2. What is Insulin?
(1)
• Polypeptide hormone
• Beta-cells of islets of Langerhans
in pancreas
• Profound effects on
• carbohydrate, fat & protein
metabolism
• To some extent on water &
electrolyte balance
• 2 chains
• 2 bonds
• Secreted as basal
& meal related (2)
• Meal related in 2
phases
3. What is Insulin?
(2)
• Insulin deficiency results in
• Elevated plasma glucose -Hyperglycemia
• Elevated plasma lipid - Hypertriglyceridemia
• Altered protein metabolism - Metabolic &
Immune defects
• Insulin replacement in diabetes tends to
restore normalcy
4. Insulin Secretion
B L S HS
Bolus
Basal
Bolus Bolus
Basal Basal
Normally secreted as basal (between meals & night
time) & Meal-related peaks (1st
& 2nd
phase)
5. Actions of Insulin
(1)
• Integrated action on carbohydrate, protein
and fat metabolism
• Dominant effect on glucose homoeostasis
predominantly exerted in 3 tissues
Liver
Skeletal muscle
Fat
6. Actions of Insulin
(2)
In Liver
• Inhibition of glycogenolysis & gluconeogenesis
• Stimulation of glycogenesis & storage
In skeletal muscle & adipocytes
• Stimulation of glucose uptake, utilization &
storage
• Increases glucose transport
• Activation/inactivation of enzymes responsible for
storage & metabolism of glucose
7. Insulin:
The Definitive Therapy for Diabetes
• DM
• Impaired insulin secretion (insulin deficiency)
• Impaired insulin action (insulin resistance)
• Insulin can overcome both the defects
• Hence: Insulin-the definitive therapy for all types
of diabetes
Insulin- a valuable therapeutic tool for early
intervention, to attain and maintain target levels of
blood glucose control.
8. Discovery of insulin (1)
“One of the greatest milestones in history of
medicine”.
9. Discovery of insulin (2)
Experiments in Toronto
University
F Banting, surgeon
C Best, medical college
student
30 July 1921
Banting & Best- extracted
insulin from dog & proved
that it controls symptoms of
diabetes in dogs – 1921
Banting & Macleod-Nobel
Prize for Medicine &
Physiology in 1923
10. 1923 – Nobel prise to Banting and
Macleod
FG
Banting
JJR
Macleod
CH Best JB Collip
11. Discovery of Insulin (3)
• 1st
patient to receive pancreatic extract (insulin)-14-yr
old Leonard Thompson.
• 1st
attempt (11th
Jan 1922)- failed but the 2nd
attempt (3rd
May 1922) succeeded in reducing urine glucose
excretion.
First patient to
benefit from insulin
–saved from death
Leonard Thompsom-1908-1935
•Grew cheerful, started
eating more, gained
weight, & cheeks started
swelling out
12. Discovery of Insulin (4)
Description of Structure
• 1955- Frederick Sanger
identified the amino acid
sequence of insulin:
• Insulin is a protein,
consisting of
• Alpha (21) and beta
(30) chains
• Half life time in blood is 4-
5 min.
B-chain
A-chain
Connecting peptide
s-
s
s-s
s-s
Another Nobel Prize in insulin history – 1958
14. Manufacture of Insulin
(1)
• 1923-Eli Lilly started manufacturing
• 1923- Novo started manufacturing
• ‘Most developments in insulin therapy have originated
from the laboratories of Novo-Nordisk’
• NPH insulin
• highly purified insulin
• monocomponent insulin
• semisynthetic insulin
• biosynthetic human insulin
• Insulin analogues: Insulin Aspart, Premixed analogue & Insulin
Detemir
Insulin
15. Manufacture of insulin (2)
• Currently NN- human insulin from yeast
(Saccharomyces cerevisiae) using rDNA
technology.
• Eli Lilly-human insulin using E. coli, a gram-
negative bacterium.
17. Types of insulin
Type of Insulin
& Brand Names
Onset Peak Duration
Role in Blood Sugar
Management
Rapid-Acting
Lispro 15-30 min. 30-90 min 3-5 hours Covers insulin needs for
meals eaten at the same
time as the injection.
Aspart 10-20 min. 40-50 min. 3-5 hours
Glulisine 20-30 min. 30-90 min. 1-2½ hours
Short-Acting
Regular
30 min- 60
min
2-5 hours 5-8 hours
Covers insulin needs for
meals eaten within 30-60
minutes
Intermediate-Acting
NPH (N) 1-2 hours 4-12 hours 18-24 hours
Covers insulin needs for
about half the day or
overnight.
18. Types of insulin
Name of
Insulin
Onset Duration
Role in Blood
Sugar
Management
Long-Acting
Long-acting
insulin covers
insulin needs
for about one
full day.
Degludec 30-90 min No peak:
insulin is
delivered at
a steady
level.
Longer than 24
hours
Glargine 30-90 min Up to 24 hours
Detemir 1-120 min 20-24 hours
19. Types of insulin
Type of Insulin Onset Peak Duration
Role in Blood Sugar
Management
Pre-Mixed*
30/70 30 min. 2-4 hours 14-24 hours These products are
generally taken two
or three times a day
before mealtime.
50/50 30 min. 2-5 hours 18-24 hours
25/75 15 min.
