The Nineteenth and the Early Twentieth Century: Discovery of Insulin

Discovery of Insulin

The Story of the Discovery of Insulin: The Young Doctors Collection

The important elements of current understanding of diabetes mellitus can be traced to nineteenth century when modern scientific disciplines, including biochemistry and experimental physiology, acquired prominence in biological studies.

In 1815, Eugene Chevreul in Paris proved that the sugar in urine of individuals with diabetes was glucose.

Von Fehling developed quantitative test for glucose in urine in 1848.

Thus, in the nineteenth century, glucosuria became an accepted diagnostic criterion for diabetes.

Claude Bernard (1813–1878)

Print of ‘Claude Bernard, French physiologist, 1876.’ in Black Frame

Claude Bernard (1813–1878), professor of physiology at Sorbonne University, was one of the most prominent and prolific experimental physiologists in nineteenth-century Europe.

In the course of his work on the physiology of gastrointestinal tract, Bernard developed an experimental operation during which the pancreatic ducts were ligated. Degeneration of the pancreas followed.

This technique proved invaluable for later experiments searching for pancreatic substance which controlled glucose level.

In addition to developing the technique for pancreatic duct ligation, Bernard also discovered that the liver stored glycogen and secreted sugary substance into the blood.

He assumed that it was an excess of this secretion that caused diabetes.

Bernard’s theory of sugar over-secretion leading to diabetes received wide acceptance.

At the same time as researchers were looking for the cause of diabetes, clinicians were further advancing the understanding of diabetes mellitus as a systemic disease with various manifestations and complications.

William Prout (1785–1850) was the first to describe diabetic coma and Wilhelm Petters in 1857 demonstrated the presence of acetone in the urine of patients with diabetes.

Adolf Kussmaul (1822–1902) proposed that acetonemia was the cause of diabetic coma.

Henry Noyes in 1869 described retinopathy in a person with advanced diabetes.

M. Troiser in 1871 observed diabetes in patients with hemochromatosis, naming it “bronze diabetes.”

John Rollo (1749–1809), surgeon general to the British Army, added the term “mellitus” (derived from the Greek word for honey) to “diabetes” in order to distinguish it from diabetes insipidus.

In 1797, Rollo developed a high-protein, low-carbohydrate diet consisting of rancid meats, blood pudding, and mixture of milk and lime water for patients with diabetes.

It has been suggested that he prescribed anorexic agents, such as antimony, digitalis, and opium to suppress appetite in patients with diabetes.

During the years prior to insulin discovery, diabetes treatment mostly consisted of starvation diets. Frederick Allen (1879–1964), a leading American diabetologist of the time, believed that, since diabetes patients could not utilize the food efficiently, limiting the amount of food would improve the disease.

The dietary restriction treatment was harsh and death from starvation was not uncommon in patients with type 1 diabetes on this therapy.

On the other hand, it is easy to understand why outcomes of low-calorie diets were often quite good in patients with Type 2 diabetes.

Discovery of insulin by Frederick Banting and Charles Best was the final step in identifying the substance whose deficiency had been identified to be responsible for development of diabetes.

This milestone, however, was preceded by a number of earlier significant advances.

Oscar Minkowski (1858–1931) and Joseph von Mering (1849–1908),

From Bird Ponds To Monsters: A History of Diabetes

Oscar Minkowski (1858–1931) and Joseph von Mering (1849–1908), working in Strasbourg in 1889, observed that the dogs whose pancreas was removed developed severe thirst, excessive urination, and weight loss with increased appetite.

Minkowski, suspecting that such symptoms were caused by diabetes, tested the urine of these dogs and found glucose.

Since Minkowski was working in the laboratory of Bernard Naunyn (1839–1925), who was interested in carbohydrate metabolism and was a leading authority on diabetes at the time,

Minkowski’s research received enthusiastic endorsement by Naunyn.

Work on pancreatic extraction ensued, but the investigators were not able to obtain presumed antidiabetic substance.

They suspected that digestive juices produced by pancreas might have interfered with their ability to purify this substance.

To prove that the absence of exocrine pancreatic secretion was not related to the development of diabetes, they ligated dog’s pancreatic duct.

This procedure led to the development of digestive problems but not the diabetes.

In 1893 a very important contribution was made by French investigator Edouard Hedon (1863–1933) in Montpellier, who showed that the total pancreatectomy was necessary for the development of diabetes.

After removing the pancreas, he grafted a small piece of it under the skin.

No evidence of diabetes in experimental animals was present at this stage.

However, removal of the graft caused the symptoms of diabetes to develop immediately.

Similar results were independently obtained by Minkowski.

