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PPT for nondiabetologists.
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Insulin Therapy
Dr Shahjada SelimEndocrinologist
Department of Medicine, ShSMCH
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
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
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)
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
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
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.
Discovery of insulin (1)
“One of the greatest milestones in history of medicine”.
Discovery of insulin (2)Experiments in Toronto
University
F Banting, surgeonC Best, medical college
student
30 July 1921
Banting & Best- extracted insulin from dog & proved that it controls symptoms of diabetes in dogs – 1921Banting & Macleod-Nobel Prize for Medicine & Physiology in 1923
1923 – Nobel prise to Banting and Macleod
FG Banting
JJR Macleod
CH Best JB Collip
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
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
Insulin Structure
VAL
2ASN
3
GLN
4
HIS
5
LEU
6
CYS
7
GLY
8
SER
9
HIS
10
LEU
11
LEU
15
ALA
14
GLU
13
VAL
12
THR
30LYS
29PRO
28
THR
27
TYR
26
PHE
25
PHE
24
GLY
23
ARG
22
GLU
21
GLY
20
TYR
16
LEU
17
VAL
18
CYS
19
GLY
1ILE
2VAL
3
GLU
4
GLN
5
CYS
6
CYS
7
THR
8
SER
9
ILE
10
CYS
11
GLN
15
TYR
14
LEU
13
SER
12
ASN
21
CYS
20LEU
16
GLU
17
ASN
18
TYR
19
A - Chain
B - Chain
S S
S
S
S
S
ALA
PHE
1
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
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.
Ad
van
cem
en
ts
Animal insulin preparations
Recombinant human insulin
Rapid-acting insulin
analogues
Basal insulin
analogues
Isolation of insulin
(Banting & Best)
Time1922
1977
Biphasicinsulin
1990s
2000s
Advancing insulin therapyAdvancing insulin therapyTowards a new stage in the evolving story of insulin Towards a new stage in the evolving story of insulin therapytherapy
Insulin degludec
Insulin degludec plus
2013
2015
Types of insulin
Type of Insulin & Brand Names
Onset Peak DurationRole 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
min2-5 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.
Types of insulin
Name of Insulin
Onset DurationRole 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
Types of insulin
Type of Insulin Onset Peak DurationRole 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
hours16-20 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).
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
DrawbackMixing insulins is tedious and problematic
Inaccuracy of dose
Not preferred –more problems for patients
Common Insulin Regimens (2)
Basal insulin
Usually given at night
Proportion/dosage of insulin titrated based on FBG
DrawbackExpensive
Fasting blood glucose is primary targeted
May be with sensitizer and or secretagogue
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
titrated based on BG profile
DrawbackMixing insulins is tedious and problematic
Inaccuracy of dose
Not preferred –more problems for patients
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
DrawbackExpensive
4 times needle prick a day.
Most preferred –most fexible
Basal Bolus Insulin
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.
CSII sets
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 T1DMEssential in T2DM
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
1Goodman & Gillman’s The pharmacological basis of therapeutics ed. 9th .pg. 15012 Harrison’s Principles of Internal Medicine (15th Edition) pg. 2131
Current recommendations for the treatment of type 2 diabetes
Diet/exercise
Start metformin
Start insulin
Add incretin therapy
Diabetes Disease Progression
An alternative approach
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
Insulin vials and syringes
Inhalation device or insulin
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)
Side effects of Insulin5 Side effects
1. Hypoglycemia
2. Allergic Reactions –• Local redness, itching – self limiting, disappears
with continuation of therapy
• Systemic allergy – angioedema, anaphylaxis; rare, requires desensitization
3. Insulin lipoatrophy
4. Insulin lipohypertrophy
5. Insulin Edema & weight gain
Barriers to Insulin therapy (1)
Hypoglycemia
Requiresspecialist
Daily inj
Compliance
Dose titration difficult
PatientRuns Away
Serious illness
CostInsulin th
erapy in ty
pe 2
diabetes
Insulin therapy in
type 2
diabetes
Insulin therapy in type 2 diabetes
Insulin therapy in type 2
diabetes
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%
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
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.
Thank you
Thanks to all