by Linda von Wartburg
The name insulin comes from the Latin insula, for islands. It refers to the pancreatic islets of Langerhans that contain the beta cells.
The Islets of Langerhans
The pancreas contains one to three million islets of Langerhans, but the islets account for only 2 percent of the total mass of the pancreas. The rest of the pancreas secretes a juice containing digestive enzymes that break down food. Within the islets of Langerhans, beta cells constitute 60 to 80 percent of all the cells.
A Once Elusive Hormone
Before Banting and Best, researchers couldn’t find insulin because the digestive juices put out by the pancreas digested it all. Banting and Best’s trick was to tie a string around the pancreatic duct of a live dog. When the dog was examined several weeks later, the pancreatic digestive cells had died and had been absorbed by the immune system, leaving the thousands of islets. They then isolated an extract from these islets, producing what they called isletin (insulin).
Detecting Insulin’s Sequence
Insulin was the first protein ever to have its sequence determined. The exact sequence of amino acids comprising the insulin molecule was found by British molecular biologist Frederick Sanger, who was awarded the 1958 Nobel Prize in Chemistry. In 1969, Dorothy Crowfoot Hodgkin determined the spatial conformation of insulin, or how it’s twisted in space.
What md/dl Stands for
The abbreviation mg/dl stands for milligrams of glucose in 100 milliliters (one deciliter) of blood. A milligram equals .0000353 of an ounce, and 100 milliliters equals something less than half a cup. In a healthy adult male of 165 pounds with a blood volume of about five quarts, a blood glucose level of 100 mg/dl corresponds to about 1/5 ounce of glucose in the blood and approximately 11/2 ounces in the total body water. All the glucose in your blood amounts to about the contents of a restaurant sugar packet.
All Creatures, Great and Small, Need It
Insulin is required for all animal life, and it works just about the same in nematode worms, fish and mammals like us. The initial sources of insulin for clinical use in humans were cow, horse, pig or fish pancreases. They all work because they’re nearly identical to human insulin. Cow insulin differs from human by only three amino acids, and pig insulin by only one. Before human recombinant analogues were available, Novo Nordisk was able to convert pig insulin into human insulin by removing the single different amino acid and chemically adding the correct one.
Hard to Swallow
Unlike many medicines, insulin cannot be taken orally. Like nearly all other proteins, it is digested into useless fragments in the gastrointestinal tract.
Where Old Insulin Goes
What happens to your old insulin? Once an insulin molecule has docked onto the receptor and done its work, it may be released back into the extracellular environment or it may be degraded, usually by liver cells.
Zinc’s Important Role
Unmodified human insulin tends to join up with zinc in the blood, forming hexamers, which means six monomers; that is, six single molecules of insulin stuck together. Insulin in the form of a hexamer will not bind to its receptors, so the hexamer has to slowly turn back into single monomers before it can work. That’s why zinc combinations of insulin are used to make slow release basal insulin. Ultralente insulin (no longer available) was a good example of this use of zinc.
Lilly had the first insulin analog with “lispro,” a rapid acting insulin analog with the trade name of Humalog®. It’s called lispro because they reversed the positions of lysine and proline in the insulin. This modification did not alter receptor binding, but blocked the formation of insulin dimers (two joined insulin molecules) and hexamers. This allowed larger amounts of active monomeric insulin to be available in the body.
Novo Nordisk created “aspart” and marketed it as NovoLog, a rapid acting insulin analogue. It’s called aspart because they switched the normal proline amino acid for an aspartic acid residue. This analogue also prevents the formation of hexamers, to create a faster acting insulin.
Aventis developed glargine (Lantus) as a longer lasting insulin analogue. It was created by adding two arginines and switching another molecule for glycine.