It was becoming clear that the internal secretion of the pancreas was pivotal to the pathogenesis of diabetes mellitus.

In 1893, French scientist Gustave–Edouard Laguesse (1861–1927) suggested that tiny islands of pancreatic tissue described in 1869 by Paul Langerhans might be the source of the substance involved in blood glucose control.

Paul Langerhans (1847–1888)

The Structure and Metabolism of the Pancreatic Islets: A Centennial of Paul Langerhans’ Discovery (Wenner-Gren Center international symposium series)

Paul Langerhans (1847–1888), distinguished German pathologist, was a student of Rudolf Virchow.

In his doctoral thesis, at the age of 22, he described small groupings of pancreatic cells that were not drained by pancreatic ducts.

In 1909, the Belgian physician Jean de Mayer named the presumed substance produced by the islets of Langerhans “insulin.”

A number of researchers worked on isolating the active component of internal pancreatic secretion.

In 1902, John Rennie and Thomas Fraser in Aberdeen, Scotland, extracted a substance from the endocrine pancreas of codfish (Gadus callurious) whose endocrine and exocrine pancreata are anatomically separate.

They injected the extract into the dog that soon died, presumably from severe hypoglycemia.

In 1907, Georg Ludwig Zuelzer (1870–1949), a German physician, removed pancreas from the dog and then injected the dog with pancreatic extract.

His experiments resulted in lowered amount of glucosuria and raised blood pH.

Zuelzer patented the extract in the United States under the name “acomatol.”

In 1908, he used it successfully to rescue a comatose diabetic patient, but, owing to likely contamination of the extract by other substances, the treatment produced severe complications and led to withdrawal of further funding of Zuelzer’s work by Schering.

Zuelzer continued his investigations, however, and developed a new extract .

The new extract produced convulsive reaction, most likely caused by hypoglycemia.

Nicolas Constantin Paulesco (1869–1931), professor of Physiology at Bucharest University in Romania, was also involved in research on pancreatic extracts.

In 1916 in the course of his first experiment, he injected the diabetic dog with the pancreatic extract.

The injection resulted in the death of the animal with symptoms of hypoglycemia.

During the experiment, dog’s blood glucose fell from 140 to 26 mg%.

Because of World War I, Paulesco did not publish the report of his experiments until 1921.
Frederick Grant Banting (1891–1941)

Print of ‘Frederick Grant Banting (1891-1941), Canadian physiologist, 1923.’ in Black Frame

Frederick Grant Banting (1891–1941) was a young (and not very successful) orthopedic surgeon when he developed interest in diabetes.

A war veteran, wounded in France in 1918, he was decorated with Military Cross for heroism.

After returning from Europe, he briefly practiced orthopedic surgery and then took the position as a demonstrator in Physiology at the University of Western Ontario, Canada.

Banting had become deeply interested in diabetes.

The work of Naunyn, Minkowski, Opie, Schafer, and others had indicated that diabetes was caused by lack of a protein hormone secreted by the islands of Langerhans in the pancreas.

To this hormone Schafer had given the name insulin, and it was supposed that insulin controls the metabolism of sugar, so that lack of it results in the accumulation of sugar in the blood and the excretion of the excess of sugar in the urine.

Attempts to supply the missing insulin by feeding patients with fresh pancreas, or extracts of it, had failed, presumably because the protein insulin in these had been destroyed by the proteolytic enzyme of the pancreas.

The problem, therefore, was how to extract insulin from the pancreas before it had been thus destroyed.

While he was considering this problem, Banting read in a medical journal an article by Moses Baron, which pointed out that, when the pancreatic duct was experimentally closed by ligatures, the cells of the pancreas which secrete trypsin degenerate, but that the islands of Langerhans remain intact.

This suggested to Banting the idea that ligation of the pancreatic duct would, by destroying the cells which secrete trypsin, avoid the destruction of the insulin, so that, after sufficient time had been allowed for the degeneration of the trypsin-secreting cells, insulin might be extracted from the intact islands of Langerhans.

Determined to investigate this possibility, Banting discussed it with various people, among whom was J.J.R. Macleod,

Banting approached John J.R. MacLeod, professor of Physiology at the University of Toronto, who agreed to provide Banting with limited space in his laboratory for the eight-week summer period in 1921.

Charles Best (1899–1978)

Print of ‘Charles Herbert Best, Canadian physiologist, 1960.’ in Black Frame

McLeod assigned a physiology student Charles Best (1899–1978) to assist Banting with the experiments (Best apparently won the opportunity to work alongside Banting on the toss of coin with another student).

In July 1921, after initial delays caused by insufficient ligature of the pancreatic ducts,

Banting and Best were able to harvest atrophied pancreatic glands from dogs, chop them up, grind the tissue in the mortar, strain the solution, and inject the extract into the vein of pancreatectomized (diabetic) dog.

