have high
blood sugar (glucose) levels during pregnancy are said to have
gestational diabetes. Gestational diabetes affects about 4% of all pregnant
women. It may precede development of type 2 (or rarely type 1). ,
untreated gestational diabetes can damage the health of the fetus or
mother. Risks to the baby include macrosomia (high birth weight),
congenital cardiac and central nervous system anomalies, and skeletal
muscle malformations. Increased fetal insulin may inhibit fetal surfactant
production and cause respiratory distress syndrome. Hyperbilirubinemia
may result from red blood cell destruction. Severe cases, perinatal death
may occur, most commonly as a result of poor placental perfusion due to
vascular impairment.

Pathogenesis of diabetes

Glucose metabolism
After consuming a meal carbohydrates are broken down to sugars which
is major source of energy to body and only source of energy to brain .if
too much of glucose is present it causes hyperglycemia. To prevent this
glucokinase acts on glucose and converts it into glycogen. In the liver. In
presence of insulin glucose is taken by heart, muscles, and it serves as
source of energy to those cells.
 Role of insulin
Insulin is released into the blood by beta cells (β-cells), found in the
Islets of Langerhans in the pancreas, in response to rising levels of blood
glucose, typically after eating. Insulin is used by about two-thirds of the
body's cells to absorb glucose from the blood for use as fuel, for
conversion to other needed molecules, or for storage. Insulin is the
principal hormone that regulates uptake of glucose from the blood into
most cells (primarily muscle and fat cells, but not central nervous system
cells). Therefore deficiency of insulin or the insensitivity of its receptors
plays a central role in all forms of diabetes mellitus.

Insulin resistance
If the amount of insulin available is insufficient, if cells respond poorly to
the effects of insulin (insulin insensitivity or resistance), or if the insulin
itself is defective, then glucose will not be absorbed properly by those body
cells that require it nor will it be stored appropriately in the liver and
muscles. The net effect is persistent high levels of blood glucose, poor
protein synthesis, and other metabolic derangements, such as acidosis.
Type 2 diabetes mellitus is characterized differently and is due to insulin
resistance or reduced insulin sensitivity, combined with relatively reduced
insulin secretion which in some cases

HEMOGLOBIN A1C AND GLUCOSE CONTROL

HbA1c is primarily used as a treatment-tracking test reflecting average
blood glucose levels over the preceding 90 days (approximately) which is
the average lifetime of red blood cells which contain hemoglobin in most
patients. However, some physicians may order this test at the time of
diagnosis to track changes over time. The current recommended goal for
HbA1c in patients with diabetes is 6.5%.

Diabetes complications

Acute complications:
Diabetic ketoacidosis, nonketotic hyperosmolar coma, hypoglycemia,
and diabetic coma
Chronic complications:
Chronic elevation of blood glucose level leads to damage of
blood vessels (angiopathy). The damage to small blood
vessels leads to a microangiopathy, which can cause one or
more of the following:

• Diabetic retinopathy, growth of friable and poor-quality new blood

vessels in the retina as well as macular edema (swelling of the
macula), which can lead to severe vision loss or blindness.
• Diabetic neuropathy, abnormal and decreased sensation, in feet but
potentially in other nerves, later often fingers and hands. Other forms
of diabetic neuropathy may present as mononeuritis or autonomic
neuropathy. Diabetic amyotrophy is muscle weakness due to
neuropathy.
• Diabetic nephropathy, damage to the kidney which can lead to
chronic renal failure, eventually requiring dialysis.
• Diabetic cardiomyopathy, damage to the heart, leading to diastolic
dysfunction and eventually heart failure.

Macro vascular disease leads to cardiovascular disease, to which accelerated

atherosclerosis is a contributor:

• Coronary artery disease, leading to angina or myocardial infarction

("heart attack")
• Stroke (mainly the ischemic type)
• Peripheral vascular disease, which contributes to intermittent
claudicating (exertion-related leg and foot pain) as well as diabetic
foot.
• Diabetic myonecrosis ('muscle wasting')

Diabetic foot, often due to a combination of sensory neuropathy (numbness

or insensitivity) and vascular damage, increases rates of skin ulcers and
infection and, in serious cases, necrosis and gangrene. It is why diabetics are
prone to leg and foot infections and why it takes longer for them to heal
from leg and foot wounds. It is the most common cause of non-traumatic
adult amputation, usually of toes and or feet, in the developed world.
Diabetes mellitus and pregnancy

For women with diabetes mellitus, pregnancy can present some particular
challenges for both mother and child. If the woman who is pregnant has
diabetes or develops diabetes during pregnancy, it can cause early labor,
birth defects, and very large babies
Risks for the child
Miscarriage, growth restriction, growth acceleration, fetal obesity
(macrosomia), polyhydramnios and birth defects.
Risks for the mother Disturbed blood glucose levels. Hypoglycemia can
occur without warning.
There are 2 classes of gestational diabetes (diabetes which began during
pregnancy):