30 min.-2½
hours
16-20 hours
Inhaler
Exubera Banned
Afrezza With in min 12 to 15 min 2-3 hours Post prandial effects.
*Premixed insulins are a combination of specific proportions of intermediate-
acting and short-acting insulin in one bottle or insulin pen (the numbers the brand
name indicate the percentage of each type of insulin).
20. Common Insulin Regimens (1)
Split Mix Regimens
Two injections (intermediate + soluble) per day
* before breakfast & before bedtime
Proportion/dosage of insulins titrated based on BG
profile
Drawback
Mixing insulins is tedious and problematic
Inaccuracy of dose
Not preferred –more problems for patients
21. Common Insulin Regimens (2)
Basal insulin
Usually given at night
Proportion/dosage of insulin titrated based on FBG
Drawback
Expensive
Fasting blood glucose is primary targeted
May be with sensitizer and or secretagogue
22. Common Insulin Regimens (3)
Basal Plus
Basal insulin at night
Any rapid acting insulin premeal.
May be useful during early years of T2DM and in
uncomplicated well motivated patients.
May be needed to shifted to Basal bolus regimen
Not preferred –more problems for patients
23. Common Insulin Regimens (4)
Basal Bolus
Basal insulin at night and one rapid acting insulin
immediately before each major meal (3 times).
Basal insulin is titrated following FBG
Rapid acting insulin is titrated by post meal BGs
Drawback
Expensive
4 times needle prick a day.
Most preferred –most fexible
25. Common Insulin Regimens
(5)
Continuous subcutaneous insulin infusion
(CSII):
Recommended for adults and children 12 years and older with
T2DM provided:
To achieve target HbA1c levels with MDIs result in the person experiencing
disabling hypoglycaemia or
HbA1c levels have remained high (8.5% or above) on MDI therapy despite
a high level of care.
27. Indications of insulin
Continuous Use
* Type 1 Diabetes
* Type 2 Diabetes with OHA failure
- Primary - Secondary
Intermittent Use
* Type 2 diabetes during
- major surgery
- pregnancy, labour and delivery
- myocardial infarction
- acute infections
- Hypergycemic emergencies: DKA & HHS
* GDM
Life-saving in T1DM
Essential in T2DM
28. Starting dose of insulin
• T1DM: 1 -0.2-1 U/kg / day1
• T2DM: 0.2-0.3 U/kg / day
In split mixed regimen- 2/3 as intermediate
acting & 1/3 as short- acting 2
In basal bolus regimen: ½ basal at bed time
and ½ bolus in 3 divided doses.
Dosage is individualized and titrated soon
1
Goodman & Gillman’s The pharmacological basis of therapeutics ed. 9th
.pg. 1501
2
Harrison’s Principles of Internal Medicine (15th
Edition) pg. 2131
29. Current recommendations for the treatment of type 2
diabetes
Diet/exercise
Start metformin
Start insulin
Add incretin
therapy
Diabetes Disease Progression
An alternative
approach
30. Why Early insulin initiation?
Clinical & Pharmacological Reasons(4)
Insulin
Improves beta-cell function
(reduces glucotoxicity &
lipotoxicity)
Reverses insulin resistance Improves Quality of Life
Beneficial effects on
lipids
Insulin provides
4 benefits beyond
glycemic control
35. Insulin administration
Sites
• Abdomen (fastest absorption & most preferred)
• Buttocks
• Upper arm
• Thigh-lateral & anterior aspects (slowest)
• Rotate the site of injection around a selected
area
(Intermediate)
36. Side effects of Insulin
5 Side effects
1. Hypoglycemia
2. Allergic Reactions –
• Local redness, itching – self limiting, disappears with
continuation of therapy
• Systemic allergy – angioedema, anaphylaxis; rare,
requires desensitization
1. Insulin lipoatrophy
2. Insulin lipohypertrophy
3. Insulin Edema & weight gain
37. Barriers to Insulin therapy (1)
Hypoglycemia
Requires
specialist
Daily inj
Compliance
Dose titration
difficult
Patient
Runs Away
Serious
illness
Cost
Insulin therapy in type 2 diabetes
Insulin therapy in type 2 diabetes
Insulin therapy in type 2 diabetes
Insulin therapy in type 2 diabetes
38. Barriers to insulin therapy (2)
• Fear of hypoglycemia
• Inconvenient timing of injection
• Complicated regimen
• to be taken 30 minutes before meal
• lifestyle to fit therapy
• Hyperglycemia immediately after meal
• Hypoglycemia before next meal
• Fear of injection
DIPPAP 2 - 53%
Patient survey – ORG-MARG
2002 – 34%
DIPPAP 2 – 35%
39. Storage of Insulin (1)
• Vials, Penfills & Pens not in use
stored between 2° & 8°C
• Storage in or near freezing compartment is to be
avoided (more important-suspensions)
• Too high temp- gradual decrease in biological potency
• In use stored at room temperature (25°C) up to 6wks
(Vials) & up to 4 wks (Penfills & Devices)
• Pens/ Penfills- in use- should not be kept in refrigerator
40.
41. Storage of Insulin (2)
Storage of patient supplies of insulin in
warm climates is not an important
practical issue, & should not interfere
with supplies of vital insulin to pts. in
developing countries.
