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Healio
Issue: January 2009
January 10, 2009
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Insulin therapy crucial discovery in diabetes care

Diabetes therapy continues to evolve.

Issue: January 2009
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More than 20 types of insulin are sold in the United States, and each is applicable to various situations and lifestyles, according to the American Diabetes Association.

Over the years, not only have the forms of available insulin changed, but also the methods of insulin delivery have evolved and continue to do so.

A move from injectable forms of insulin has introduced innovative delivery options such as insulin pumps, inhalable insulin, intranasal, and transdermal and oral insulin. The future of insulin therapy may lie in pancreas transplantation or in therapy that mimics a pancreas; building upon the years of research and testing it took to arrive where diabetes care is today.

Discovery leads to progress

Until the latter half of the 20th century, type 1 diabetes was a fatal disease.Previously, there was little that could be done to treat the disease, primarily because it was not recognized.

In the spring of 1921, however, Frederick Grant Banting, an orthopedic surgeon from Ontario, Canada, approached J.J.R Macleod, head of physiology at the University of Toronto and well-known physician in the field of diabetes, regarding laboratory space. It was here that Banting began to investigate the function of the pancreatic islets. His work would lead to the discovery of insulin, one of the greatest contributions to modern medicine, which eventually led to further advancements in insulin therapy and seemingly endless possibilities.

Charles Best, a medical student at the time, assisted Banting with his experiments that were originally conducted on several experimental dogs. Banting’s hypothesis was that ligation of the pancreatic ducts before extraction of the pancreas destroyed the enzyme-secreting parts, whereas the islets of Langerhans, internal secretion regulators of sugar metabolism, remained intact.

Banting’s idea was to intentionally ligate pancreatic ducts, therefore, allowing time for the acinar cells to degenerate leaving just the islet cells. He speculated that isolating this internal section, which was already proven to help metabolize sugar, could potentially be a treatment for diabetes.

The experiments produced an extract of pancreas, which would later be termed “insulin,” that reduced hyperglycemia in the dogs that were made diabetic through removal of the pancreas.

Macleod assigned chemist James Bertram Collip to aid in purification of the extract, which proved successful in clinical trials that were conducted on patients with diabetes.

Frederick Grant Banting conducted the first research on the islets of Langerhans
Frederick Grant Banting conducted the first research on the islets of Langerhans, which led to major advancements in insulin therapy. He hypothesized that ligation of the pancreatic ducts before extraction of the pancreas would allow the islet cells to remain intact.

Source: http://nlmn.nih.gov

Less than two months later, in December of 1921, insulin was tested for the first time in humans — 14-year-old Leonard Thompson was dying from severe diabetes. At the Toronto General Hospital, Banting, Best, Macelod and Collip injected the patient with the extract, which Collip made and purified from an ox pancreas. This resulted in a lowering of Thompson’s blood sugar, a reduction in a 24-hour excretion of glucose and cleared him of other signs of diabetes. The first paper on this discovery was published a month later.

Subsequently, more patients were treated successfully, and a series of clinical trials which followed defined the biological effects of insulin and established guidelines for its use.

Nobel Prize winners

Attempts were later made at mass production of insulin through financing by Connaught Laboratories and Eli Lilly  Company. After much trial and error, the production problem was solved and by February of 1923 there were large reserves of insulin.

The researchers were granted a patent on both insulin and Toronto’s method of making it.

Later in October of 1923, their work would gain Banting and Macleod the Nobel Prize. Banting gave half of his prize money to Best and Macleod gave half of his money to Collip, as much controversy had developed over who was due credit for the investigational work and discoveries.

Significant strides had been made in the utilization of insulin and future progress was yet to come; however, insulin was far from perfected.

Room for improvement

After the discovery of insulin, it was in short supply and beef and pork derivative insulin caused immune reactions, with some people becoming intolerant or resistant.

Additionally, early insulin injections were painful and because they were short acting, they had to be injected several times daily. Insulin was still so impure that after the first insulin injection in Thompson he was left with a 7.5 cm callus at the site of injection on his left buttock. Banting, Best, Macelod and Collip continued to work making insulin safer and more effective by purifying the insulin extract.

Later, in 1936, protamine, a slow-release insulin was developed, which led to development of the first slow-acting insulin — protamine zinc insulin. Then in 1950, a 24-hour insulin capable of being mixed with a fast-acting insulin was produced (neutral protamine Hagedorn). Six years later, the first antidiabetic oral medications (sulfonamide and biguanide derivatives) were on the market.

Eventually, between 1963 and 1966, human insulin was chemically synthesized in several countries. In 1975, a fully synthetic insulin was developed in Basel, Switzerland.

Then, in 1978, scientists from San Francisco produced an insulin with the same amino sequence observed in humans using a genetically altered E. coli bacteria. A few years later 17 participants in England without diabetes received recombinant human insulin.

In 1982, the FDA approved rapid insulin and a neutral protamine Hagedorn insulin in the United States. As technology expanded, so too did the progression of insulin therapy.

Major advances in biotechnology throughout the years allowed for modified insulins and less invasive insulin delivery systems, but the beginnings of the utilization of insulin are rooted firmly in the research and investigations that occurred in the early 1920s. – by Christen Haigh

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