When it was clear that the dog’s condition improved, they proceeded to repeat the experiments with other diabetic dogs, with similar dramatic results.

They also experimented with fresh pancreata, fetal calf pancreata, and different routes of administration (rectal, subcutaneous, and intravenous).

At the end of 1921, biochemist James Collip joined the team of Banting and Best and was instrumental in developing better extraction and purification techniques.

First report of successful animal experiments with Banting’s pancreatic extracts was presented at Physiological Journal Club of Toronto on November 14, 1921 and American Physiological Society later that year.

On January 11, 1922, Banting and Best injected Leonard Thompson, a 14-year old boy being treated for diabetes at Toronto General Hospital, with their extract.

At the time Thompson’s weight was only 64 lb. After having 15 cm3 of “thick brown” substance injected into the buttocks, Thompson became acutely ill upon developing abscesses at the injection sites.

Second injection, using a much improved preparation made with Collip’s method, followed on January 23.

This time the patient’s blood glucose fell from 520 to 120 mg/dl within about 24 h and urinary ketones disappeared.

Thompson received ongoing therapy and lived for another 13 years but died of pneumonia at the age of 27.

On May 3, 1922, McLeod presented results of Toronto group’s research to the Association of American Physicians and received standing ovation. Banting and Best were not present at the meeting.

In 1923, the Nobel Prize was awarded for discovery of insulin

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In 1923, the Nobel Prize was awarded for discovery of insulin, but only to Banting and MacLeod, who shared their portions of the prize with Best and Collip, respectively.

The new proposed antidiabetic substance was named by Banting “isletin.”

The name was later changed by MacLeod to “insulin.”

MacLeod apparently did not know that this name had already been coined by de Mayer in 1909.

Later, Banting and Best fully acknowledged this fact.

In April 1922, Banting and Best accepted the offer by Eli Lilly Company to work on purification and largescale commercial production of insulin.

The Board of Governors of the University of Toronto and Eli Lilly signed the agreement, providing that Lilly would pay royalties to the University of Toronto to support research in exchange for manufacturing rights for North and South America.

The announcement of insulin discovery was greeted with tremendous enthusiasm around the world.  Previously doomed patients were getting the new lease on life.

Indeed, Ted Ryder, one of the first four children to receive insulin in 1922 in Toronto, died at the age of 76 in 1993.

Over the years, insulin purification methods improved and new insulin formulations were developed. Protamine–zinc insulin, a long-acting insulin, was introduced in the 1930s; Neutral Protamine Hagedorn (NPH) was introduced in the 1940s; and Lente series of insulin in the 1950s.

Among the people who first witnessed the introduction of insulin into clinical use was a Portuguese physician Ernesto Roma, who was visiting Boston shortly after insulin became available.

Upon returning to Portugal he founded the world’s first organization for people with diabetes – the Portuguese Association for Protection of Poor Diabetics.

The association provided insulin free of charge to the poor.

Living with Non-insulin Dependent Diabetes: Handbook of the British Diabetic Association

Subsequently, the British Diabetic Association was founded in 1934 by Robin Lawrence, a physician with diabetes whose life was saved by insulin, and the writer H.G. Wells, who had diabetes.

A few years later, at a meeting of the American College of Physicians in 1937, a small group of doctors with interest in diabetes met for lunch.

They felt that diabetes management was inadequately covered at regular meetings.

They realized a need of a platform to share their experiences.

After two years of deliberations, in April 2, 1940, delegates from local societies in the United States met and founded the National Diabetes Association.

Both the first president of the association Dr. Cecil Striker and the vice-president Dr. Herman O. Mosenthal were very instrumental in the founding of the association.

Subsequently, as per Dr. Mosenthal’s suggestion, the association was renamed American Diabetes Association to include the Canadian doctors, there being no such association in Canada at the time as well as to pay homage to the country where insulin was discovered.

Nordisk Insulin Company

Principles of Diabetes Mellitus

In 1922, August Krogh of Denmark, winner of the Nobel Prize for his studies of capillaries, was lecturing in the United States, accompanied by his wife Marie, who had recently been diagnosed with diabetes. Krogh and his wife were informed by famous diabetologist of the time Eliot P. Joslin about new diabetes treatment developed in Toronto by Banting’s group.

Marie and August Krogh decided to visit Toronto and stayed as John McLeod’s guests.

After return to Denmark, Krogh, with H.C. Hagedorn, founded Nordisk Insulin Company, a not-for-profit concern that, together with Novo Company, was responsible for making Denmark the main insulin-producing country outside of the United States.

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