Dr.

Mohammed Qasim
2017-2018
4th Grade
 Learning Objectives
• Upon completion of this lecture, you will be able to:
1. Describe the pathophysiology of diabetes mellitus,
including alterations in metabolic pathways and
changes to basement membranes.
2. Describe the therapeutic actions, indications,
pharmacokinetics, contraindications, most common
adverse reactions, and important drug–drug
interactions associated with insulin and other
antidiabetic .
3. Compare and contrast the prototype drugs insulin,
with other types of insulin
• adiponectin: hormone produced by adipocytes that acts to increase
insulin sensitivity, decrease the release of glucose from liver, and protect
the blood vessels from inflammatory changes
• diabetes mellitus: a metabolic disorder characterized by high blood
glucose levels and altered metabolism of proteins and fats; associated with
thickening of the basement membrane, leading to numerous complications
• dipeptidyl peptidase-4 (DDP-4): enzyme that quickly metabolizes
glucagon-like polypeptide-1
• endocannabinoid receptors: receptors found in the adipose tissue,
muscles, liver, satiety center, and GI tract that are part of a signaling
system within the body to keep the body in a state of energy gain
• glucagon-like polypeptide-1 (GLP-1): a peptide produced in the GI tract
in response to carbohydrates that increases insulin release, decreases
glucagon release, slows GI emptying, and stimulates the satiety center in
the brain
• glycogen: storage form of glucose; can be broken down for rapid glucose level increases
during times of stress
• glycosuria: presence of glucose in the urine
• glycosylated hemoglobin: a blood glucose marker that provides a 3-month average of
blood glucose levels (HbA1c)
• hyperglycemia: elevated blood glucose levels (>106 mg/dL) leading to multiple signs
and symptoms and abnormal metabolic pathways
• hypoglycemia: lower-than-normal blood sugar ( <40 mg/dl)often results from
imbalance between insulin or oral agents and patient’s eating, activity, and stress
• incretins: peptides that are produced in the GI tract in response to food that help to
modulate insulin and glucagon activity
• insulin: hormone produced by the beta cells in the pancreas;
stimulates insulin receptor sites to move glucose into the cells;
promotes storage of fat and glucose in the body
• ketosis: breakdown of fats for energy, resulting in an increase in
ketones to be excreted from the body
• polydipsia: increased thirst; seen in diabetes when loss of fluid
and increased tonicity of the blood lead the hypothalamic thirst
center to make the patient feel thirsty
• polyphagia: increased hunger; sign of diabetes when cells
cannot use glucose for energy and feel that they are starving,
causing hunger
• sulfonylureas: oral antidiabetic agents used to stimulate the
pancreas to release more insulin
• The pancreas produces the peptide hormones insulin, glucagon, and
somatostatin.
• The peptide hormones are secreted from cells in the islets of
Langerhans (β cells produce insulin, α cells produce glucagon, and δ
cells produce somatostatin).
• These hormones play an important role in regulating metabolic
activities of the body, particularly glucose homeostasis.
• A relative or absolute lack of insulin, as seen in diabetes mellitus, can
cause serious hyperglycemia. Left untreated, retinopathy, nephropathy,
neuropathy, and cardiovascular complications may result.
• Administration of insulin preparations or other glucose-lowering
agents can reduce morbidity and mortality associated with diabetes
Glucose control
• There is debate over whether prolonged high glucose
levels lead to the basement membrane changes and
complications of diabetes or whether the basement
membrane thickening is the initial problem that leads to
lack of insulin and changes in insulin receptors; whichever
comes first, replacement or stimulation of insulin release is
the mainstay for treatment of diabetes mellitus
• Glycosylated hemoglobin levels, or an HbA1c test, provide
a 3-month average of glucose levels. Red blood cells are
freely permeable to glucose, and this test gives an average
range of glucose exposure over the life of the red blood
cell, about 120 days. This test does not require fasting
before blood is drawn or the oral intake of glucose before
testing. Elevations above 6% may be an early indicator of a
prediabetic state, before changes are noted in the fasting
blood sugar level. Once a baseline is established, the goal
of therapy for a diabetic patient is an HbA1c level
 DM Type I
• Generally associated with onset at a young age
(<40years old).
• It may be caused by destruction of beta-cells
following certain viral infections or due to an
autoimmune process.
• It is characterised by an inability of the beta-cells to
produce insulin and is fatal if not treated.