• Class A1: gestational diabetes; diet controlled

• Class A2: gestational diabetes; insulin controlled

Treatment of pregnant women with diabetes

Blood glucose levels in the pregnant woman should be regulated as

strictly as possible. In diabetes mellitus type 2, oral antidiabetic
drugs should be replaced with insulin

Lipoatrophic diabetes

Lipoatrophic diabetes is a type of diabetes mellitus presenting with severe

lipodystrophy in addition to the traditional signs of diabetes.
Lipodystrophy is a medical condition characterized by abnormal or
degenerative conditions of the body's adipose tissue. ("Lipo" is Greek for
"fat" and "dystrophy" is Greek for "abnormal or degenerative condition".) A
more specific term, lipoatrophy is used when describing the loss of fat from
one area (usually the face).
Insulin injections

A lipodystrophy can be a lump or small dent in the skin that forms when a
person keeps performing injections in the same spot. These types of
lipodystrophies are harmless. People who want to avoid them can do so by
changing (rotating) the places where they perform injections. For people
with diabetes, using purified insulin

Diagnosis
The diagnosis of type 1 diabetes, and many cases of type 2, is usually
prompted by recent-onset symptoms of excessive urination (polyuria)
and excessive thirst (polydipsia), and often accompanied by weight
loss. Diabetes is often detected when a person suffers a problem that is
frequently caused by diabetes, such as a heart attack, stroke,
neuropathy, poor wound healing or a foot ulcer, certain eye problems,
certain fungal infections, or delivering a baby with macrosomia or
hypoglycemia. Diabetes mellitus is characterized by recurrent or
persistent hyperglycemia, and is diagnosed by demonstrating any one
of the following:

• Fasting plasma glucose level at or above 126 mg/dL (7.0 mmol/L).

• Plasma glucose at or above 200 mg/dL (11.1 mmol/L) two hours after
a 75 g oral glucose load as in a glucose tolerance test.
• Symptoms of hyperglycemia and casual plasma glucose at or above
200 mg/dL (11.1 mmol/L).

ROLE OF HORMONES INFLUENCING BLOOD

GLUCOSE LEVELS

• INSULIN
• GLUCAGON
• SOMATOSTATIN
• AMYLIN

•
INSULIN

Insulin is a peptide hormone composed of 51 amino acids and has a

molecular weight of 5808 Da. It is produced in the islets of Langerhans in
the pancreas. The name comes from the Latin insula for "island".Insulin's
structure varies slightly between species of animal. Insulin from animal
sources differs somewhat in 'strength' (in carbohydrate metabolism control
effects) in humans because of those variations. Porcine (pig) insulin is
especially close to the human version.

Physiological effects

Effect of insulin on glucose uptake and metabolism. Insulin binds to its

receptor (1) which in turn starts many protein activation cascades (2). These
include: translocation of Glut-4 transporter to the plasma membrane and
influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid
synthesis (6).

The actions of insulin on the global human metabolism level include:

• Control of cellular intake of certain substances, most prominently

glucose in muscle and adipose tissue (about ⅔ of body cells).
• Increase of DNA replication and protein synthesis via control of
amino acid uptake.
• Modification of the activity of numerous enzymes.

The actions of insulin on cells include:

• Increased glycogen synthesis – insulin forces storage of glucose in

liver (and muscle) cells in the form of glycogen; lowered levels of
insulin cause liver cells to convert glycogen to glucose and excrete it
into the blood. This is the clinical action of insulin which is directly
useful in reducing high blood glucose levels as in diabetes.
• Increased fatty acid synthesis – insulin forces fat cells to take in blood
lipids which are converted to triglycerides; lack of insulin causes the
reverse.
• Increased esterification of fatty acids – forces adipose tissue to make
fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes
the reverse.
• Decreased proteolysis – decreasing the breakdown of protein.
• Decreased lipolysis – forces reduction in conversion of fat cell lipid
stores into blood fatty acids; lack of insulin causes the reverse.
• Decreased gluconeogenesis – decreases production of glucose from
non-sugar substrates, primarily in the liver (remember, the vast
majority of endogenous insulin arriving at the liver never leaves the
liver); lack of insulin causes glucose production from assorted
substrates in the liver and elsewhere.
• Decreased autophagy - decreased level of degradation of damaged
organelles. Postprandial levels inhibit autophagy completely.
• Increased amino acid uptake – forces cells to absorb circulating amino
acids; lack of insulin inhibits absorption.
 • Increased potassium uptake – forces cells to absorb serum potassium;
lack of insulin inhibits absorption. Thus lowers potassium levels in
blood.
• Arterial muscle tone – forces arterial wall muscle to relax, increasing
blood flow, especially in micro arteries; lack of insulin reduces flow
by allowing these muscles to contract.
• Increase in the secretion of hydrochloric acid by Parietal cells in the
stomach

