Insulin

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 Overview
 The pancreas is both an endocrine and
exocrine gland.
 An exocrine pancreas produces digestive
enzymes.
 Islets of langerhans (endocrine pancreas)
secrete the peptide hormones insulin,
glucagon, and somatostatin.
 These hormones play an important role in
regulating homeostasis of blood glucose.

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 Overview
 Hyperinsulinemia can cause severe
hypoglycemia.
 Absolute lack of insulin, such as in diabetes
mellitus, can cause serious hyperglycemia.
 If it is untreated, can result in retinopathy,
nephropathy, neuropathy, and
cardiovascular complications.
 Administration of insulin preparations or oral
hypoglycemic agents can prevent morbidity
and reduce mortality associated with
diabetes.
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Clinical Manifestations
People with diabetes ……
•have 2.5 times increased risk of heart attacks.
•represent the largest prevalence of blindness
among grown-ups.
•60-65% have high blood pressure.
•60-70% have injuries in the vascular and nervous
system, which makes diabetes the most
significant reason for amputations.
What commonly causes Diabetes?

 Genetics (heredity)
 Obesity

 Irregular and unhealthy eating habits

 Stress

 Other Reasons

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 Diabetes Mellitus
 The incidence of diabetes is growing rapidly
worldwide.
 More than 180 million people worldwide are
afflicted with diabetes.
 The prevalence is expected to more than
double by the year 2030.
 Type I diabetes: Insulin-dependent diabetes
mellitus (IDDM).
 Type II diabetes: Non-insulin dependent
diabetes mellitus (NIDDM).

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 Diabetes Mellitus

 Diabetes Mellitus is a heterogeneous group

of syndromes characterized by an elevation
of blood glucose caused by a relative or
absolute deficiency of insulin.
 Gestational diabetes is defined as
carbohydrate intolerance with onset or first
recognition during pregnancy.

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 Type-1 Type-2
• >40, “overweight”
– now appearing in obese
• Typically younger, “thin” teenagers
subjects • Much higher prevalence;
– But can develop at all – ~90% of all diabetics
ages – Prediabetic or incipient phase of
hyperinsulinaemia & glucose
• Lower prevalence/ incidence; intolerance:
– ~10% of all diabetics Failing ß cell function with
• Auto-immune destruction of insulin resistance
Islet ß cells: & eventual insulin dependence
– Insulin dependence from • Aetiological factors:
– Strong genetic predisposition
outset
– Environmental lifestyle factors
– No insulin resistance include high glycaemic index
• Ketoacidosis risk (sugary/starchy) food; overeating;
being overweight; sedentary
lifestyle / lack of Exercise
 Type 1 diabetes

 Most commonly afflicts individuals in

puberty or early adulthood, but some
latent forms can occur later in life.
 Type 1 diabetes is characterized by an
absolute deficiency of insulin caused by
massive islet cell necrosis.
 As a result the pancreas fails to respond to
glucose.
 Either immune mediated or idiopathic

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 Type 1 diabetes

 Type 1 diabetic shows classic symptoms

of insulin deficiency (polydipsia,
polyphagia, polyuria, and weight loss).
 Type 1 diabetics require exogenous
insulin (injection) to avoid the catabolic
state characterized by hyperglycemia and
life-threatening ketoacidosis.

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 Cause of Type 1 diabetes
 A burst of insulin secretion occurs within two
minutes after ingesting a meal, in response to the
levels of circulating glucose and amino acids.
 This lasts for up to 15 minutes, and, is followed by
the postprandial secretion of insulin.
 The Type 1 diabetic can neither maintain a basal
secretion level of insulin nor respond to variations in
circulating fuels.
 The development and progression of neuropathy,
nephropathy, and retinopathy are directly related
to the extent of glycemic control.

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 Treatment
 The goal in administering exogenous
(injection) insulin to Type 1 diabetics is to
maintain blood glucose concentrations as
close to normal as possible.
 Continuous subcutaneous insulin infusion
also called the insulin pump is another
method of insulin delivery.
 This method of administration may be more
convenient for some patients, eliminating the
multiple daily injections of insulin.
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Insulin pump

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 Treatment
 The pump is programmed to deliver a basal rate of
insulin secretion.
 It allows the patient to control delivery of a bolus of
insulin to compensate for high blood glucose or in
anticipation of postprandial needs.
 Other methods of insulin delivery, such as
transdermal, buccal, and intranasal, are currently
under investigation.
 Amylin is a hormone that is cosecreted with insulin
from pancreatic cells following food intake.
 Pramlintide, a synthetic analog of amylin, may be
used as an adjunct to insulin therapy.

