This document discusses different types of insulin, including rapid-acting, long-acting, and premixed analogs. Rapid-acting analogs like insulin lispro and insulin aspart have a faster onset and shorter duration than regular human insulin. Long-acting analogs such as insulin glargine, insulin detemir and insulin degludec are designed to provide basal insulin levels for 24 hours or more with less variability than NPH insulin. Premixed analogs contain both rapid- and long-acting components. The document also briefly mentions new methods of insulin delivery under development.

1. Types of insulin
Domina Petric, MD

2. Introduction
Insulin can not be taken as a pill:
stomach acid would destroy it.
Insulin is taken as a
subcutaneous injection.

3. Rapid acting insulin analogs
• Regular human insulin comes as a hexamer in
solution.
• Upon subcutaneous application there is a delay in
action due to dissociation and resorption.
• Peak plasma concentrations are reached 45-120
minutes after the application.
• Such insulinemic profile does not reproduce the
dynamics of endogenous insulin secretion in
healthy individuals after β cell stimulation.

4. Rapid acting insulin analogs
• An interval of at least 15 minutes between
the application and meal is mandatory.
• Snacks between meals are needed to avoid
postprandial hypoglycemia due to
prolonged insulin action.
• Ideal rapid acting insulin would have the
peak action after 30-60 minutes and rapid
return to basal levels after 180 minutes.

5. Rapid acting insulin analogs
Insulin lispro
Insulin aspart

6. Rapid acting insulin analogs
Insulin lispro
• In the insulin lispro molecule, the sequence of
28th and 29th molecule is inversed: proline-lysine
into lysine-proline.
• This inversion results in modification of the
conformation of the insulin molecule, which
becomes more similar to insulin like growth
factor 1 (IGF-1) molecule.
• The affinity to form dimers and hexamers
decreases.

7. Rapid acting insulin analogs
Insulin lispro
• The pharmacokinetics of insulin lispro is more
similar to the insulin response in healthy
individuals.
• The rise in insulin concentration is faster and
peak concentrations are higher than with regular
insulin.
• Insulin lispro can better manage postprandial
hyperglycemia than regular human insulin
without increasing the risk of hypoglycemia.

8. Rapid acting insulin analogs
Insulin lispro
• Postprandial hyperglycemia is contributing to the
metabolic regulation in general, but it is also an
independent risk factor for cardiovascular
morbidity and mortality.
• With insulin lispro hypoglycemia occurs most
frequently about 90 minutes upon application.
• Regular insulin usually causes late hypoglycemia.

9. Rapid acting insulin analogs
Insulin lispro
• The IGF-1 receptor affinity of insulin lispro is
increased as compared with regular insulin.
• More rapid progression of diabetic retinopathy
was observed in few pregnant diabetic patients
using insulin lispro.
• From the patient´s point of view, the principal
advantages of insulin lispro are application
immediately before the meal and less
hypoglycemias.

10. Rapid acting insulin analogs
Insulin aspart
• In the insulin aspart molecule, the 28th aminoacid of
B-chain proline is substituted for aspartate.
• The charge of the molecule is changed and the
affinity for self-association decreased.
• Insulin aspart has a slightly longer duration of action
than insulin lispro.
• Glucose escape is less pronounced.
• IGF-1 receptor affinity and mitogenic potential are
similar to those of human insulin.

11. Insulin lispro
Rxlist.com

12. Insulin aspart
Medicineonline.com

13. Long-acting insulin analogs
• Human insulin preparations with prolonged action
are aimed to cover the basal insulin requirements:
fasting and between the meals.
• NPH (neutral protamine Hagedorn) and zinc-insulin
are two basic types of long-acting analogs.
Both of them are associated with two major problems:
• suspensions (mixing prior to use is critical, possibility of
mistake)
• significant inter- and intraindividual differences in the
absorption rates and bioavailability

14. Long-acting insulin analogs
• Neither NPH nor zinc-insulin preparations can
cover the basal insulin needs for entire 24 hours.
• In the multiple injection therapy regimen with
regular insulin, the prolonged action of regular
insulin also covers the basal insulin needs
between the meals during the day.
• With the advent of new and shorter-acting insulin
analogs the necessity for more than one dose of
basal insulin has emerged.