GLUCAGON

Mechanism of action

Glucagon binds to the glucagon receptor, a G protein-coupled receptor

located in the plasma membrane. The conformation change in the receptor
activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When
the G protein interacts with the receptor, it undergoes a conformational
change that results in the GDP molecule, that was bound to the α subunit, to
be replaced with a GTP molecule. This substitution results in the releasing
of the α subunit from the β and γ subunit. The alpha subunit specifically
activates the next enzyme in the cascade, adenylate cyclase.Adenylate
cyclase manufactures cAMP (cyclical AMP), which activates protein kinase
A (cAMP-dependent protein kinase). This enzyme, in turn, activates
phosphorylase kinase, which, in turn, phosphorylates glycogen
phosphorylase, converting into the active form called phosphorylase A.
Phosphorylase A is the enzyme responsible for the release of glucose-1-
phosphate from glycogen polymers
glucagon stimulates glycogenolysis and gluconeogenesis.

Uses
An injectable form of glucagon is vital first aid in cases of severe
hypoglycemia when the victim is unconscious or for other reasons cannot
take glucose orally. The dose for an adult is typically 1 milligram, and the
glucagon is given by intramuscular, intravenous or subcutaneous injection,
and quickly raises blood glucose levels. Glucagon can also be administered
intravenously at 0.25 - 0.5 unit.Anecdotal evidence suggests a benefit of
higher doses of glucagon in the treatment of overdose with beta blockers; the
likely mechanism of action is the increase of cAMP in the myocardium,
effectively bypassing the inhibitory action of the β-adrenergic second
messenger system Glucagon acts very quickly; common side-effects include
headache and nausea. Drug interactions: Glucagon interacts only with oral
anticoagulants, increasing the tendency to bleed

SOMATOSTATIN
somatostatin has 5 types of receptors (sst1-sst5)
somatostatin has variety of functions

• Sst1 sst2 sst3 sst5 Inhibitor of growth harmone

• The ss4 receptor is responcible for the inhibition of insulin release

AMYLIN
it is consecrated along with insulin in the pancreatic cells. it works with
insulin to provide a glucose control

The imbalance between any of the hormones that is less insulin or more
glucagon causes DIABETES MELLITUS

Treatment and management of diabetes

Careful control is needed to reduce the risk of long term complications. This
is theoretically achievable with combinations of diet, exercise and weight
loss (type 2), various oral diabetic drugs (type 2 only), and insulin use
(type 1 and for type 2 not responding to oral medications, mostly those with
extended duration diabetes). In addition, given the associated higher risks of
cardiovascular disease, lifestyle modifications should be undertaken to
control blood pressure and cholesterol by exercising more, smoking less or
ideally not at all, consuming an appropriate diet, wearing diabetic socks,
wearing diabetic shoes, and if necessary, taking any of several drugs to
reduce blood pressure.

• Many type 1 treatments include combination use of regular or NPH

insulin, and/or synthetic insulin analogs (e.g., Humalog, Novolog or
Apidra) in combinations such as Lantus/Levemir and Humalog,
Novolog or Apidra.
• Another type 1 treatment option is the use of the insulin pump (e.g.,
from Deltec Cozmo, Animas, Medtronic Minimed, Insulet Omnipod,
or ACCU-CHEK). A blood lancet is used to pierce the skin (typically
of a finger), in order to draw blood to test it for sugar levels.
 • Type 2 diabetes is usually first treated by increasing physical activity,
and eliminating saturated fat and reducing sugar and carbohydrate
intake with a goal of losing weight. These can restore insulin
sensitivity even when the weight loss is modest,

Anti diabetic drugs

There are several drugs available for type 2 diabetics—most are unsuitable
or even dangerous for use by type 1 diabetics. They fall into several classes
and are not equivalent, nor can they be simply substituted one for another.
All are prescription drugs.

Metformin 500mg tablets

One of the most widely used drugs now used for type 2 diabetes is the
biguanide metformin; it works primarily by reducing liver release of blood
glucose from glycogen stores and secondarily by provoking some increase in
cellular uptake of glucose in body tissues. Both historically, and currently,
the most commonly used drugs are in the Sulfonylurea group, of which
several members (including glibenclamide and gliclazide) are widely used;
these increase glucose stimulated insulin secretion by the pancreas and so
lower blood glucose even in the face of insulin resistance
Newer drug classes include:

