Insulin and Insulin Analogues -detailed content

Topic of Diabetes -explaining the insulin in detail

1. Dr Aditi Chaturvedi

2. MCQ
Insulin causes all of the following except:
a)Glycolysis
b)Glycogenesis
c)Lipogenesis
d)Ketogenesis
Answer: d
Aiims 2010

3. MCQ
Insulin acts by stimulation of:
a)Ionotropic receptor
b)enzymatic receptor
c)metabotrophic receptor
d)nuclear receptor
Answer: b

4. cAMP is messenger for the following except:
a)TSH
b)Insulin
c)LH
d)FSH
Answer: b

5. By the end of Lecture:
Preparations of Insulin---
1.Animal
2.Human –less antigenic, more rapid
3. Insulin Analogues—Better Pharmacokinetics—consistent
and more predictable action
All preparations come in:
1.Regular—short acting (6-8 hrs)
2.Retard —intermediate acting (20-24hrs)

6. By the end of Lecture:
Preparations of Insulin---
1.Animal(Commercial with impurities / Monocomponent
insulins-less antigenic)
2.Human –less antigenic, more rapid (bacteria, yeast, enzyme
modification-recombinant dna technology)
3. Insulin Analogues—Better Pharmacokinetics—consistent
and more predictable action—recombinant dna tech.
All preparations come in:
1.Regular—short acting (6-8 hrs)
2.Retard —intermediate acting (20-24hrs)

7. Regimens of Insulin
Short acting and long acting insulins given together for
meal time glucose control and basal glucose control.
Early Post Prandial Hyperglycemia and late post
prandial hypoglycemia
Reactions to Insulin
Hypoglycemia, Inj site reactions, allergy, Insulin
Odema

8. Preparations of Insulin-SN
1.Animal-Commercial Preparations(Regular/Retard)
2.Animal-Monocomponent-Highly Purified pork and
Beef Insulin(Regular/Retard)-SN
3.Human Insulin(Regular/Retard)-SN
4.Insulin Analogues—(Regular/retard )SN
The older commercial insulin preparations were
produced from beef and pork pancreas.
They contained approx. 1% of other proteins
(proinsulin, other polypeptides)—which were
antigenic

9. 1. Highly Purified Insulin Preparations
Purification techniques like:
1.Gel filtration
2.Ion exchange chromatography were applied to produce
single peak and monocomponent (MC)insulins which
contain < 10ppm proinsulin.
The advantages of MC insulins over commercial prep. are:
less antigenic
less injection site lipodystrophy (Lipodystrophy occurs
due to antigens)
less insulin resistance –therefore dose is less
Immunogenicity similar to human insulin

10. Gel Filtration
Ion exchange
Chromatography

11. Human Insulin
In 1980s the human insulin were produced by recombinant
DNA technology in:
1.E-coli-proinsulin recombinant bacterial(prb)
2.yeast-Precursor yeast recombinant(pyr)
3.Enzymatic modification of porcine insulin (emp)

12. Recombinant
DNA
Technology

13. In India—pork and beef insulins used as they are more
cost effective
Human insulins---more water soluble and slightly
more rapid acting by s.c. route

14. Purified Pork insulins and
Human Insulins
There is an allegation that human insulins produce more
hypoglyceamic unawareness—though its not
substantiated.
Clinical superiority of human insulin over pork insulin has
also not been demonstrated.
Indication from transfer of purified pork to human insulin
is allergy to pork insulins

15. Animal insulin-
(monocomponent) to Human
Insulin
It is unwise to transfer stabilized
patients from one to another
species insulin without good
reasons

16. Regular Insulin(Animal/Human)
Insulin stabilized by small amounts of Zinc
The insulin molecules self aggregate to form hexamers
around the zinc ions.
After sc. injection—insulin monomers are released
gradually by dilution so that absorption occurs slowly.
Peak action is produced only after 2-3 hrs and action
continues for 6-8 hrs

18. Regular Insulin (animal/human)—
only insulin that can be given i.v.
Regular insulin is optimally injected 1 hr before a meal.
Why?
When injected just before a meal, this pattern often creates a
mismatch between the need and availability of insulin to
result in early post prandial hyperglycemia and late post
prandial hypoglycemia
Regular insulin injected s.c. is not suitable for providing a
low constant basal level of action in the inter-digestive
period.
Regular insulin is the only insulin used for iv inj.

19. Early Post prandial
Hyperglycemia
Late Post prandial
Hypoglycemia
Meal time insulin---short acting
Insulin—Regular Insulin
Basal Insulin—long acting insulin
Blood Glucose Level

20. Intermediate acting or retard
preparations...
Modified or retard preparations of insulin
Regular insulin—unmodified insulin
For obtaining retard preparations, insulin is rendered
insoluble either by:
1.complexing it with protamine—Isophane insulin
2.by ppt it with excess Zn and increasing particle size--
-Lente Insulin.

21. Isophane insulin or Neutral
Protamine Hagedorn
Protamine is added in a quantity just sufficient to
complex all insulin molecules
Ph is neutral.
On sc injection—the complex dissociates slowly to
yield an intermediate duration of action.

22. Lente Insulin(Insulin Zn
Suspension)
Two types of insulin Zn suspension have been
produced.
1. Large particles(Ultralente)—is and
practically insoluble in water(ultralente)—it is long
acting.
2. Small particle(Semilente) and is
(semilente) and is short acting
Their mixture 7: 3 is called Lente Insulin and is
intermediate acting.