15. Long-acting insulin analogs
• The peak action of NPH insulin is 5-7 hours after
the application.
• If the evening dose is given at bedtime (around
10 p.m.), the peak action will be between 3 and 5
a.m., when the need for insulin is lowest: high
risk of hypoglycemia.
• In patients with type I diabetes treated with
multiple injection therapy, about 50% of all
hypoglycemic episodes occur during the night.

16. Long-acting insulin analogs
• Between 5 and 8 a.m. insulin sensitivity
decreases and so does insulin
concentration: dawn phenomenon.
• The dawn phenomenon (dawn effect) is the
term used to describe an abnormal early-
morning increase in blood sugar (glucose),
usually between 2 a.m. and 8 a.m., in
people with diabetes.

17. Long-acting insulin analogs
• The natural overnight release of the counter-
regulatory hormones, including growth hormone,
cortisol, glucagon and epinephrine, increases
insulin resistance, causing blood sugar to rise.
• High morning blood sugar may also be caused by
insufficient insulin the night before, insufficient
anti-diabetic medication dosages or carbohydrate
snack consumption at bedtime.

18. Long-acting insulin analogs
Insulin glargin
• The molecule of glargine has isoelectric point of pH
6,7 in contrast to pH 5,4 of human insulin.
• Modification has been made on the C-terminal end
of B-chain, where two arginine molecules are
added.
• Glycine on A-21 position is substituted by arginine.
• The pH of the preparation is 4,0: at this pH glargine
is completely soluble.

19. Long-acting insulin analogs
Insulin glargin
• At a more neutral pH of the tissue,
microprecipitation takes place, which delays
resorption.
• Resorption is also additionally delayed with a small
amount of zinc added.
• Glargine has the same affinity for insulin receptor
as human insulin.
• The affinity for IGF-1 receptor is 3-14 times greater.

20. Long-acting insulin analogs
Insulin glargin
• After subcutaneous application glargine
reaches its maximum activity after 4-5 hours,
which then remains even without pronounced
peaks.
• Patients receiving glargine may have less
nocturnal hypoglycemias, less symptomatic
hypoglycemias and less severe hypoglycemia
than with NPH.

21. Long-acting insulin analogs
Insulin detemir
• In the detemir molecule, the threonine on B30
position is removed.
• Myristoyl fatty acid is acylated to lysine at B29.
• Prolonged action is probably due to a combination of
hexamer formation and reversible albumin binding.
• About 98% of detemir in plasma is bound to albumin.
• Only the free fraction can activate insulin receptor.

22. Long-acting insulin analogs
Insulin detemir
• Detemir is soluble at neutral pH and
subcutaneous depot remains in soluble state,
which makes the resorption surface larger and
diminishes resorption variability.
• Detemir has a lower receptor affinity than human
insulin.
• It has even lower IGF-1 affinity and mitogenic
potential.

23. Long-acting insulin analogs
Insulin detemir
Detemir has a lower intraindividual
pharmacokinetic variability than NPH
insulin.
Detemir also has a relatively stronger
effect on the liver than on peripheral
tissues.

24. Long-acting insulin analogs
Insulin degludec
• Ultralong-acting basal insulin analog.
• Insulin degludec is a modified insulin that
has one single amino acid deleted in
comparison to human insulin, and is
conjugated to hexadecanedioic acid via
gamma-L-glutamyl spacer at the amino acid
lysine at position B29.

25. Long-acting insulin analogs
Insulin degludec
• It is administered via subcutaneous
injection once daily.
• It has a duration of action that lasts up
to 42 hours (compared to 18 to 26 hours
provided by other marketed long-acting
insulins such as insulin
glargine and insulin detemir).

26. Premixed insulin analogs
Low-mixture preparations contain
25-50% of rapid-acting component.
High-mixtures contain 75% of rapid-
acting component.

27. www.rn.com

28. New methods of insulin delivery
enteral insulin
oral insulin with nanoparticles
transdermal insulin
artificial beta cell prototype

29. Literature
• Novak B. Metelko Ž. New trends in
insulin therapy. Diabetologia Croatica
2003;32-2.
• Medicineonline.com
• Rxlist.com
• Mayoclinic.org
• www.rn.com