Title: Use of Insulin in

Diabetes Mellitus
Name: Prof. Dr. Renu
Agarwal

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Learning outcomes
At the end of the plenary, students should be able to
1. list different insulin preparations and provide example for each type.
a. Human insulins
• Short-acting: Humulin R
• Intermediate acting: Isopahne (NPH, Protamine), Lente (Zinc)
b. Insulin analogues
• Ultrashort-acting: Lispro
• Long acting: Glargine
c. Mixed insulin
2. discuss the clinical relevance of pharmacokinetic parameters of rapid,
short, intermediate and long-acting insulin preparations and describe their
mechanism of action and pharmacological effects.
3. discuss the therapeutic uses, clinically important drug interactions and
common and major adverse effects of insulin and its analogues.
4. describe the principles of management of diabetic ketoacidosis and
hyperosmolar hyperglycaemic non-ketotic syndrome.
Diabetes mellitus: Therapeutic goals

Diabetes mellitus type I Diabetes mellitus type 2

What is the therapeutic goal?
To achieve adequate insulin
level and glycemic control
• How can it be achieved?
Exogenous insulin
• What is the therapeutic goal?
To achieve glycemic control
• How can it be achieved?
Improving insulin resistance
Increasing insulin secretion
Reducing glucose absorption
Enhancing glucose excretion
Insulin Discovery

Frederick Banting Charles Best James Collip John MacLeod

In 1923, the Nobel Prize was awarded to Banting and Macleod for
insulin discovery and each shared their portion of the prize
money with the other researchers on the project.
 Insulin Discovery

The The
Discovery
11thofofInsulin: An Important
January of 1922 Milestone inLeonard
the HistoryThompson
of Medicine. (1908 -
the first injection of insulin 1935) was
Vecchio I, Tornali C, Bragazzi NL, Martini M. Front Endocrinol the very first
(Lausanne).
2018 Oct 23;9:613 patient who received
was done in Toronto (Canada) injection of insulin as a
“The Discovery of Insulin” by Michael Bliss treatment for diabetes.
Insulin
• Insulin is a peptide hormone
produced in the pancreas
within the beta cells of islets
of Langerhans.
 The name comes from the Latin
insula for "island".
 Alpha cells - Glucagon
 Beta cells - Insulin and Amylin
 Delta cells - Somatostatin
www.tutorvista.com
Insulin

• Insulin is composed of
two peptide chains (A
and B) that are
connected by
disulfide bonds.

• The chain A consists of

21 amino acids and
the chain B consists of
30 amino acids.

www.pharmacology2000.com
 Insulin Secretion n
BOLUS INSULIN SECRETION (50%)

BASAL INSULIN SECRETION (50%)

• The daily insulin secretion splits 50:50 between basal (24 hours)
secretion and bolus (prandial) secretion in response to meals.
• Normal fasting blood glucose levels in people who do not have
diabetes is 3.9 – 5.5 mmol/L.
Insulin. Mechanism of Action

• In tissues insulin binds to

insulin receptors.
• Insulin receptor has two
alpha subunits and two beta
subunits.

What type of
receptor is
insulin receptor Copyright Bowen, 2004.
http://arbl.cvmbs.colostate.edu/hbooks/pathphys/e
ndocrine/pancreas/insulin_phys.html
 Enzyme-linked receptors

Ins
ulin Dimerization
Ins
ulin
A A

Cell membrane GLUT4

R R R R
Enzyme
Enzyme
activation
More glucose taken
up by cells
Activation of
transcription factors

Cellular response GLUT4

Insulin Target Tissues and Organs

INSULIN

Liver
Muscles

Adipose tissue
 Insulin: effects on Metabolism

Lower BG Fat-sparing effect Anabolic effect

Facilitates  Stimulates amino
 Promotes
glucose uptake acids uptake by
lipogenesis.
by peripheral tissues.
tissues.  Inhibits  Increases protein

Stimulates lipolysis. synthesis

glycogenesis.  Inhibits

Inhibits proteolysis.
glycogenolysis.
Insulin Preparations

• Human insulins
Humulin R
Isopahne (NPH; Protamine)
Lente (Zinc)
First Banting-Best’s insulin plant
Ultralente (Zinc)
• Insulin analogues
Insulin Lispro
Glargine
• Mixed insulins
• Newer insulin formulations

A recombinant bioreactor used for synthesis ‘human’ insulin

 Human Insulins

• Have the same amino acid sequence as native human insulin.