• Testosterone treatment is very efficient to reduce insulin resistance

without digestive problems (a very common side effect of other anti-
diabetes drugs)
• Thiazolidinediones (TZDs) (rosiglitazone, pioglitazone, and
troglitazone -- the last, as Rezulin, was withdrawn from the US
 market because of an increased risk of systemic acidosis). These
increase tissue insulin sensitivity by affecting gene expression
• α-glucosidase inhibitors (acarbose and miglitol) which interfere with
absorption of some glucose containing nutrients, reducing (or at least
slowing) the amount of glucose absorbed
• Meglitinides which stimulate insulin release (nateglinide, repaglinide,
and their analogs) quickly; they can be taken with food, unlike the
sulfonylureas which must be taken prior to food (sometimes some
hours before, depending on the drug)
• Peptide analogs which work in a variety of ways:
o Incretin mimetics which increase insulin output from the beta
cells among other effects. These includes the Glucagon-like
peptide (GLP) analog exenatide, sometimes referred to as
lizard spit as it was first identified in Gila monster saliva
o Dipeptidyl peptidase-4 (DPP-4) inhibitors increase Incretin
levels (sitagliptin) by decreasing their deactivation rates
o Amylin agonist analog, which slows gastric emptying and
suppresses glucagon (pramlintide)

Study of individual class of drugs

INSULIN SECRETOGOGUES

FIRST GENERATION
Sulphonyl ureas
Examples:chlorpropramide ;tolazamide;tolbutamide
SECOND GENERATION
Examples:glipizide ;gliburide;gliclazide

MECHANISM OF ACTION

• Pancreas
to stimulate the release of insulin from β cells by increasing their
sensitivity to glucose .they act on SUR cells linked to k ions by
binding to SUR1 K EFFLUX IS BLOCKED LEADING TO
DEPOLARISATION OF MEMBRANE depolarisation opens Ca
channelresulting in influx of Ca,with exocytosis of insulin.sulphonyl
ureas increase the insulin concentrations slowly for prolonged period
of time
• Liver
sulphonyl urea inhibit neoglucogenesis and glycogenolysis.there fore
liver releases less glucosecausing hypoglycemia

PHARMACOLOGICAL EFFECTS

• Given orally or parenterally these drugs reduce blood sugar in

diabetes and non diabetic patients
• In diabetes they lower the elevated plasma FFA levels ,even before
they lower the blood sugar
• The beneficial effect of sulphonyl ureas on the serum lipid and
lipoprotein levels are due to improved control of diabeties

PHARMACOKINETICS AND METABOLISM

• Sulphonyl ureas are highly protein bound ,primarily to albumin which

leads to a large volume of distribution
• Food can delay absorption
• Metabolised in liver,metabolites excreted renally
• Chlorpropamide has longest half life and has greater tendency of
adverse effects
• Tolbutamide and tolazamide undergo benzylic oxidation leading to an
inactive benzoic acid derivative. an alternative hydroxylation of
aliphatic ring of tolazamide leads to an active metabolite showing
longer activity
• Major metabolite of acetohexamide is reduction to keto group,
forming an alcohol
• Glipiide and gliburide are extensively metabolised to less active or
inactive metabolites.
• Glimipride is metabolised in liver by CYP2C9 to M-1

ADVERSE EFFECTS
• Weight gain
• Hypoglycemia
• Allergic reaction
skin rash ;bone marrow depression with leucopenia thrombocytopenia
• Liver
cause cholestic jaundice and pulmonary eosinophilia
 • Drug interactions
• With barbiturates and sedative hypnotics prolong CNS effects
• Therapeutic applications
• Mostly used to treat diabetes mellitus type 2

Limitations
very long diabetes mellitus type 2;diabetic coma ;parectomy
destruction of pancreas;ketonuria

Dosage
• Tolbutamide 3g 2-3 times a day
• Chlorpromide >500mg per day
• Glibenclamide 2.5-20mg

Biguanides
Examples: phenformin,metformin,buformin

Mechanism of action
• Inhibit Hepatic Gluconeogenesis and decrease hepatic and renal
glucose output
• Increase the peripheral glucose utilization by enhancing anaerobic
glycolysis
• Act as insulin sensitizers in the muscle and adipose tissue and reduce
hyperinsulinemia
• Delay glucose absorption
• Reduce the appetite
• Pharmacological actions
• These agents do not lower the blood sugar in normal subject but do so
in diabetics
• They potentiate the hypoglycemic action of insulin and sulfonylurea
• They decrease glycogen content of the liver
• They reduce plasma content and LDL cholesterol
• Biolysis and FFA production and lipid oxidation are reduced by
Biguanides

Pharmacokinetics and metabolism

• Metformin is quickly absorbed from the small intestine bio
availability is 50 to 60% and drug is not protein bound PPC 2 hours
• Metformin is excreted in urine and half life is 2 to 5 hours

Adverse reactions
• Nausea, Anorexia and Abdominal discomfort
• They produce lethargy, muscular weakness and weight loss
• COPD, CHF, chronic kidney failure