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 Type 2 diabetes

 Most diabetics are Type 2. The disease is influenced

by genetic factors, aging, obesity.
 The peripheral insulin resistance & Relative insulin
deficiency due to impaired beta-cell function rather
than by autoimmune processes or viruses.
 The metabolic alterations observed are milder than
those for Type 1 for example, Type 2 patients
typically are not ketotic.
 The long-term clinical consequences can be just as
devastating (for example, vascular complications
and subsequent infection can lead to amputation of
the lower limbs).
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 Causes of Type 2 diabetes

 In Type 2 diabetes, the pancreas retains some cell

function, but variable insulin secretion is insufficient
to maintain glucose homeostasis.
 The beta cell mass may become gradually reduced
in Type 2 diabetes.
 In contrast to patients with Type 1, those with Type 2
diabetes are often obese.
 This resistance to insulin is considered to be a major
cause of this type of diabetes .

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 Treatment
 The goal in treating Type 2 diabetes is to
maintain blood glucose concentrations within
normal limits.
 Weight reduction, exercise, and dietary
modification decrease insulin resistance.
 However, most patients are dependent on
pharmacologic intervention with oral
hypoglycemic agents.
 As the disease progresses, beta cell function
declines, and insulin therapy is often required to
achieve satisfactory serum glucose levels.

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INSULIN

 It is a Peptide hormone.
 It consists of 2 amino acid (51AA) chains that
are joined together by disulphide linkages. If
the 2 AA chains are split apart then the
functional activity of insulin is lost.
 It has a molecular weight of 5808.
 Plasma half-life: 6 minutes
 Cleared from the circulation in 10-15 minutes
 Insulin and Its Analogs
 Insulin is a polypeptide hormone consisting of
two peptide chains that are connected by
disulfide bonds.
 It is synthesized as a precursor (pro-insulin)
that undergoes proteolytic cleavage to form
insulin and C peptide, both of which are
secreted by the beta cells of the pancreas.
 Type 2 patients secrete high levels of
proinsulin.
 The measurement of circulating C peptide
provides a better index of insulin levels.
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The structure of insulin

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Synthesis of Insulin
 Insulin is initially produced
as Preprohormone (mw:
11,500) which is cleaved in
the ER to yield Proinsulin
(mw: 9,000).
 Proinsulin is further
cleaved in Golgi apparatus
to yield Insulin and its
peptide fragment which is
also called the C-peptide
(connecting peptide)
 These both are then
packaged in secretory
vesicles & released when
the stimulus arrives.
Preprohormone (ER)
(11,500)
↓
Proinsulin (Golgi Apparatus)
(9,000)
↓
Insulin + C-peptide
(stored in secretory vesicles)
↓
Secreted into blood
↓
After use degraded by the
enzyme called as
Insulinase in the liver & to
a lesser extent in the
kidneys & muscles
 Insulin secretion
Insulin release is not
continuous even after a
meal but oscillates with a
period of 3-6 minutes: spurts
of insulin release.
This oscillation is important
to consider when
administering insulin-
stimulating medication as
oscillation is the target & not
a constant high
concentration.
 Insulin secretion
 Insulin secretion is regulated not only by
blood glucose levels but also by certain
amino acids, other hormones.
 Secretion is most commonly triggered by high
blood glucose, which is taken up by the
glucose transporter into the beta cells of the
pancreas.
 There, it is phosphorylated by glucokinase,
which acts as a glucose sensor.
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 Insulin secretion
 The products of glucose metabolism enter
the mitochondrial respiratory chain and
generate adenosine triphosphate (ATP).
 The rise in ATP levels causes a block of K+
channels, leading to membrane
depolarization and an influx of Ca2+, which
results in pulsatile insulin exocytosis.
 The sulfonylureas and meglitinides owe their
hypoglycemic effect to the inhibition of the K+
channels.
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 Sources of insulin
 Human insulin is produced by recombinant
DNA technology using special strains of
Escherichia coli or yeast that have been
genetically altered to contain the gene for
human insulin.
 Modifications of the amino acid sequence of
human insulin have produced insulins with
different pharmacokinetic properties.