• Are produced by recombinant DNA technology with genetically
altered E.coli strains.
• Isophan and lente/ultralente are added with protamine/zinc to
prolong the duration of action.
• Human insulins vs animal insulins:
less allergic reactions
less insulin resistance
less local adverse drug reactions at the sites of injections.
Insulin Analogues

Insulin analogues are genetic engineered altered insulin

Have modified pharmacokinetics but perform the same
pharmacodynamic effects as 'human insulins’.
 Insulin lispro (rapid-acting) is absorbed and acts more
rapidly than regular human insulins. [The amino acid
sequence at position 28 and 29 in the B chain]
 Insulin glargine (long-acting) precipitates at the
injection site and has slower onset and prolonged effect
(has no peak plasma concentration).
 Zinc/protamine insulin

https://www.dreamstim
e.com/stock-image-
insulin-hexamer-
https://memorang.com/flashcards/114162/Diabetic+Drugs image26419461
Insulin Preparations
According to the onset and duration of action

Bolus insulins Basal insulins

Administered to mimic the Administered to mimic the
prandial (mealtime) release of basal insulin production.
insulin • Intermediate-acting (Lente,
• Rapid-acting NPH)
Lispro Isophan (NPH)

• Short-acting (Regular, R) • Long-acting (Ultralente)

Humulin R Ultralente Humulin
Glargine
Bolus insulins (Rapid and Short-
acting)
Administered subcutaneously or intravenously (in
emergencies).
Rapidly lower blood glucose.
Administered usually 3 times a day 20-30 minutes
prior to each meal (short-acting) or just prior to a
meal (rapid-acting).
Basal insulins (Intermediate and Long-
acting)
Human intermediate and long-acting
insulins contain protamine (polypeptide)
or zinc that prolong insulin absorption and
time of action.
Subcutaneously only.
Once or twice daily:
Morning or bedtime - long-acting
insulins
Morning + bedtime - intermediate-
acting insulins
Mixed Insulins

Mixed Insulins are fixed combinations of basal and

bolus insulins (70% basal + 30% bolus or 50% basal +
50% bolus etc).
 Insulin Preparations

Type of insulin Onset of Action Peak of Duration of

Action Action
Rapid-acting (Lispro) 10-15 mins 30-90 mins 3-5 hrs

Short-acting (Humulin R) 30-60 mins 1 - 4 hrs 4 - 8 hrs

Intermediate-acting 1-3 hrs 4-8 hrs 12-18 hrs

(Isophan NPH)
Long-acting 4-8 hrs 8-12 hrs 24 - 36 hrs
(Ultralante Humulin, Glargine)

The onset, peak, and duration of action of these

Mixed Insulins mixtures would reflect a composite of the
intermediate and short- or rapid-acting components.
Insulin administration
BOLUS INSULINS (SHORT-ACTING) (50%)

Breakfast Lunch Dinner

BASAL INSULINS (INTERMEDIATE-ACTING)(50%)

Morning Bedtime
Insulin Indications

• Insulin is used to treat all forms of diabetes

mellitus.
• Diabetes mellitus type 1: Must be treated with
insulin
• Diabetes mellitus type 2 not controlled by oral anti-
diabetic drugs
 Any complications of diabetes (ketoacidosis etc)

 Trauma, infections, surgery

 Pregnancy
Insulin Injections

• No
Youoral
arebioavailability, given parentrally
treating an athlete (subcutaneous).
with insulin injections
subcutaneously,
• Insulin is absorbedfor diabetes
more rapidlyand you
when need to
injected into the
ensure that blood sugar levels do not fall below
abdominal wall,can
normal as this as compared to the
cause serious arms oreffects.
adverse legs.

You are concerned about the effects that exercise

may have on the activity of the insulin and the
patient’s blood sugar.

Is this concern valid?

The Sites of Insulin Injections

• The shaded areas may

be used for insulin
injections.
• Injection sites should be
rotated to avoid
lipodystrophy.
Insulin Delivery Systems

• Insulin syringe
• Insulin pen
• Insulin pump
• Inhaled insulin
Advantages of insulin pen

• More convenient.
• More accurate dosage.
• Less painful.
• Special design enhances the
quality of life.
Insulin Pump

• Insulin pump is a medical

device used for
continuous subcutaneous
insulin infusion therapy.
• Insulin pump can mimic
both basal and bolus
insulin releases.
• Decreases the risk of
hypoglycemia.
 Inhaled Insulin

Exubera is the first insulin

used with a special
inhalation delivery system.
Exubera is a short-acting
insulin
Insulin: Adverse effects