Therapeutic uses
• Obese patients with T2 DM
• Secondary sulfonylurea urea failure
• Non alcoholic teato hepatitis

Contra indications
• Renal insufficiency, livery disease, alcohol abuse
Dosage
• Metformin 500 to 800 mg tablets 2 to 3 times before meals

INSULIN SENSITIZERS

Thiazolidinedones
Examples: troglitazone ; piglitazone ; rosiglitazone

Mechanism of action
• They stimulate peroxisome proliferator activated receptor stimulation.
The PPAR binds to nuclear response elements leading to the
transcription of insulin sensitive genes and subsequently a wide
variety of actions including
• Increase in glucose uptake by liver , muscle, adipose tissue
• Lipogenesis in adipose tissue
• Fatty acid uptake and glycolysis and glucose oxidation
• Decrease in gluconeogenesis and glyco genolysis in liver

Pharmacological actions
• Increase in insulin sensitivity of the adipose tissue and lower the
plasma FFA levels . As a result insulin sensitivity in liver and muscle
increase
• Reduce the production of proinflammatory cytokines by the visceral
adipocytes and increase the adipose tissue production of adiponectin
• Increase HDL
• Preserve and enhance betacell and vascular function by reducing
inflammatory milieu in the body.

Pharmacokinetics and metabolism

• Troglitazone is metabolized by CYP2C8 and CYP3A4 to quinone
product M3
• Pioglitazone is metabolize by oxidation at either carbon adjacent to
pyridine ring and found in urine and bile
• Rosiglitazone metabolites consist of sulfate and glucuronic acid
conjugates of hydroxylation and N-demethylation

Adverse reactions
• Liver
Hepatotoxicity,
• Weight gain
• Fluid retention , heart failure

Therapeutic uses
• In T2DM
• Polycystic ovary syndrome
• NASH

Dosage
• Rosiglitazone 4 to 8 mg per day
• Pioglitazone 15 to 45 mg per day

α Glucosidase inhibitors
Examples:acarbose ;miglitol

Mechanism of action
• They prevent the hydrolysis of carbohydrates, their absorption rate is
reduced. It binds competitively to carbohydrates binding region of
alpha glycosides enzymes

Pharmacological action
• Acarbose reduce the hyperglycemia

Adverse reactions
• Flatulence, abdominal discomfort and loose stools

Therapeutic uses
• The drug is useful in patients on high carbohydrates diet
• INSULINOMIMETICS
• Examples:repaglinide nateglinide
• Mechanism of action
• It binds to SUR1,SUR2A,SUR2Bto block

INSULINO MIMETICS
• Examples :ripaglinide ;nataglinide

Mechanism of action
• Binds toSUR2;SUR1 block ATP sensitive K ions resulting in insulin
secretion in βcells
• It doesn’t produce prolonged hyperinslimia as sulphonyl ureas so less
side effects

Pharmacokinetics
• Nateglinide is protein bound and has 90%bioavailability.excreted in
urine unchanged. major metabolites are hydroxyl derivatives and
glucoronide conjugates

Adverse effects
• Weight gain;
• Dangerous hypoglycemia
• Type II changed to type I and still worsen the condition

DUAL PPAR α AND PPAR γ COACTIVATORS

Examples; muraglitazar ;testaglitazar

Mechanism of action
• Activation of PPR α is reported to reduce plasma triglyceride levels
and to increase high density lipo protein levels

Side effects ;cardiovascular effects ;MI;CHF

DRUG DEVELOPMENT RELATED TO OTHER HORMONES

1 GLUCAGON ANTAGONISTS
• BAY-27-995 is being investigated on type 2 diabetes patients

2 AMYLIN AGONISTS
• They produce similar actions as amylin like they lower the glucagon
and may produce insulin in severities of type 2 diabetes
Example:pramlintide:
• It is administered sc half life 29 min

Mechanism of action
• Stimulate the amylin receptors present in brain reduces food uptake
and decreases gastric motility
• Side effect :nausea

3 Glucagon like peptide 1 agonists

• Glucagon like peptide 1 is a mammalian incretin hormone consisting
of two peptides secreted by endocrine glands of small intestine

Mechanism of action
• The GLP1stimulate the first phase of release of insulin from βcells
and inhibit release of glucagon
• It slows down gastric emptying and there by causes a feeling of
fullness and decreased food intake

Most available GLP1 is Exenitide

• Discovered from saliva of Gila monster
• It binds to GLP1and shows its action

ADVERSE EFFECT
• Pancreatitis ;nausea ,vomiting diarrhoea

4 DPP IV INHIBITORS
• Dipeptidyl peptidase remove 2 amino acids from GLP1 and there by
inactivating GLP1
Approaches in discovery and development phases

RETINOID X receptor modulators

RXRforms functional heterodimer withPPAR as well as other nuclear
hormone receptors .thePPAR complex is activated and there by improving
the animal to develop glucose tolerance.selectivity to dimer is must to
decrease the side effects .analogues are in earlier stage of development

Protein thyrosine phosphatase 1B inhibitor

Mice laking Protein thyrosine phosphatase 1Bare generally found to produce
greater insulinand gain less weight.the enzyme dephosporelates both the
insulin receptor and insulin receptor substrate -1 leading to decreased insulin
sensitivity .hence act as active target to type 2 diabetes
Insulin preparations

If antidiabetic drugs fail (ie, the clinical benefit stops), insulin therapy may
be necessary – usually in addition to oral medication therapy – to maintain
normal or near normal glucose levels.