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 Sources of insulin
 For example, three such insulins lispro,
aspart, and glulisine have a faster onset
and shorter duration of action than
regular insulin, because they do not
aggregate or form complexes.
 On the other hand, glargine and detemir
are long-acting insulins and show
prolonged, flat levels of the hormone
following injection.

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Pharmacokinetic Properties
 Directly absorbed in blood bypassing lymphatic system after SC
injection.
 Rate-limiting step is absorption from site of injection after SC
injection.
 In case of IV, almost 100% comes in central compartment.
 Exogenous insulin is degraded at both renal and extra-renal (liver
& muscle) sites.
 30-80% cleared by kidney from systemic circulation.
 On the other hand, endogenous insulin is secreted directly to
portal system and primarily cleared by liver in non-diabetics.
 Insulin is filtered by glomerular capillaries, but >99% is
reabsorbed by proximal tubules.
 Insulin is then degraded in glomerular capillary cells and
postglomerular peritubular cells.
Physical & Chemical Properties

 Insulin lispro, aspart, regular and glargine are clear

solution.

 Insulin glargine should not be administered intravenously

because it is designed to precipitate at physiologic pH.

 NPH, lente, ultralente are suspension in which insulin

has been crystillized with protamine and zinc to extend
their actions. These must be mixed well and should
never be administered intravenously.
Factors altering O.o.A & D.o.A
 Insulin administration
 Because insulin is a polypeptide, it is
degraded in the gastrointestinal tract if
taken orally.
 It therefore is generally administered by
subcutaneous injection.
 In a hyperglycemic emergency, regular
insulin is injected intravenously.
 Insulin preparations vary primarily in their
times of onset of activity and in their
durations of activity.

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 Insulin administration
 This is due to differences in the amino acid
sequences of the polypeptides.
 Dose, site of injection, blood supply,
temperature, and physical activity can affect the
duration of action of the various preparations.
 Insulin is inactivated by insulin degrading
enzyme (insulin protease), which is found mainly
in the liver and kidney.

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 Adverse reactions of insulin
 Hypoglycemia
 Other adverse reactions include
weight gain
lipodystrophy
allergic reactions
local injection site reactions.
 Diabetics with renal insufficiency may
require adjustment of the insulin dose.

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Unwanted effects of insulin
Insulin allergy
• IgE antibodies; mostly to non-
insulin protein contaminants;
local or general urticaria;
anaphylaxis if severe
• Now rare (highly purified
preparations)
• IgG mediated; occurs in most
pts with negligible effect
• Hypertrophic lipodystrophy
• Local injection site
hypertrophy of subcutaneous
fatty tissue
• Avoid by rotating injection
sites
Hypoglycaemia
• Dose too large or subject
didn’t eat
• Light-headedness;
drowsiness
• Tachycardia; sweating;
skeletal muscle tremor
• If profound, loss of
consciousness;
• seizures
• Give glucose + glucagon
• Patients to carry sweets or
raisins
• Keep blood glucose >
4mmol/L
• Fear of hypoglcyaemia an
issue
 Rapid-acting and short-acting insulin
preparations
 Four insulin preparations fall into this category:
regular insulin, insulin lispro, insulin aspart,
and insulin glulisine.
 Regular insulin is a short-acting, soluble,
crystalline zinc insulin and is usually given
subcutaneously (or IV in emergencies), and it
rapidly lowers blood glucose.
 Regular insulin, insulin lispro, and insulin aspart
are pregnancy category B. Insulin glulisine has not
been studied in pregnancy.

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Rapid-acting and short-acting insulin
preparations
 Peak levels of insulin lispro are seen at 30 to
90 minutes after injection, as compared with
50 to 120 minutes for regular insulin.
 Insulin lispro is usually administered 15
minutes prior to a meal or immediately
following a meal.
 Insulin glulisine can be taken either 15
minutes before a meal or within 20 minutes
after starting a meal.
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Rapid-acting and short-acting insulin
preparations
 Insulin aspart must be administered just
prior to the meal.
 All of the rapid-acting formulations are
suitable for intravenous administration.
 Insulin lispro, insulin aspart, and insulin
glulisine may also be used in external
insulin pumps.