• Hypoglycemia.
• Lipodystrophy at injection sites.
• Allergy.
• Insulin resistance.
 Hypoglycemia
•MsHypoglycemia
Chen recently started
is the receiving
most common insulin and
complication her insulin
of insulin dose
therapy.
has been well optimized for adequate control of blood sugar
 Wrong dose, missed meal, DDI (ODA).
level.
•ThisSymptoms:
morning she reports with dizziness, and tremors after insulin
shot indicating
weakness fall in blood sugar level below normal.
• Shesays that she has not skipped meal and has taken the
dizziness
exact dose prescribed.
 tachycardia
• Doctor: “did you do anything that you normally do not do?”
 tremor
Is treated with:
sweating“nothing except that after insulin shot I spent
• MrsChen:
sometime for hot water bath in the bath tub as it was a
 confusion.
weekend and I wanted to relax.•But Sugar-sweetened
soon after I had the food
symptoms”. • Dextrose
• Do you think her symptoms could be related to hot water bath?
• Injection of glucagon (severe
hypoglycemia)
Lipodystrophy

• Repeated insulin injections at the

same spot.
• Atrophy of subcutaneous fatty tissue
at the site of injection due to local
immune reaction.
• Prevention:
change (rotate) the site of insulin injections.
Immune Insulin Resistance

• Insulin may cause anti-insulin antibodies production

that neutralize the action of insulin and leads to
insulin resistance.
• Prevention:
Use ‘human’ insulins or insulin analogues.
Hyperglycaemic emergencies
Hyperglycaemic emergencies
 Management of hyperglycaemic ketoacidosis
• Key components:
• Hyperglycemia, glycosuria, ketonuria, acidosis, low
intracellular K, fluid and electrolyte imbalance
• Treatment
• Correct fluid imbalance with normal saline
• Correct Serum potassium
• Subcutaneous rapid acting OR IV short acting
insulin infusion
• Bicarb only for extreme acidosis
• Treat the cause
Hypokalemia may be life threatening
• if not corrected
Management of hyperosmolar hyperglycaemic
non-ketotic syndrome.

• Treatment of HHS requires more free water and

greater volume replacement than needed for
patients with DKA
• Caution is required in the elderly with preexisting
heart disease
• Subcutaneous rapid acting OR IV short acting insulin
infusion
• Serum potassium, usually not significantly affected
on admission (unless in renal failure)
Non-diabetic conditions (infection,
pregnancy)

•Diabetes during pregnancy should be treated

with insulin.

•In the presence of infection, dose requirement

for insulin generally increases.
Summary

• Exogenous insulin is the only treatment for diabetes

mellitus type I.
• It is also used for diabetes mellitus type II and acute
complications of diabetes.
• Insulin is an anabolic hormone that acts through enzyme
linked receptors.
• Human insulin and insulin analogues are used in the
treatment of diabetes mellitus.
• Route of administration: parenteral
• Total insulin: bolus and basal insulin.
• HYPOGLYCAEMIA is the major adverse effect of insulin.
• Other adverse effects: allergy, resistance, lipodystrophy.
 Future

• New inhaled insulins?

• Oral insulins?
• Nasal insulins?
• Transdermal insulins (insulin patch)?
• Plant-based insulin?
• Islet cell transplantation?
• Artificial pancreas?

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• A 45 year old man is on treatment with a combination of
oral anti-diabetic agents. However, considering poor
glycaemic control and appearance of complications of
diabetes over past 10 months, physician decides to stop
OAD and start him on insulin.
• What is an appropriate regimen for this patient?
• Pre-meal ultralente+ bedtime regular insulin
• Pre-meal insulin glargine + bedtime insulin lispro
• Pre-meal insulin lispro + bedtime insulin glargine
• Pre-meal insulin lispro + bedtime insulin lispro
•A 17 year old boy was brought to emergency
department with abdominal pain and vomiting. He is
on insulin for the past 10 years for diabetes mellitus
type 1. His blood investigations show a
hyperglycemia, ketonuria and a pH of 6.9.
•Which preparation is most unlikely to be included in
the treatment of this patient?
•Insulin glargine
•Potassium chloride
•Insulin lispro
•Sodium bicarbonate
 References
Goodman & Gilman's the pharmacological basis
of therapeutics. (Ed.), Laurence L Brunton, Bruce
A Chabner, Björn C Knollmann. 12th ed. New
York : McGraw-Hill, 2011.
Basic and Clinical Pharmacology. (Ed.) Katzung
BG, Masters SB, Trevor AJ. (2012). (14th Edition).
Mc Graw-Hill: New York
Rang and Dale’s Pharmacology. (Ed.) Rang HP,
Ritter JM, Flower RJ, Henderson G. (2015). 8th
Edition), Churchill Livingstone: Edinburgh.

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