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Part 2: Different types of insulin
 We discussed the nature of diabetes and the control measures required to keep it under check in the previous article. Let us now delineate the different types of insulin available for treatment to suit the specific needs of patients.
The composition and linear arrangement of the amino acids in insulin is highly conserved (kept constant) in mammals. Porcine (pig) insulin has only a single amino acid variation from the human, and bovine (bull) insulin varies just by three amino acids. Both of them are quite active on the human insulin receptor to the same extent as the human insulin. Porcine insulin was also converted enzymatically into the human form. Animal insulins are well accepted by a large number of patients and they are still in use in several countries of the world.
Bovine and porcine insulins were used widely until human insulin was produced by recombinant techniques. Lilly started marketing Humulin (in 1983), which was produced in a bacterium using a human gene. Humulin revolutionised diabetic treatment in that it was identical to natural insulin and the patients did not have to worry about any allergic reaction. However, it is far from perfect in the sense its use had to be fine-tuned such that it did not produce too low or too high glucose level in the blood. The diabetic patient requires a constant modulation of insulin levels to regulate glucose metabolism. Ideally, the patient requires a dose of rapid-acting insulin during mealtime and a basal level of long-acting insulin to modulate glucose levels throughout the day.
To address this situation, the drug companies took two measures. The first one was to formulate the insulin in such a way to make it quick-acting in one form (soluble version) and long-acting in another form (a suspension). The second approach was to tweak the insulin by changing the composition slightly so that the functional part was left unchanged but small changes were made by replacing certain amino acids in order to produce an analog which would function in the body either rapidly or over a long period of time.
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Structure of Humalog showing the difference from Humulin at positions B29-30
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Regular short-acting insulins: These constitute the synthetic human insulins such as
Humulin R and Novolin R which are zinc-insulin crystalline suspensions dissolved in appropriate physiological medium to produce clear liquids. The activity onset time is 30-60 minutes after injection, peaking at 2-5 hours and the total duration of action is 5-8 hours. The insulin in these preparations is in an associated form which slowly dissociates to the active form.
Rapid-acting insulins: This class consists of engineered synthetic insulins usually with a slight alteration or transposition of one or two amino acids from the natural sequence.
Humalog (Lilly; FDA approved in 1996)) (insulin lispro) is made by interchanging the positions of proline and lysine at positions (B28 and B29).
Novolog (Novo; FDA approved in 2001) (insulin aspart) is made by replacing B28 proline with aspartic acid.
Apidra (Sanofi-Aventis; FDA approved in 2004) (insulin glulisine) is made by changing B3 Asparagine to Lysine and B29 lysine to glutamic acid. These changes prevent self-association of insulin thereby allowing large amounts of monomeric (active) insulin to be available for injections during mealtime. The onset time for these is very rapid, usually 10-30 minutes with peak activity at 1-2 hours and total duration lasting 3-5 hours. These preparations, called insulin analogs, are clear solutions.
Intermediate-acting insulins: Humulin L (lente), Humulin N (NPH), and
Novolin N (NPH) fall in this category. These are also synthetic human insulins. Humulin lente is a suspension and so are the other two. The NPH designation indicates a neutral protamine crystalline suspension. All the three are cloudy preparations and before injection the vials have to be gently rolled and the required dose has to be drawn from a homogenous suspension. The onset time is usually 2-4 hours with peak activity at 4-12 hours with a total duration of action lasting 18-24 hours.
 Long-acting insulins:
Lilly’s Humulin U (ultralente), Sanofi-Aventis’ Lantus (insulin glargine), and Novo’s
Levemir fall in this class. Humulin U is a crystalline suspension with zinc of Humulin while Lantus and Levemir are engineered analogs. The onset time is 4-6 hours for Humulin U and 1-2 hours for the other two. There is no peak effect with these insulins. The activity lasts for a long time — usually 24-36 hours.
In addition, mixtures of two classes are also available. They are usually designated as Humulin 70/30, Humulin 50/50, Novolin 70/30, Humalog Mix75/25, and Novolog Mix 70/30. These mixtures are formulated by the companies under sterile conditions. The patients are advised not to mix any two insulins themselves.
Dosage: With a variety of insulins available for different needs, it is really a balancing act to use the right kind at the proper dose. The dosage must be customised for each individual. Some patients may require one injection daily while others may require two to four injections. The timing may also change from one individual to another. Most insulin doses are injected roughly 30 minutes prior to a meal (Humalog is recommended to be given 15 minutes before or immediately after a meal while Novolog is recommended to be given 5-10 minutes before the start of a meal. The patient’s history of glucose control has to be evaluated properly before the physician can prescribe the appropriate doses. Other than mealtime injections, most doctors will also advise their patients to take an injection of Lantus or Levemir before bedtime to keep a basal level of insulin for a 24-hour period.
In addition to injectable forms of insulin, an inhalable form of insulin called
Exubera (Pfizer) was approved by FDA in 2006. It is also synthetic human insulin which is short-acting and works faster than the injectable version. It is inhaled through the nose at a pre-dialed dose. It is usually a convenient and painless operation compared to the injection.
There are two other injectable drugs approved for use which work in conjunction with insulin.
Symlin (approved in 2005) is usually prescribed for type 1 diabetics. It suppresses glucagon production by the pancreas. Glucagon is responsible for stimulation of liver to produce glucose under normal circumstances. Another drug called
Byetta (exenatide) induces insulin secretion by pancreas in type 2 diabetics whose pancreas is still functioning. However, these two drugs are not indicated for most diabetics but restricted to only a few by the physicians who treat them.
Through a judicious choice of the different types of insulins at appropriate doses glucose control can be achieved effectively. It can, however, never be emphasised enough that diabetes management is an integrated effort involving eating the right kind and quantity of food, doing exercise (even a 30-minute walk per day is enough), and taking oral medications and/or insulin as needed. While there is no cure for diabetes as yet, effective treatment is still possible and the patients can still lead a quite active life. We will look at the aspect of “eating the right kind of food” in a future article.
Part 1
Sethuraman Subramanian
subramaniansethu@hotmail.com
Disclaimer: The information provided here is for information only and the readers are encouraged to contact their physicians for proper medical advice regarding insulin therapy.c
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