Insulin -- Its History and Future

Diabetes was first described and named by Aratacus of Cappadocia in Asia Minor in the first century AD. The name came from the analogy that diabetics urine was like water coming through a siphon.

The sweet smell of the urine of diabetics was first noted in the 17th century by the Oxford physician, Thomas Willis, but ancient Indians in the 4th century, are said to have noted ants congregating at the urine of diabetics. Attempts at treatment began when no more was known about diabetes than the polyuria. John Rollo, Surgeon-General to the Royal Artillery treated a patient by dietary restriction in 1706.

The great figure in the story of diabetes in the first half of the 19th century was Claude Bernard. This man, who was trained as a pharmacist, became a dominant figure in physiology and medicine in France and all of Europe. In fact when he died in 1878, he was given a state funeral. Bernard discovered that the liver stored glycogen and secreted a sugary substance into the blood. He assumed it was this substance that caused diabetes. At that time it was thought that the nervous system controlled secretary organs. This led him to a second discovery, that pricking the brain stem in a conscious animal caused temporary diabetes.

In 1879, Von Mering, a German physician, disproved Bernard’s liver theory when he found that removing the pancreas caused diabetes. His partner Minkowski and he worked on extracting an antidiabetic substance from the pancreas but could not find a way to do this. The idea that the antidiabetic substance might come from the islets of Langerhans was widely held. This was reasoned because the rest of the gland was quite different and therefore would have a different function.

The story of the triumphant discovery of insulin took place in 1921 in Canada by Fredrick Banting, an unsuccessful orthopedic surgeon, who after reading about the association between the pancreas and diabetes became convinced that he could find the antidiabetic substance. He persuaded J.J.R. Macloud, the Professor of Physiology at Toronto to let him try. Macloud assigned a young medical student, Charles Best, to work with him and later when the going got rough, he put a visiting professor of biochemistry, J.B. Collip on the problem with positive results.

After many failures the group prepared an extract from the atrophied pancreas of a dog. They then isolated two other dogs with diabetes, administered the extract to one, and nothing to the other. Four days later the control dog died, but the dog which received the extract lived for three weeks, dying only after there was no more extract. On Jan. 11, 1922, a 14 year old boy became the first human patient to receive insulin made by Banting and Best. This failed but purified injections developed by Collip were given starting January 23, 1922. This time the patient’s blood glucose levels dropped. News spread all over the world and within weeks leaders came to Toronto to see for themselves if the rumors were true and to learn how to make the insulin, both from Connaught in Toronto and from Eli Lilly, of Indianapolis, Indiana, with whom the researches collaborated to produce insulin in the United States and Latin America. While Lilly was successful in manufacturing insulin, the Toronto team continued to struggle and by mid-July 1922 there was a severe shortage in Toronto. Lilly shipped the product and by the end of 1923, insulin was being produced commercially and used to treat diabetes in most western countries.

August Krogh of Denmark, a Nobel Prize winner for his research on capillaries, was in the US to talk about his work, but found that everyone was talking about insulin. When he returned home he laid the foundation for the Danish insulin manufacturing industry and Nordisk Insulin Company. This was a non-profit-making company which together with the Novo Company was responsible for making Denmark the main insulin producing company outside of the US.

The first insulin was a quick and short acting ‘soluble’ or ‘regular’ insulin. It had to be injected twice daily. These insulins were crude and impure and early patients had to endure intramuscular injections of 5 to18 ml. Pain and abscesses were common. There was an obvious need for a longer acting insulin and in 1936 protamine zinc insulin was introduced and in 1954 the lente insulins were introduced.

Impurities in early insulin was mainly due to pancreatic peptides which were present in tiny concentrations. The Danes produced a purer type of insulin. ‘Monocomponent’ insulin, and other ‘highly purified insulins’ were made. When the Danes began to capitalize on these improved products, the Americans reacted by producing ‘human’ insulin, a genetically engineered insulin which now dominates the market. Previously, insulin had come from animal sources, mainly cattle in the US and pigs in Denmark. These differ from each other in one to three amino acids and are all effective.

Insulin was crystallized in 1926 by J.J. Abel. Its composition, two chains of 51 amino acids linked by disulphide bridges, was discovered by Fredrick Sanger of Cambridge. For his work he received the Nobel Prize in 1955. For later work, he received another. The three dimensional structure of the insulin molecule was discovered 14 years later in Oxford by Dorothy Hodgin. She won the Nobel Prize for her work with insulin and vitamin B 12. The scientific investigation of diabetes was improved by the technique of immunoassay by Solomon Berson and Rosalind Yalow in 1957. Minute concentrations of insulin can be consistently measured, a huge improvement on the previous methods of bioassay. Yalow, who survived Berson, received the Nobel Prize, knowing that their work transformed endocrinology.

Types of Insulin

Today in the United States biosynethic human insulin is made by recombinant DNA technology, a scientific process that allows for the production of nearly unlimited quantities of human insulin. Because insulin needs vary from person to person different types of Humalin insulin are available.

These include:

1. Regular or R -- a short acting insulin that begins to work within an hour but stops working sooner than intermediate or long-acting insulins. Peaks 2 to 4 hours. Duration 6 to 8 hours
2. NPH or N -- an intermediate-acting insulin that peaks in 6 to12 hours and lasts 18 to 26 hours.
3. Lente or L -- another intermediate acting insulin
4. Ultralente -- long acting insulin begins to act in 6 to 8 hours, peaks in 14 to 24 hours and lasts 28 to 36 hours
   Combinations of insulin in 70% N and 30 % R as well as 50 % N and 50% R are available.
5. Humalog, lispro -- rapid acting insulin is an analog of recombinant DNA technology in which two amino acids of the human insulin molecule -- proline and lysine -- have been reversed. It begins to work in 15 to 30 minutes, peaks 1 1/2 to 2 hours, and lasts 4 hours.

1. Injections are the most common delivery system.
2. Insulin pens- look like a pen with a cartridge which holds 100 to 200 units of insulin.
3. Insulin jet injectors. Look like a large pen. They send a fine spray of insulin through the skin at high pressure- Tend to be expensive.
4. External insulin pumps- About the size of a pager--these are attached to the body through a narrow flexible tube with a needle just under the skin. A refillable cartridge holds insulin good for about 2 days. The needle and tubing need to be changed every other day and frequent glucose monitoring is necessary, but usually no more than if you take multi injections a day to keep tight control.
5. Internal insulin pumps are surgically implanted, usually in the abdomen. Users deliver insulin doses above and beyond the basal dose delivered by the pump during the day. The insulin goes directly to the liver as would normally occur in a person without diabetes.
6. The insulin patch is placed on the skin and gives a continuous low dose of insulin during the day. To receive more insulin the user pulls off a tab on the patch.

In the future researchers are looking at delivering insulin through the pulmonary system using a powder and an inhaler. Eli Lilly has just started a project with Dora Pharmaceuticals to research this alternative delivery system. Other researchers are examining ways of encapsulating beta cells in a semi-permeable membrane to protect them from immune attacks after transplantation. Bioengineers are working on creating artificial beta cells that secrete insulin in response to glucose. These are but a few of the roads that researchers are following to control and cure diabetes. Insulin, that complex three-D protein, holds the secrets, but wouldn’t the early researchers be astounded at the progress, and wouldn’t they jump in to continue the fight? We all continue the battle as we care for ourselves and others on a daily basis. Make sure you remain an active partner in the search for better treatments and a cure by contributing whatever and whenever possible to diabetes research. For further interesting information, mead The Discovery of Insulin by Michael Bliss (University of Chicago Press.)