The insulin hexamer

Rapid acting insulins are mutant forms of insulin that have been engineered to work faster upon injection than regular human insulins. The need for a rapid acting insulin can be illustrated from an all too common scenario: You have taken your insulin shot about 30 minutes ahead of time in preparation for dinner and just as you sit down, you get an emergency phone call. Alternatively, you have taken your insulin shot just before getting seated at your favorite restaurant and 45 minutes later the waitress sheepishly informs you that your dinner got dropped and will just be a bit longer. A lot can happen in between your shot and your meal. Rapid acting insulins allow you to take your shot just as you need it, giving you more flexibility in your schedule.

In order to understand why these mutant insulins have a more rapid onset than other insulins, we need to consider insulin structure. Insulin is a protein and if you are a regular reader of this column you are probably aware that proteins are long chains of amino acids. Proteins work by folding up into shapes. These shapes can function as machines that do things or as information that gets processed. Insulin functions as a bit of information that binds to, and activates, a machine: the insulin receptor. Now, the important concept here involves the folding of insulin. Amino acids have the beautiful ability to form weak interactions with each other. For example, the positively charged lysine might attract the negatively charged aspartic acid. Hydrophobic phenylalanine will hide next to another phenylalanine to avoid the positive and negative charges of water molecules. These interactions are what stabilize the protein folds. Additionally, these interactions allow separate proteins to interact with each other. Indeed, we spend a great deal of effort in trying to understand how proteins interact with one another.

Insulin happens to really like to bind to itself to form groups of 6: called insulin hexamers. This self interaction probably evolved to allow more to be packaged into the secretory granules of the pancreatic beta cells. When the insulin granules are released from the beta cells and enter the blood, the forces of the blood overwhelm the weak interactions between insulin molecules and the hexamer dissolves. Individual insulin molecules can now bind to the insulin receptor. When a synthetic insulin such as Humulin is injected into the abdomen, it enters a relatively sheltered region between cells. The hexamers break apart, but absent from the rough and tumble of the blood, they do so slowly.

Protein biochemists and molecular biologists have studied insulin structure for years as well as their closely related cousins, the insulin-like growth factors. It was this line of inquiry which led to the development of rapid acting insulins. Insulin-like growth factors do not interact with each other as insulin does. This was curious as the two proteins were extraordinarily similar – indeed so similar that they could activate each other’s receptors (inefficiently, it is true, but activate none the less). Once the receptor binding surfaces were identified and removed from consideration, researchers turned to the other end of the molecule. There, they found a few amino acid differences. Molecular biologists, using the power of DNA, constructed mutants of insulin that contained those few insulin-like grow factor amino acids and…it worked! Thus was rapid acting insulin born.

Since there are a number of different mutations that one can make which result in the block of self interaction, numerous companies developed and patented their own forms of rapid insulin. Eli-Lilly developed the first insulin mutation -  Lispro and markets it under the name: Humalog. Sanofi-Aventis markets insulin-glulisine under the name: Apidra. Novo-Nordisk developed Insulin aspart which it markets under the name: NovoLog. All have similar insulin receptor binding domains and each has its own patented change that keeps it from self associating.

Now if we could just do something about those annoying  phone calls just before dinner.