This document discusses newer insulin preparations that have been developed through genetic engineering to better mimic the body's natural insulin secretion patterns. It introduces several newer rapid-acting and long-acting insulin analogs such as insulin lispro, insulin aspart, insulin glargine, and insulin detemir. These analogs were designed to have faster onset of action, shorter duration, or longer duration compared to older insulin preparations. The document also briefly discusses inhaled insulin and newer advances in insulin delivery technologies.

1. NEWER
INSULINS
Dr. Arun Sharma

2. Overview
 Introduction & Journery over the years.
 Insulin Preparations.
 Insulin Delivery Systems.
 Conventional Insulin Problems.
 Newer Insulins
 Ultrashort / Rapid Acting
 Long Acting
 Inhaled Insulins
 Merits, Demerits & Use in Special Conditions.
 New Advances
 Conclusion
2

3.  The most powerful agent we have to
control glucose.
 Miracle discovery that saved many lives.
 Leonard Thompson was the first patient to have
effective insulin treatment (1922).
 Banting and Macleod : Nobel Prize for Medicine
(1923).
 Later on 3 more Nobel Prizes : F. Sanger (1958),
D. Hodgkins (1964) & Yalow et al (1977) leading to
better understanding of structure and mechanism
of action.
INSULIN
3

4. Insulin Journey over the years
 1921 : Insulin extracted by Banting & Best.
Conventional insulin preparations from beef/pork
pancreas (antigenic)
 1970s : Highly purified porcine insulins. Single
peak insulins & monocompetent insulins (greater
efficacy & lesser side effects)
 1980s : Human insulins by recombinant DNA
technology.
 1990 : Insulin analogues with novel
pharmacokinetics.
4

5. INSULIN PREPARATIONS &
CHEMISTRY
 With advent of human insulin, beef/porcine
insulin not produced anymore.
 Human insulin produced by recombinant DNA
technology.
 Insulin preparations are expressed in
International Units (IU).
 One unit of insulin is defined as the amount
required to reduce the blood glucose
concentration in a fasting rabbit to 45 mg/dL (2.5
mM).
 Work is ongoing to develop delivery approaches
5

6. INSULIN DELIVERY
SYSTEMS
 A. Standard Delivery :
 The standard mode of insulin therapy is s.c.
injection using disposable needles and
syringes.
 B. Portable Pen Injectors
 To facilitate multiple s.c. injections of insulin,
portable pen-sized injectors have been
developed.
 These contain cartridges of insulin and
6

7. INSULIN DELIVERY
SYSTEMS
 C. Continuous Subcutaneous Insulin
Infusion Devices (CSII, Insulin Pumps) :
 External open-loop pumps for insulin delivery.
 The devices have a user programmable pump
that delivers individualized basal and bolus
insulin replacement doses based on blood
glucose self-monitoring results.
 Advanced insulin pumps also have an “insulin
on board” feature that adjusts a high blood
glucose correction dose to correct dose.
7

8. INSULIN DELIVERY
SYSTEMS
 Device is about the size of a pager.
 Usually placed on belt or in a pocket, and
insulin is infused through thin plastic tubing that
is connected to the subcutaneously inserted
infusion set.
 Programming is done through a hand-held unit
that communicates wirelessly with the pump.
 CSII delivery is regarded as the most
physiologic method of insulin replacement.
8

9. INSULIN DELIVERY
SYSTEMS
 D. Insulin Inhalers : Most recent delivery
system in which powdered insulin is
administered via a whistle sized inhaler.
 The powder dissolves immediately when inhaled
into the lungs, and the insulin’s then quickly
dumped into the bloodstream to start working.
 Long term conclusive data however still lacking.
 E. Orally Absorbed Insulin (Oralin): Generex
is developing Aersol containing insulin for buccal
absorption
9

10. PROBLEMS WITH
CONVENTIONAL INSULINS
 Normally, insulin concentration peaks at 30-45
minutes after a meal and returns to basal level
after 2-3 hrs.
 The onset of action of regular insulin is too slow
(peak action 1-2 hr) & the duration of action is
too long (6 hrs) to mimic the physiological insulin
pattern.
 This leads to post prandial hyperglycemia and
late hypoglycemia.
 It is therefore, recommended to administer
10

11. PROBLEMS WITH
CONVENTIONAL INSULINS
 Also, intermediate or long acting insulin
preparation are unable to provide continuous
basal insulin for 24 hrs.
 This caused premeal and fasting
hyperglycaemia and night hypoglycaemia.
 Moreover, conventional human and porcine
insulins tend to form hexamer in contact with
zinc in the bloodstream.
 Insulin in the form of hexamer will not bind to its
receptors because, hexamer has to slowly
equilibrate back into monomers to be clinically
11

12.  Regular insulins form hexamers which dissociate
slowly into monomers thus delaying absorption.
 Delayed onset of action (1/2 -1 hr)
 Prolonged time of peak action (2 to 3 hrs)
 Duration of action (5 to 8 hrs)
Hence regular insulins cause a mismatch
between need & availability of bolus insulin
and do not ideally mimic physiological bolus
secretion of insulin.
Post prandial hyperglycemia
Late post prandial hypoglycemia

