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 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 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.

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