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