Pharmacological management
• Replace insulin in an attempt to return blood glucose
to normal and preventing diabetic complications.
• A person with type 1 diabetes must rely on exogenous
insulin to control hyperglycemia, avoid ketoacidosis, and
maintain acceptable levels of glycosylated hemoglobin
(HbA1c).
• [Note: The rate of formation of HbA1c is proportional to
the average blood glucose concentration over the previous
3 months. A higher average glucose results in a higher
HbA1c.]
• The goal of insulin therapy in type 1 diabetes is to maintain
blood glucose as close to normal as possible and to avoid
wide swings in glucose
• Insulin is a peptide hormone, produced by beta cells of the
pancreas, and is central to regulating carbohydrate and fat
metabolism in the body.
• Insulin causes cells in the liver, skeletal muscles, and fat
tissue to absorb glucose from the blood.
• In the liver and skeletal muscles, glucose is stored as
glycogen, and in fat cells (adipocytes) it is stored as
triglycerides.
• When control of insulin levels fails, diabetes mellitus can
result. As a consequence, insulin is used medically to treat
some forms of diabetes mellitus.
 STRUCTURE OF INSULIN
• Human insulin consists of 51aa in two chains connected by
2 disulfide bridges (a single gene product cleaved into 2
chains during posttranslational modification).
• T1/2~5-10 minutes, degraded by glutathione-insulin
transhydrogenase (insulinase) which cleaves the disulfide
links.
• Bovine insulin differs by 3aa, pork insulin differs by 1aa.
• Insulin is stored in a complex with Zn2+ ions.
STRUCTURE OF INSULIN
 Therapeutic Actions and Indications
• Insulin is a hormone that:
• promotes the storage of the body’s fuels
• facilitates the transport of various
metabolites and ions across cell membranes
• stimulates the synthesis of glycogen from
glucose, of fats from lipids, and of proteins
from amino acids.
• Insulin does these things by reacting with
specific receptor sites on the cell.
 MECHANISM OF ACTION
• Insulin acts on specific receptors located on the cell
membrane of practically every cell, but their density
depends on the cell type: liver and fat cells are very rich.
• The insulin receptor is a receptor tyrosine kinase (RTK)
which is a heterotetrameric glycoprotein consisting of 2
extracellular α and 2 transmembrane β subunits linked
together by disulfide bonds, orienting across the cell
membrane as a heterodimer
• It is oriented across the cell membrane as a heterodimer.
• The α subunits carry insulin binding sites, while the β
subunits have tyrosine kinase activity.
 Actions of insulin
• Insulin facilitates glucose transport across cell membrane;
skeletal muscle and fat are highly sensitive.
• Insulin facilitates glycogen synthesis from glucose in liver,
muscle and fat by stimulating the enzyme glycogen
synthase.
• Insulin inhibits gluconeogenesis (from protein, FFA and
glycerol) in liver.
• Insulin inhibits lipolysis in adipose tissue and favours
triglyceride synthesis.
• In diabetes increased amount of fat is broken down due to unchecked
action of lipolytic hormones (glucagon) → increased FFA and glycerol
in blood → taken up by liver to produce acetyl-CoA.

• Normally acetyl-CoA is resynthesized to fatty acids and triglycerides,

but this process is reduced in diabetics and acetyl CoA is diverted to
produce ketone bodies (acetone, acetoacetate,β-hydroxy-butyrate).

• Insulin facilitates AA entry and their synthesis into proteins, as well as

inhibits protein breakdown in muscle and most other cells. Insulin
deficiency leads to protein breakdown → AAs are released in blood →
taken up by liver and converted to Glucose.
 Fate of insulin
• Insulin is distributed only extracellularly.
• It is a peptide; gets degraded in the g.i.t. if
given orally.
• Injected insulin or that released from
pancreas is metabolized primarily in liver
and to a smaller extent in kidney and
muscles.
• The plasma t½ is 5–9 min.
 Clinical use
Diabetes mellitus :
• Insulin is effective in all forms of diabetes mellitus and is a must for IDDM cases, as
well as for post pancreatectomy diabetes and gestational diabetes.
• Many NIDDM cases can be controlled by diet, reduction in body weight and
appropriate exercise. Insulin needed by some such patients:
i) Not controlled by diet and exercise or when these are not practicable.
ii) Primary or secondary failure of oral hypoglycemic or when these drugs are not
tolerated.
iii) Under weight patients.
iv) Temporarily to tide over infections, trauma, surgery, pregnancy.
v) Any complication of diabetes, e.g. Ketoacidosis, nonketotic hyperosmolar coma,
gangrene of extremities.
Other : Hyperkalemia
 Insulin preparations
Human Insulin analogues
• Modified insulin peptides (insulin lispro and insulin aspart) - have a
rapid onset but short duration of action
• May be injected just before a meal or when necessary just after a meal.
• Increase flexibility and are useful for pts prone to pre-lunch
hypoglycaemia and those who tend to eat late in the evening and may
be at risk of nocturnal hypoglycaemia.
Short-acting insulins
• Soluble insulins have relatively short-lived effects of 6-8 hours, with
peak effects at 2-5 hours. These are given approximately 15-30
minutes before meals.
Intermediate and long-acting insulins
• Combination of insulin with protamine gives rise to intermediate acting
insulin (isophane insulin), binding to zinc gives intermediate to long
acting insulin and combination with protamine plus zinc gives long-
acting insulin. Crystalline insulin zinc suspensions are also long-acting.
Biphasic preparations contain both an intermediate-acting agent (e.g.
isophane insulin) with a shorter acting form (e.g. soluble insulin).
 Rapid-acting and short-acting insulin
preparations
• Four preparations fall into this category:
( regular insulin, insulin lispro ,insulin aspart ,and insulin glulisine .)