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 Intermediate-acting insulin
 Neutral protamine Hagedorn (NPH) insulin is a
suspension of crystalline zinc insulin combined at
neutral pH with a positively charged polypeptide,
protamine.
 NPH was created in 1936 when Nordisk formulated
"isophane" porcine insulin by adding neutral
protamine to regular insulin.
 NPH also known as Humulin N, Novolin N,
isophane insulin.
 Its duration of action is intermediate.
 This is due to delayed absorption of the insulin
because of its conjugation with protamine, forming a
less-soluble complex.

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 Intermediate-acting insulin

 NPH insulin should only be given

subcutaneously (never intravenously)
and is useful in treating all forms of
diabetes except diabetic ketoacidosis or
emergency hyperglycemia.
 It is used for basal control and is usually
given along with rapid- or short- acting
insulin for mealtime control.

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 Long-acting insulin preparations
 Insulin glargine: The isoelectric point of
insulin glargine is lower than that of human
insulin, leading to precipitation at the
injection site, thereby extending its action.
 It is slower in onset than NPH insulin and
has a flat, prolonged hypoglycemic effect
that is, it has no peak.
 Like the other insulins, it must be given
subcutaneously.
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Long-acting insulin preparations

 Insulin detemir:
 Insulin detemir has a fatty-acid side chain.
 The addition of the fatty-acid side chain
enhances association to albumin.
 Slow dissociation from albumin results in
long-acting properties similar to those of
insulin glargine.

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 Insulin combinations

 Various premixed combinations of

human insulins, such as:
1. 70-percent NPH insulin plus 30-percent
regular insulin.
2. 50 percent NPH insulin plus 50-percent
regular insulin.
3. 75 percent NPL insulin plus 25 percent
insulin lispro, are also available.
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Standard treatment versus intensive
treatment
 Standard treatment of patients with diabetes
mellitus involves injection of insulin twice
daily.
 In contrast, intensive treatment seeks to
normalize blood glucose through more
frequent injections of insulin (three or more
times daily).
 Mean blood glucose levels of 170 mg/dL or
less can be achieved with intensive
treatment.
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 Synthetic Amylin Analog
 Pramlintide is a synthetic amylin analog that
is indicated as an adjunct to mealtime insulin
therapy in patients with Type 1 or Type 2
diabetes.
 By acting as an amylinomimetic, pramlintide
delays gastric emptying, decreases
postprandial glucagon secretion, and
improves satiety.

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 Synthetic Amylin Analog
 Pramlintide is administered by
subcutaneous injection and should be
injected immediately prior to meals.
 When pramlintide is initiated, the dose of
rapid- or short-acting insulin should be
decreased by 50% prior to meals to avoid
a risk of severe hypoglycemia.

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 Synthetic Amylin Analog
 Pramlintide may not be mixed in the same
syringe with any insulin preparation.
 Adverse effects are mainly gastrointestinal
and consist of nausea, anorexia, and
vomiting.
 Pramlintide should not be given to
patients with diabetic gastroparesis
(delayed stomach emptying).

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 Pharmacokinetics of Insulin
ONSET DURATION
AGENT PEAK (H) CONSIDERATIONS
(H) (H)
NPH 2-4 4-10 10-16 Greater risk of nocturnal hypoglycemia
(Neutral compared to insulin analogs
Protamine
Basal

Hagedorn)
Glargine ~1-4 No pronounced Up to 24† Less nocturnal hypoglycemia compared to
Detemir peak* NPH

Regular U-500 ≤0.5 ~2-3 12-24  Inject 30 min before a meal

Prandial

 Indicated for highly insulin resistant

Basal-

individuals
 Use caution when measuring dosage to
avoid inadvertent overdose
Regular ~0.5-1 ~2-3 Up to 8  Must be injected 30-45 min before a meal
 Injection with or after a meal could
Prandial

increase risk for hypoglycemia

Aspart <0.5 ~0.5-2.5 ~3-5  Can be administered 0-15 min before a

Glulisine meal
Lispro  Less risk of postprandial hypoglycemia
Inhaled insulin compared to regular insulin
 Intensive Insulin Therapy is indicated for
patients;
 Type-1 DM→ inject 3-4 doses of insulin per day.
 Diabetic women who plan to conceive.
 Pregnant diabetic patients.
 Patients with other complications.
 Type-1 DM patients ≥ 15 years.
 Non-compliant individuals.