24. Insulin Analogues
Insulin analogues
1.Rapid acting—1-1.5 hrs (insulin lispro, aspart,
glulisine)
2.Long acting preparations-->24hrs(insulin glargine)

25. Insulin analogues
Using Recombinant DNA technology—analogues of
insulin have been produced with better
pharmacokinetics
Greater stability and consistency are the advantages
Better glycemic control-HbA1C

26. 28, 29
29,23
28
29
31,32

27. Rapid acting –Insulin analogues
Rapid Insulin Lispro, glulisine, aspart: Rapid acting
insulins
It forms very weak hexamers that dissociate rapidly after
sc injections resulting in a quick and more defined peak
as well as shorter duration of action.
1.To be injected immediately before or after meal..
2.Less late post prandial hypoglycemia
3.Better glycemic-- hbA1c control

28. Rapid acting –Insulin analogues
Rapid acting Insulin
analogue
It forms very weak
hexamers predictable
and rapid dissociation
To be injected
immediately before or
after meal..
Less late post prandial
hypoglycemia
Better glycemic - hbA1c
control
Regular Insulin
Hexamers dissociate slowly
and in unpredictable
manner
Injected 1 hr before
Early post prandial
hyperglycemia and late post
prandial hypoglycemia

30. Insulin Glargine-Long acting
Insulin analogues
This long acting biosynthetic insulin has two
additional arginine residues at the carboxy terminus of
B chain and glycine replaces asparagine at A21.
This analogue remains soluble at PH4 of the
formulation but ppts at neutral PH encountered on sc
inj.
A depot is created from which monomeric insulin
dissociates slowly to enter the circulation.
Peakless effect is obtained—for 24hrs

31. Insulin Glargine
Thus it is available for od injection to provide background
insulin action.
Injected mostly at bed time
Lower incidence of night time hypoglycemia compared to
isophane insulin.
Retard preparations—more night time glycemia
Because of acidic PH it cannot be mixed with any
other insulin

32. Split Mixed RegimenBasal and Bolus Regimen

33. Insulin Detemir and degludec
Insulin Determir: Myristoyl(a fatty acid) radical is
attached to the amino group of lysine at B29 of insulin
chain. As a result it binds to albumin after sc injection
from which the free form becomes available slowly.
Pattern of action similar to Insulin Glargine obtained
but twice a day dosing is needed.
Insulin Degludec: new ultralong acting insulin
analogue with a flat plasma glucose lowering effect
lasting for 40 hrs suitable for meeting basal insulin

34. Regimens of Insulin
Split Mixed Regimen
Basal and Bolus Regimen

35. Split Mixed RegimenBasal and Bolus Regimen

36. INSULIN REGIMEN
Should provide:
1. Basal control -----by inhibiting hepatic glucose output,
lipolysis and protein breakdown
2. Extra amount to meet postprandial needs for disposal of
absorbed glucose and amino acids.
No single injection---can satisfy both needs
Frequently selected regimen:
1. Split Mixed regimen
2. Basal-bolus regimen

37. Split Mixed Regimen
Regular + lente/isophane(NPH) insulin
The total daily dose of a 30:70 or 50:50 mixture of regular
and NPH insulin is usually split into two (split-mixed
regimen)
s.c. injection before breakfast and before dinner.
Advantage—only two injections required
Problem—Post lunch glycemia not controlled well and late
post prandial hypoglycemia.

38. Split Mixed Regimen
Late post prandial
hypoglycemia

39. Basal Bolus Regimen
Needs 3–4 daily injections.
A long-acting insulin (glargine) is injected once daily
either before breakfast or before bed-time for basal
Along with 2–3 meal-time injections of
a rapid acting preparation (insulin lispro or aspart).
Achieves round-the-clock euglycaemia, but are more
injections and expensive.
Strict euglycemia—may have higher incidence of
hypoglycemia

40. Split Mixed RegimenBasal and Bolus Regimen

41. Avoid Basal Bolus Regimen in:
Children (risk of hypoglycaemic brain damage)
Elderly (more prone to hypoglycaemia
and its serious consequences).

42. Reactions/Side Effects to Insulin
1.Hypoglycemia,
2.Local reactions at injection site
3. allergy
4.edema

43. Hypoglycemia
Hypoglycemia: Most frequent and the most serious
reaction
Hypoglycemia can occur in any diabetic:
1.Accidental large dose
2.Missing a meal
3.Vigorous exercise

44. Symptoms: sympathetic stimulation and
neuroglucopenic symptoms
Sympathetic Stimulation: sweating, palpitations,
tremors, anxiety
Neuroglucopenic symptoms: Dizziness, headache, visual
changes, mascular inco-ordination
Sympathetic symptoms occur before the neuroglucopenic
symptoms.
Hypoglycemic unawareness-loss of warning symptoms
tends to develop in patients who experience frequent
episodes of hypoglycemia—in pts of diabetic neuropathy

45. BGL--< 40mg/dl---seizure and coma occur
Treatment: Glucose-15- 20g orally reverses the
symptoms rapidly in most cases.
If no improvement occurs, the same amount may be
repeated after 15-20 min.
In severe cases 30-50ml of 50% glucose may be
injected iv over 10 min.
Glucagon -0.5-1mg iv/ Adrenaline(0.2mg sc) are also
helpful.

46. Local Reactions: Swelling, erythema, rash
lipodystrophy at inj site.
Allergy: Rare with human, highly purified insulins.
Urticaria, angiodema and anaphylaxis
Edema: Some patients develop short lived dependent
odema when insulin therapy is started—na+ retaining
effect

47. Assignment-2
a)Please compare Animal Insulins, Human Insulins
and Insulin Analogues (3 marks)
b)Describe the two regimens for Insulin(split mixed
and basal bolus regimen with diagram (2 marks)
c)Compare Regular and Retard insulin preparations(2
marks)