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Standard disclaimers: I am not a doctor, pharmacist, or biochemist. Consult your physician for treatment guidelines.

Rapid-Acting Human Insulin Analogs

Human insulin analogs (also spelled "analogue") are biosynthetically created medications for diabetes, primarily used to treat insulin-dependent diabetes mellitus. As the name implies, they are molecules very similar to natural human insulin, but with some chemical differences that alter their action in the human body.


Pharmaceutical giants Eli Lilly and Novo Nordisk constantly compete for the global insulin market. Much of the battle takes place in the arena of science: every fifth Lilly employee and every sixth Novo employee works in R&D. Every ten years or so, one of them develops a revolutionary new insulin product and the other soon follows with one that is pretty much identical in function, but contains a minor chemical difference. Consequently, they share about 7/8 of the world's insulin market.

In the 1980s, insulin research focused on altering the genes of bacteria to make them synthesize previously unavailable or nonexistent forms of the human insulin molecule. Both companies considered developing faster-acting insulin products a top priority.

Lilly won the race in 1989. Their scientists modified the gene sequence for human insulin and inserted the modified sequence to a laboratory strain of Escherichia coli. Well, that's how I grok it, but I'm no biochemist.
Anyway, the bacterium started to synthesize the protein decreed by its now modified DNA - one that was almost identical to the one secreted by the beta cells of the Islets of Langerhans in the healthy human pancreas.

Biosynthetic human insulin had been produced for quite some time (Lilly had been using E. coli, Novo preferred yeast cells), but this new molecule was better for Lilly - and for diabetics everywhere. You see, while human insulin is the natural form of insulin for us, it only works quickly enough when produced naturally in the pancreas, where it is rapidly absorbed into the bloodstream. When injected subcutaneously, it is absorbed quite slowly. This is bad, since controlling blood sugar is much more difficult if you have a 30 to 60 minute lag with each shot.


The insulin molecule created in 1989 carries two variations on the hormonal theme performed by the pancreas of a healthy person. Insulin is a combination of two chains of 21 and 30 amino acids. Lilly's scientists had merely swapped two amino acids at positions 28 and 29 on the B chain. In human insulin, B28 is proline and B29 lysine, but in the analog form, B28 is lysine and B29 proline.
The molecule was initially named "lyspro" after these two amino acids, but the name was later changed to lispro because some languages lack the letter y.

In storage (in an ampule or in the pancreas), insulin is clustered together in groups of six, called hexamers. When injected, the hexamers must dissociate and release their constituent insulin molecules before they can be absorbed from the subcutaneous tissue. Lispro hexamers break down much faster than regular human insulin hexamers and are thus absorbed more rapidly.

Novo eventually developed an insulin analog of their own, insulin aspart (marketed as NovoRapid in Europe and NovoLog in the US). It works just like lispro, but its only difference from human insulin is an aspartic acid molecule in the B28 position, hence the name.

Aventis Pharmaceuticals also made a rapid-acting human insulin analog, insulin glulisine (trade name Apidra). Again, the name is derived from the differing amino acids - glutamic acid at B29 and lysine at B3. It too is functionally identical to lispro.

Any references in this writeup to the use and activity of lispro are equally true for aspart and glulisine.


The activity of lispro starts about ten minutes after subcutaneous injection. Peak activity is achieved around one hour (slightly faster if injected in the abdomen). After that, the effect gradually fades, most of it gone after two and a half hours and none left after four. This pattern is very well suited to meal insulin, regardless of whether it is taken 15 minutes before a meal or just before eating. Note that, with all forms of insulin, your mileage may vary.


Human insulin analogs are used by subcutaneous injection. Unless an insulin pump is used for continuous infusion, a long-acting insulin is added so that the body is never entirely without insulin. Lispro insulin can be mixed with long-acting NPH or Ultralente insulin, if the mixture is immediately injected. Analogs are also used intravenously in hospitals to stabilise a newly diagnosed patient's blood sugar (since it's usually sky-high).

Lispro has some advantages over regular human insulin, which usually takes 2-4 hours to reach peak blood levels. Carbohydrates are absorbed more quickly than this, raising blood glucose and leading inevitably to a period of hyperglycemia (high blood sugar) after meals. This can contribute to nasty complications over time.
Also, the action of regular insulin lasts so long that it may cause hypoglycemia (low blood sugar) even 8 hours after an injection. Eating smaller amounts of food, but more often, would balance these fluctuations, but that may not be practical.
If an appropriate dose of lispro is taken a suitable time prior to eating, blood sugar will not have a peak. The rapid absorption and activity also means that lispro can be taken just before a meal.
Parents of small children may give lispro injections after finding out how much the child felt like eating. (If insulin was given before a meal and the child would not eat enough, carbohydrates then fed to prevent hypoglycemia would reward the child's poor eating habits.)

Lispro is ideal when used with an insulin pump. Each dose issued is no longer accompanied by the nuisance of injection, so insulin can be taken whenever needed. If doses are accurately matched with carbohydrates, blood glucose variations are minimised. Since the pump makes taking small doses practical, the user can fine-tune blood glucose and learn to read biological feedback more accurately.
While very good blood glucose levels can be maintained with injected insulin as well, this requires careful advance planning. Things like changes in the timing of meals are also more difficult to incorporate into the treatment regime.
Using an insulin pump as the delivery system for a rapid-acting human insulin analog decreases the risks associated with them and is currently the best treatment option for most people with insulin-dependent diabetes mellitus.


While studies have shown that using lispro decreases the risk of severe hypoglycemic episodes, there are some risks in using rapid-acting human insulin analogs.
Accidental overdosing is more dangerous than with slower-acting insulin, since severe hypoglycemia will develop sooner.
If no other type of insulin is used, problems with insulin supply (such as an insulin pump running out of insulin while the user is asleep) can soon lead to ketoacidosis.
Those who eat very slowly are also at risk to develop hypoglycemia during a meal, so they should either use regular insulin or an insulin pump that can be programmed to infuse the meal insulin at a slower rate.


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