Goal of intensive insulin therapy is to have

normoglycaemia and less complications.
Principles of Insulin Therapy in T1D

 Starting dose based on weight

 Range: 0.4-0.5 units/kg per day
 Daily dosing
 Basal
 40% to 50% TDI
 Given as single injection of basal analog or 2 injections of NPH per
day
 Prandial
 50% to 60% of TDI in divided doses given 15 min before each meal
 Each dose determined by estimating carbohydrate content of meal
 Higher TDI needed for obese patients, those with
sedentary lifestyles, and during puberty
Site of insulin injection

40 units/ml
100 units/ml

Tuberculin syringe
Teach pt. on correct administration of insulin
and other hypoglycemic agents.
1. insulin in current use may be stored at
room temp., all others in ref. or cool area
2. avoid injecting cold insulin  lead to
tissue reaction
3. roll insulin vial to mix, do not shake,
remove air bubbles from syringe
4. press (do not rub) the site after injection
(rubbing may alter the rate of absorption of
insulin)
5. avoid smoking for 30 mins. after injection
(cigarette smoking absorption)
6. Rotate sites
 Failure to rotate sites may lead to Lipodystrophy
 Lipodystrophy – localized disturbance of fat
metabolism
 Ex. Lipohypertrophy – thickening of
subcutaneous tissue at injection site, feel lumpy
or hard, spongy
 result to  absorption of insulin 
making it difficult to control the pt.’s
blood glucose
 PEN INJECTORS
• Easy to carry
• Easier to accurately measure dose
• more expensive than vials

JET INJECTORS
Needleless system.
Uses high pressure air to force a tiny
stream of insulin through the skin
Inhaled Insulin (Exubera)
Advantages
Improved pt convenience
Faster onset of action compared to Regular SC insulin
No needles risk of infection
Potential earlier onset of insulin therapy in Type 2 DM
Insulin Storage

 Insulin manufacturers, it is recommended that

insulin be stored in a refrigerator at
approximately 35 to 46°F.

 However, all of the available insulin products

may be left un-refrigerated (between 59 and 86
degrees F) for up to 28 days and still maintain
potency.
Management of Hypoglycaemia

 Most of the mild hypoglycaemic reactions are

managed readily with the equivalent of 10-20gm
of glucose.

 Moderate to severe hypoglycaemic reactions

can be managed by injecting 1mg glucagon.
Diabetic Ketoacidosis

DKA is caused by profound insulin

deficiency. Insulin deficiency leads to:
 Impairment of glucose uptake
 Excess hepatic glucose production
 Impairment of protein synthesis
 Excessive protein degradation
 Loss of lean body mass
Diabetic Ketoacidosis Treatment

Goals
Correct fluid and electrolyte imbalance
Provide adequate insulin to:
 Correct acidosis.
 Restore and maintain normal glucose
metabolism.
 Prevent complications from treatment.
 Provide education and follow-up.
Diabetic Ketoacidosis Treatment

Mild Ketoacidosis
 Oral Hydration
 Small sips of sodium containing fluids frequently
 Need to replace carbohydrates on meal plan.
Diabetic Ketoacidosis Treatment

Moderate and Severe Ketoacidosis

 Establishment of diagnosis;
 Patient cannot retain oral fluids
 Presence of ketones in urine
 Lowered serum NaHCO3
 Lowered arterial pH
Management of DKA
 Fluid Administration
 To resolve dehydration.
 Replacement.
 Insulin
 Cont. IV infusion of regular insulin is preferred
 LD: 0.15U/Kg, MD: 0.1U/Kg/hr
 Potassium
 Add 20-40mEq to IV fluids except in CRF or K>5.5mEq.
 Phosphate
 Add only if level <1mg/dL, add 20-30mEq
 Bicarbonate
 Use is controversial, may be use only in patients with
severe acidosis pH<6.9
 Q&A

THANK YOU

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