• Regular insulin is a short-acting, soluble.

• Insulin lispro, aspart, and glulisine are classified as rapid-acting
insulins.
• Modification of the amino acid sequence of regular insulin produces
analogs that are rapid-acting insulins.( For example, insulin lispro
differs from regular insulin in that the lysine and proline at positions
28 and 29 in the B chain are reversed). This modification results in
more rapid absorption, a quicker onset, and a shorter duration of action
after subcutaneous injection.( Peak levels of insulin lispro are seen at
30 to 90 minutes, as compared with 50 to 120 minutes for regular
insulin).
• Rapid- or short-acting insulins are administered to mimic the prandial
(mealtime) release of insulin and to control postprandial glucose.
• They may also be used in cases where swift correction of elevated
glucose is needed.
• Rapid- and short-acting insulins are usually used in conjunction with a
longer-acting basal insulin that provides control of fasting glucose.
• Regular insulin should be injected subcutaneously 30 minutes before a
meal, whereas rapid-acting insulins are administered in the 15 minutes
proceeding a meal or within 15 to 20 minutes after starting a meal.
Rapid-acting insulins are commonly used in external insulin pumps,
and they are suitable for IV administration, although regular insulin is
most commonly used when the IV route is needed.
 Intermediate-acting insulin
• Neutral protamine Hagedorn (NPH) (isophane) insulin is an
intermediate-acting insulin formed by the addition of zinc and
protamine to regular insulin.

• The combination with protamine forms a complex that is less soluble,

resulting in delayed absorption and a longer duration of action.

• NPH insulin is used for basal (fasting) control in type 1 or 2 diabetes

and is usually given along with rapid- or short-acting insulin for
mealtime control.

• NPH insulin should be given only subcutaneously (never IV), and it

should not be used when rapid glucose lowering is needed (for
example, diabetic ketoacidosis).
 Long-acting insulin preparations
• The isoelectric point of insulin glargine is lower than that of human
insulin, leading to formation of a precipitate at the injection site that
releases insulin over an extended period. It has a slower onset than
NPH insulin and a flat, prolonged hypoglycemic effect with no peak.

• Insulin detemir has a fatty acid side chain that enhances association
to albumin. Slow dissociation from albumin results in long-acting
properties similar to those of insulin glargine.

• As with NPH insulin, insulin glargine and insulin detemir are used for
basal control and should only be administered subcutaneously. Neither
long-acting insulin should be mixed in the same syringe with other
insulins, because doing so may alter the pharmacodynamic profile
 Insulin combinations
• Various premixed combinations of human
insulins, such as 70% NPH insulin plus
30% regular insulin ,or 50% of each of
these are also available.
• Use of premixed combinations decreases
the number of daily injections but makes it
more difficult to adjust individual
components of the insulin regimen.
 Standard treatment versus intensive treatment
• Standard insulin therapy involves twice-daily injections.
• In contrast, intensive treatment utilizes three or more injections daily
with frequent monitoring of blood glucose levels.
• The ADA recommends a target mean blood glucose level of 154
mg/dL or less (HbA1c ≤ 7%), and intensive treatment is more likely to
achieve this goal.
• The frequency of hypoglycemic episodes, coma, and seizures is higher
with intensive insulin regimens .However, patients on intensive
therapy show a significant reduction in microvascular complications of
diabetes such as retinopathy, nephropathy, and neuropathy compared
to patients receiving standard care .
• Intensive therapy should not be recommended for patients with long-
standing diabetes, significant microvascular complications, advanced
age, and those with hypoglycemic unawareness.
 Regimens
• No fixed rules and regimens can be adopted to suit the
individual needs:
Twice daily regimens: 2 daily injections, one 30 minutes before
breakfast and one before the evening meal of short- and longer-
acting insulins in combination, with two thirds of the insulin given
as the morning dose. This is the most common regimen.
Multiple dosing regimens: a single dose of medium-acting insulin is
given at bedtime and doses of short acting insulin are given 30
minutes before each meal. This allows more flexibility with the
timing of meals. Termed ‘Basal-bolus regimen’.
• Alternatively, a short-acting insulin mixed with intermediate-
acting insulin is given before breakfast; short-acting insulin is
given before the evening meal and an intermediate-acting
insulin given at bedtime.
.
Single daily regimens: these are rarely used but involve
1 daily injection before breakfast or at bedtime of
intermediate-acting insulin, with or without a short-
acting insulin. It is generally for patients with type 2
diabetes who are unable to control their blood
glucose with antidiabetic drugs.