Typical total daily dosage of insulin is 0.6 U/kg. But, of course, best timing
and indeed total amounts depend on diet (composition, amount, and timing)
as well the degree of insulin resistance. More complicated estimations to
guide initial dosage of insulin are:

• For men, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight

[kg]÷(14.3xheight [m])–height [m])
• For women, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight
[kg]÷(13.2xheight [m])–height [m])

The initial insulin regimen is often chosen based on the patient's blood
glucose profile. Initially, adding nightly insulin to patients failing oral
medications may be best. Nightly insulin combines better with metformin
than with sulfonylureas. The initial dose of nightly insulin (measured in
IU/d) should be equal to the fasting blood glucose level (measured in
mmol/L). If the fasting glucose is reported in mg/dl, multiply by 0.05551 to
convert to mmol/L

When nightly insulin is insufficient, choices include:

• Premixed insulin with a fixed ratio of short and intermediate acting

insulin; this tends to be more effective than long acting insulin, but is
associated with increased hypoglycemia. Initial total daily dosage of
biphasic insulin can be 10 units if the fasting plasma glucose values
are less than 180 mg/dl or 12 units when the fasting plasma glucose is
above 180 mg/dl".A guide to titrating fixed ratio insulin is available.

• Long acting insulin’s such as insulin glargine and insulin detemir. A

meta-analysis of randomized controlled trials by the Cochrane
Collaboration found "only a minor clinical benefit of treatment with
long-acting insulin analogues for patients with diabetes mellitus type
2" More recently, a randomized controlled trial found that although
long acting insulins were less effective, they were associated with
reduced hypoglycemic episodes.
 RECENT ADVANCEMENTS TO TREAT DIABETES

Pancreas transplantation

Pancreas transplants are generally performed together with or some time

after a kidney transplant. One reason for this is that introducing a new
kidney requires taking immunosuppressive drugs such as ciclosporin.
Nevertheless this allows the introduction of a new, functioning pancreas to a
patient with diabetes without any additional immunosuppressive therapy.
However, pancreas transplants alone can be wise in patients with extremely
labile type 1 diabetes mellitus Scientists have found another alternative
mode of pancreas transplantation through the use of xenografts especially
from animals such as pigs. This alternative mode of transplantation from
animals, provides an alternative therapy for the treatment of Type 1 diabetes

Islet cell transplantation

Islet cell transplantation is expected to be less invasive than a pancreas

transplant which is currently the most commonly used approach in humans.

In one variant of this procedure, islet cells are injected into the patient's
liver, where they take up residence and begin to produce insulin. The liver is
expected to be the most reasonable choice because it is more accessible than
the pancreas, and islet cells seem to produce insulin well in that
environment. The patient's body, however, will treat the new cells just as it
would any other introduction of foreign tissue, unless a method is developed
to produce them from the patient's own stem cells or there is an identical
twin available who can donate stem cells. The immune system will attack
the cells as it would a bacterial infection or a skin graft. Thus, patients now
also need to undergo treatment involving immunosuppressants, which
reduce immune system activity.

Recent studies have shown that islet cell transplants have progressed to the
point that 58% of the patients in one study were insulin independent one
year after islet cell transplant. Ideally, it would be best to use islet cells
which will not provoke this immune reaction, but scientists in New Zealand
are also looking into placing them within a protective housing derived of
seaweed which enables insulin to flow out and nutrients to flow in while
protecting the islets from immune system attack via white blood cells.
Encapsulation approach

The Bio-artificial pancreas: a cross section of bio-engineered tissue with

encapsulated islet cells delivering endocrine hormones in response to
glucose

A biological approach to the artificial pancreas is to implant bioengineered

tissue containing islet cells, which would secrete the amounts of insulin,
amylin and glucagon needed in response to sensed glucose.

When islet cells have been transplanted via the Edmonton protocol, insulin
production (and glycemic control) was restored, but at the expense of
continued immunosuppression drugs. Encapsulation of the islet cells in a
protective coating has been developed to block the immune response to
transplanted cells, which relieves the burden of immunosuppression and
benefits the longevity of the transplant.