13. Other limitations of regular insulins
 Regular insulin has to be administered 30-
45mins before meal - dose of insulin cannot
be adjusted according to size of meals.
 Time of onset, peak action & duration of action is
dose dependent (increases with dose)
 Absorption varies with injection site &
exercise (variability of absorption as much as
25%)

14. NEWER INSULINS
 Novel long and short acting insulin
analogues, the so-called ‘Designer insulins’.
 Developed through genetic engineering in the
1990s, paved the way for more physiological
insulin therapy.
 They made the treatment flexible, safer and
simpler.
 Theoretically less problematic in terms of
hypoglyce-mia and patient satisfaction.
 Newer Insulins are faster acting preprandial
14

15. NEWER INSULINS
 Exist as monomers and are absorbed much
faster (insulin aspart or lispro) or absorbed very
slowly (insulin glargine or detemir).
 They have increased stability, less variability and
selective action which helps in developing
individualized treatment patterns.
 The B 26-30 region (critical for insulin receptor
recognition) is the site preferred for structural
alteration of insulin molecule to design novel
insulins.
 Risk of carcinogenicity on long term use is major
15

16. A) Ultrashort/Rapid acting
 They have rapid onset and shorter duration of
action.
 The peak of onset corresponds more closely
with the post prandial glucose peak.
 Therefore, can be administered immediately
before meals.
 This avoids post prandial hypoglycaemia that
occurs due to long duration of action of soluble
insulin.
 The shorter duration of action of these
16

17. A) Ultrashort/Rapid acting
1) Insulin Lispro :
 First FDA approved designer insulin (1996).
 Developed with the aim of improving glycaemic
control at meal times.
 There is inversion of proline at position 28 with
lysine at position 29.
 This allows larger amount of active monomeric
insulin to be available postprandial or after
meal.
 In pregnancy and gestational diabetes, found to
be as effective as regular insulin with no
17

18. A) Ultrashort/Rapid acting
2) Insulin Aspart :
 Substitution of proline at 28 position with
aspartic acid.
 Prevents the formation of hexamers, leading to
rapid absorption from subcutaneous tissue.
 Its absorption and activity profile are similar to
those of insulin lispro.
 Similar binding properties and mitogenecity
characteristics as regular human insulin and
has equivalent immunogenecity.
18

19. A) Ultrashort/Rapid acting
3) Insulin Glulisine :
 Substitution of asparagine at position B3 by
lysine and lysine at position B 29 by glutamine.
 Exerts its action by causing insulin receptor
substrate-2 (IRS-2) phosphorylation.
 Has additional antiapoptotic activity, counteracts
autoimmune and lipotoxicity induced β-cell
destruction.
 But insulin glulisine carry the risk of
tumorogenecity and increased mitogenic activity.
19

20. B) Long Acting
 Ideal basal insulin has long duration of action
and provides 24 hour control with minimum
variation.
 Traditional intermediate and long acting
analogues i.e. isophane, lente and ultralente are
unsatisfactory.
 Long acting insulin analogues have made
significant improvements in the management of
type 1 DM.
 Developed on two approaches:
20

21. B) Long Acting
1) Insulin Glargine :
 first long acting basal human insulin available in
the market (soluble, “peakless” analog).
 Less soluble at physiological pH and more
soluble at acidic pH.
 It precipitates at physiological pH and absorbs
slowly from injection site. Thus , it provides basal
insulin that mimics insulin profile of healthy
individual.
 Slow onset of action (1–1.5 hours) and achieves
a maximum effect after 4–6 hours. Given once
21

22. B) Long Acting
 Insulin glargine is not to be mixed with other
insulin, as it becomes cloudy and results in
alteration of pharmacokinetic and
pharmacodynamics profile.
 Injection site pain is more in patients with insulin
glargine than isophane insulin.
 The absorption pattern of insulin glargine
appears to be independent of the anatomic site
of injection.
 Associated with less immunogenicity than
human insulin.
22

23. B) Long Acting
2) Insulin Detemir :
 Modifying insulin by binding to serum protein
albumin prolongs the duration of action.
 It is a soluble basal insulin analogue at neutral
pH.
 Threonine at B30 is removed and myristic
acid(14-C fatty acid chain) is attcahed to terminal
B29 Lysine.
 Its slow dissociation from albumin results in
delayed action.
23

24. B) Long Acting
 Given twice daily to obtain a smooth basal
insulin level.
 Reduction in body weight is an advantage which
may be due to direct effect on hypothalamus.
 Lower affinity for insulin receptor necessitates
higher doses compared to human insulin.
 Less potent in binding to IGF-1R therefore, it has
reduced risk of inducing tumours.
 Shown to be as effective as other long acting
analogues i.e. isophane insulin (NPH) in
maintaining glycemic control with fewer episodes
24

25. B) Long Acting
3) Insulin Degludec :
 Newest long acting basal insulin with longer half
life (25-40 hr).
 Can be given any time of the day or thrice
weekly.
 Unlike glargine, it is effective at physiological pH.
 Following s.c. administration, it forms
multihexamers which form “s.c. depots” thereby
ensuring slow insulin release into systemic
circulation.
25