• Insulin requirement is increased by stress, infection,

accidental or surgical trauma, puberty (effects of
growth hormone) and during the latter two trimesters
of pregnancy. Reduced insulin requirements may
occur in coeliac disease, renal or hepatic impairment
and endocrine disorders such as untreated Addison’s
disease
 Administration
• Intravenous infusion is a reliable route of administration and may be
used in hospital in an acute setting, to bring the diabetes under control.
The amount required to control blood glucose may give an indication of
daily requirements for future treatment. In the early stages, patients
may encounter what is termed a ‘honeymoon period’, during which
time less insulin is required.
• The most conventional route is via subcutaneous injection using a
disposable syringe, in which the different insulins may be mixed to
achieve the desired combination. This method has largely been
superseded by the introduction of more convenient injection pens and
biphasic insulins.
• Subcutaneous injection of insulin itself may lead to changes in the skin.
At a site of repeated injections, there may be lipohypertrophy, leading
to unpredictable insulin absorption. It is for this reason that patients
should rotate the sites used.
• Insulin pumps may be used which allow continuous subcutaneous
administration. These are particularly useful in the difficult to control
diabetes. They have the advantage of providing a continuous infusion,
which may be increased at meal times. However, they are expensive
and are not available on prescription.
 SYNTHETIC AMYLIN ANALOG
• Amylin is a hormone that is cosecreted with insulin from β cells
following food intake.
• It delays gastric emptying, decreases postprandial glucagon secretion,
and improves satiety.
• Pramlintide :is a synthetic amylin analog that is indicated as an
adjunct to mealtime insulin therapy in patients with type 1 and type 2
diabetes.
• Pramlintide is administered by subcutaneous injection immediately
prior to meals. When pramlintide is initiated, the dose of mealtime
insulin should be decreased by 50% to avoid a risk of severe
hypoglycemia. Other adverse effects include nausea, anorexia, and
vomiting.
• Pramlintide may not be mixed in the same syringe with insulin, and it
should be avoided in patients with diabetic gastroparesis (delayed
stomach emptying), cresol hypersensitivity, or hypoglycemic
unawareness.
 INCRETIN MIMETICS
• Oral glucose results in a higher secretion of insulin than occurs when
an equal load of glucose is given IV. This effect is referred to as the
“incretin effect” and is markedly reduced in type 2 diabetes.
• The incretin effect occurs because the gut releases incretin hormones,
notably glucagonlike peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide, in response to a meal. Incretin hormones
are responsible for 60% to 70% of postprandial insulin secretion.
• Exenatide and liraglutide are injectable incretin mimetics used for the
treatment of type 2 diabetes.
A. Mechanism of action :The incretin mimetics are analogs of GLP-1 that exert
their activity by acting as GLP-1 receptor agonists. These agents improve
glucosedependent insulin secretion, slow gastric emptying time, reduce food
intake by enhancing satiety (a feeling of fullness), decrease postprandial
glucagon secretion, and promote β-cell proliferation. Consequently, weight
gain and postprandial hyperglycemia are reduced, and HbA1c levels decline.

B. Adverse effects :The main adverse effects of the incretin mimetics consist of
nausea, vomiting, diarrhea, and constipation. Exenatide and liraglutide have
been associated with pancreatitis. Patients should be advised to discontinue
these agents and contact their health care provider immediately if they
experience severe abdominal pain. Liraglutide causes thyroid C-cell tumors in
rodents. However, it is unknown if it causes these tumors or thyroid carcinoma
in humans
 ADVERSE EFFECTS OF INSULIN

• Hypoglycaemia :
• can occur in any diabetic following inadvertent injection of large dose, by
missing a meal after injection or by performing vigorous exercise.
• The symptoms can be divided into
those due to counter-regulatory sympathetic stimulation—sweating,
palpitation, tremor;
• and those due to deprivation of the brain of its essential nutrient
glucose (neuroglucopenic symptoms)—dizziness, headache, behavioural
changes,fatigue.
• Treatment : Glucose must be given orally or i.v. (for severe cases)—reverses the
symptoms rapidly.
• .Local reactions:
• Lipodystrophy of the subcutaneous fat
around the injection site may occur if the
same site is injected repeatedly. This is rare
with the newer preparations.
• Allergy: This is due to contaminating
proteins, and is very rare with human/highly
purified insulins. Urticaria, angioedema and
anaphylaxis are the manifestations.