One concept of the bio-artificial pancreas uses encapsulated islet cells to

build an islet sheet which can be surgically implanted to function as an
artificial pancreas

This islet sheet design consists of:

• An inner mesh of fibers to provide strength for the islet sheet;

• Islet cells, encapsulated to avoid triggering a proliferating immune
response, adhered to the mesh fibers;
• A semi-permeable protective layer around the sheet, to allow the
diffusion of nutrients and secreted hormones;
• A protective coating, to prevent a foreign body response resulting in a
fibrotic reaction which walls off the sheet and causes failure of the
islet cells.

Islet sheet with encapsulation research is pressing forward with large animal
studies at the present, with plans for human clinical trials within a few years.

Clinical studies underway in New Zealand by Living Cell Technologies

have encapsulated pig islet cells in a seaweed derived capsule. This
approach has had very positive clinical studies and is currently underway in
human trials as of 2008. So far, treatment using this method of cell
encapsulation has been proven safe and effective and is the first to achieve
insulin independence in human trials without immunosuppressant drugs.

Islet cell regeneration approach

Research undertaken at the Massachusetts General Hospital between 2001

and 2003 demonstrated a protocol to reverse type 1 diabetes in non-obese
diabetic mice (a frequently used animal model for type 1 diabetes mellitus)
Three other institutions have had similar results, as published in the March
24, 2006 issue of Science. A fourth study by the National Institutes of Health
achieved similar results, and also sheds light on the biological mechanisms
involved.

Other researchers, most notably Dr. Aaron I. Vinik of the Strelitz Diabetes
Research Institute of Eastern Virginia Medical School and a former
colleague, Dr. Lawrence Rosenberg (now at McGill University) discovered
in a protein they refer to as INGAP, which stands for Islet Neogenesis
Associated Protein back in 1997. INGAP seems to be the product of a gene
responsible for regenerating the islets that make insulin and other important
hormones in the pancreas.

INGAP has had commercialization difficulties. Although it has appeared

promising, commercial rights have changed hands repeatedly, having once
been owned by Procter & Gamble Pharmaceuticals, which eventually
dropped it. Rights were then acquired by GMP Companies. More recently,
Kinexum Metabolics, Inc. has since sublicensed INGAP from GMP for
further clinical trials. Kinexum has continued development under Dr. G.
Alexander Fleming, an experienced metabolic drug developer, who headed
diabetes drug review at the FDA for over a decade. As of 2008, the protein
had undergone Phase 2 Human Clinical Trials, and developers were
analyzing the results. At the American Diabetes Association's 68th Annual
Scientific Sessions in San Francisco, Kinexum announced a Phase 2 human
clinical trial with a combination therapy, consisting of DiaKine's Lisofylline
(LSF) and Kinexum's INGAP peptide, which is expected to begin in late
2008.[14] The trial will be unique in that patients who are beyond the 'newly
diagnosed' period will be included in the study. Most current trials seeking
to treat people with type 1 diabetes do not include those with established
disease.
Stem cells approach

Research is being done at several locations in which islet cells are developed
from stem cells.

In January 2006, a team of South Korean scientists has grown pancreatic

beta cells, which can help treat diabetes, from stem cells taken from the
umbilical cord blood of newborn babies.

]Brazil

In April 2007, it was reported by the Times Online that 15 young Brazilian
patients diagnosed with type 1 diabetes were able to naturally produce
insulin once again after undergoing mild chemotherapy to temporarily
weaken their immune systems and then injection of their own stem cells.
This allowed the pancreatic beta cells to produce insulin. Since white blood
cells were blocking the pancreas from producing insulin, Dr. Voltarelli and
colleagues killed the immune cells, allowing the pancreas to secrete insulin
once more.

However, there were no control subjects, which mean that all of the
processes could have been completely or partially natural. Secondly, no
theory for the mechanism of cure has been promoted. It is too early to say
whether the results will be positive or negative in the long run

University of North Carolina

In September 2008, scientists from the University of North Carolina at

Chapel Hill School of Medicine have announced their success in
transforming cells from human skin into cells that produce insulin.

The skin cells were first transformed into stem cells and then had been
differentiated into insulin-secreting cells.

However, other scientists have doubts, as the research papers fail to detail
the new cells' glucose responsiveness and the amount of insulin they are
capable of producing.
Gene therapy approach

Gene therapy: Designing a viral vector to deliberately infect cells with DNA
to carry on the viral production of insulin in response to the blood sugar
level.