26. B) Long Acting
 Unlike glargine & detemir, it can be mixed with
other insulins.
 However, it has shown high incidence of
hypoglycemia in CTs.
 Currently approved for use in Europe (Tresiba) &
will be marketed in US after submitting cardiac
studies.
26

27. C) Inhaled Insulins
 Earliest marketed products caused pharyngitis &
pulmmonary fibrosis.
 Exubera (Pfizer) was approved in 2006 but was
discontinued later due to lung complications and
inconvenient use reported by users.
 Afrezza is a ultarapid acting insulin which is
inhaled at beginning of a meal & was approved
in 2014 by the FDA.
 administered via a whistle-sized inhaler called
the ‘Dreamboat’.
27

28. C) Inhaled Insulins
 Afrezza peaks within 12 -15 minutes and is out
of the system within an hour.
 The Dreamboat is meant to be thrown away after
15 days to prevent any powder buildup inside
that could clog the device.
 Unlike traditional insulin, it needs no
refrigeration, but rather is kept at room
temperature.
 Each single-use cartridge holds either 4 or 8
units.
28

29. C) Inhaled Insulins
 Not recommended for people with diabetes who
smoke, nor for treating diabetic ketoacidosis
(DKA).
 Can cause bronchospams in asthma/COPD
patients.
 Hypoglycemia, cough, and throat pain or
irritation are the common side effects reported in
CTs.
 Long term PMS studies are underway to
29

30. Merits of insulin analogues
 Better mimicking of physiological insulin
secretion.
 Better control of post prandial blood glucose
levels
 Better control of glucose levels in the fasting,
interdigestive period.
 Lesser risk of hypoglycemia (esp. nocturnal)
 Action profile independent of dose/site of
injection/exercise- more predictable action.
 Greater flexibility with short acting analogues

31. Merits of insulin analogues
 Compliance is improved with long acting
analogues as once a day the insulin
 The need for snacks between meal may be
reduced with short acting analogues
 Advantage in term of weight loss epically with
detemir insulin.

32. DEMERITS
 No significantly different adverse effects when
compared to standard insulins.
 Worsening Retinopathy with Lispro (homologous
to IGF-1)
 ???Carcinogenicity: Concerns over Glargine
carcinogenicity (FDA considers Glargine as a
Black triangle drug)
 HIGH COST

33. Insulin analogues are preferred
in :
 Persons with uncertain lifestyle/qty of
meals/time of meals (busy persons) not
controlled by std.insulins
 High unpredictable FBS/PPBS
 Risk of hypoglycemia esp. nocturnal (elderly)
 Unexpected exercise (sportsmen/policemen)
 Critical patients (hepatic & renal disease, ICU
patients shifted from iv to s/c, periop patients)
 Weight gain with standard insulins (detemir).

34. INSULIN ANALOGUES IN
SPECIAL SITUATIONS
 Diabetic ketoacidosis – Lispro (i.v)
 Pregnancy
 Lispro & Aspart demonstrated efficacy &
safety
(Cat B)
 Long acting analogues not studied.
 Children
Data on insulin analogues is limited.
 Elderly (at risk of nocturnal hypoglycemia)
Insulin analogues preferred.

35. Newer Advances
35
 LY2605541 is a PEGylated basal insulin lispro.
 Has completed Phase II clinical trials.
 insulin molecule is embedded in a polyethylene
glycol (PEG) chain.
 The resultant molecule is quite large and
absorption from the subcutaneous space is
slowed significantly, prolonging the duration of
action.
 Comparable or better glycaemic control than
insulin glargine aswell as reduced weight in
patients with T1DM and T2DM.

36. Conclusion
 These analogues have shown equal or superior
efficacy and have lower incidence of
hypoglycaemia.
 But insulin analogues are more expensive than
human insulin.
 The proper use of insulin analogues will allow
the diabetics greater flexibility in the timing of
meals, snacks and exercise which will improve
their quality of life.
 Other newer routes of insulin administration are
also showing promise & research is ongoing in
36

37. References
37
 Chapter 41.Pancreatic hormones and antidiabetic drugs.
Bertram G. Katzung Basic & Clinical Pharmacology. 12th
edition 2012, pp 746-751.
 Hirsch IB. Insulin analogues. N Engl J Med 2005; 352 :
174-83.
 Setter SM, Corbett CF, Campbell RK, White JR. Insulin
aspart: a new rapid – acting insulin analog. Ann
Pharmacother 2000;34:1423-31.
 Vajo Z, Duckworth W. Genetically engineered insulin

38. References
38
 Zib I, Raskin P. Novel insulin analogues and its mitogenic
potential. Diabetes Obes Metab 2006;8:611-20.
 Mandal TK. Inhaled insulin for diabetes mellitus. Am J
Health Syst Pharm 2005;54:1359-64.
 Owens DR, Zinman B, Bolli G. Alternative routes of insulin
delivery. Diabet Med 2003;20:886-98.
 www.fda.gov/newsevents/newsroom/pressannouncements/
ucm403122.htm [FDA Approved Afrezza to treat diabetes].