Technology for gene therapy is advancing rapidly such that there are
multiple pathways possible to support endocrine function, with potential to
practically cure diabetes

• Gene therapy can be used to manufacture insulin directly: an oral

medication, consisting of viral vectors containing the insulin
sequence, is digested and delivers its genes to the upper intestines.
Those intestinal cells will then behave like any viral infected cell, and
will reproduce the insulin protein. The virus can be controlled to
infect only the cells which respond to the presence of glucose, such
that insulin is produced only in the presence of high glucose levels.
Due to the limited numbers of vectors delivered, very few intestinal
cells would actually be impacted and would die off naturally in a few
days. Therefore by varying the amount of oral medication used, the
amount of insulin created by gene therapy can be increased or
decreased as needed. As the insulin producing intestinal cells die off,
they are boosted by additional oral medications.
• Gene therapy might eventually be used to cure the cause of beta cell
destruction, thereby curing the new diabetes patient before the beta
cell destruction is complete and irreversible.
• Gene therapy can be used to turn duodenum cells and duodenum
adult stem cells into beta cells which produce insulin and amylin
naturally. By delivering beta cell DNA to the intestine cells in the
 duodenum, a few intestine cells will turn into beta cells and
subsequently adult stem cells will develop into beta cells. This makes
the supply of beta cells in the duodenum self replenishing, and the
beta cells will produce insulin in proportional response to
carbohydrates consumed.

Yonsei University

Scientists in the South Korean university of Yonsei have, in 2000, succeeded

in reversing diabetes in mice and rats. Using a viral vector, a DNA encoding
the production of an insulin analog was injected to the animals, which
remained non-diabetic for at least the eight months duration of the study

Prevention

"Immunization" approach

If a biochemical mechanism can be found that prevents the immune system

from attacking beta cells, it may be administered to prevent commencement
of diabetes type 1. Several groups are trying to achieve this by causing the
activation state of the immune system to change from Th1 state (“attack” by
killer T Cells) to Th2 state (development of new antibodies). This Th1-Th2
shift occurs via a change in the type of cytokine signaling molecules being
released by regulatory T-cells. Instead of pro-inflammatory cytokines, the
regulatory T-cells begin to release cytokines that inhibit inflammation.[24]
This phenomenon is commonly known as "acquired immune tolerance".

DiaPep277

A substance designed to cause lymphocyte cells to cease attacking beta cells,

DiaPep277 is a peptide fragment of a larger protein called HSP60. Given as
a subcutaneous injection, its mechanism of action involves a Th1-Th2 shift.
Clinical success has been demonstrated in prolonging the "honeymoon"
period for people who already have type 1 diabetes. The product is currently
being tested in people with latent autoimmune diabetes of adults (LADA).
Ownership of the drug has changed hands several times over the last decade.
In 2007, Clal Biotechnology Industries (CBI) Ltd., an Israeli investment
group in the field of life sciences, announced that Andromeda Biotech Ltd.,
a wholly owned subsidiary of CBI, signed a Term Sheet with Teva
Pharmaceutical Industries Ltd. to develop and commercialize DiaPep277

Intra-nasal insulin

There is pre-clinical evidence that a Th1-Th2 shift can be induced by

administration of insulin directly onto the immune tissue in the nasal cavity.
This observation has led to a clinical trial, called INIT II, which began in
late 2006, based in Australia and New Zealand.

BCG research

Tumor necrosis factor-alpha, or TNF-α, is part of the immune system. It

helps the immune system distinguish self from non-self tissue. People with
type 1 diabetes are deficient in this substance. Dr. Denise Faustman
theorizes that giving Bacillus Calmette-Guérin (BCG), an inexpensive
generic drug, would have the same impact as injecting diabetic mice with
Freund's Adjuvant, which stimulates TNF-α production. TNF-α kills the
white blood cells responsible for destroying beta cells, and thus prevents, or
reverses diabetes. She has reversed diabetes in laboratory mice with this
technique, but was only able to receive funding for subsequent research from
The Iaccoca Foundation, founded by Lee Iacocca in honor of his late wife,
who died from diabetes complications. Human trials are set to begin in 2008.

Diamyd

Diamyd is the name of a vaccine being developed by Diamyd Medical.

Injections with GAD65, an autoantigen involved in type 1 diabetes, has in
clinical trials delayed the destruction of beta cells for at least 30 months,
without serious adverse effects. Patients treated with the substance showed
higher levels of regulatory cytokines, thought to protect the beta cellsPhase
III trials are under way in the USA and in Europe, with most sites actively
pursuing participants. Two prevention studies, where the vaccine is given to
persons who have not yet developed diabetes, will start in 2009
REFERENCES

• Pharmacology and pharmacotherapy by sathoskar

• Text book of pharmacology by Tripathi
• Text book of pharmacology by rang and dale
• The pharmacological basics of therapeutics: good Mann Gilman
• Wikipedia

• Pittas, AG and Greenberg AS. Contemporary Diagnosis

and Management of Diabetes. Handbooks in Health Care
Co, Newtown, PA. 2003.

• Report of the Expert Committee on the Diagnosis and

Classification of Diabetes Mellitus, Diabetes Care 24
(suppl. 1): 2003