CME INDIA Presentation by Admin.

Everything begins with an idea – Earl Nightingale.

Insulin’s centenary year appears to be 2020 if you appreciate the birth of an idea.

Is Oct 31, 1920, an appropriate date for tribute, if so let us reverberate it now. November 14 is the World Diabetes Day and this month is so precious – Robert A Hegele, Grant M Maltman.

At 2:00 h on Oct 31, 1920, Frederick G Banting, a surgeon practicing in London, ON, Canada, conceived an idea to isolate the internal secretion of the pancreas.

Consideration to commemorate insulin’s centenary

May 17, 1921,

• Frederick G Banting and Charles H Best (under the supervision of John J R Macleod) commenced preclinical studies at the University of Toronto, Toronto, ON, Canada.

Aug 3, 1921

• Banting and Best’s crude extracts from the pancreas of a dog first showed activity in reducing hyperglycaemia in a pancreatectomised dog.

Jan 23, 1922

• Leonard Thompson, a 14-year-old patient with type 1 diabetes at Toronto General Hospital, Toronto received the first dose

The Discovery of Insulin

We recount the events before and after the morning of Oct 31, 1920, which transformed the field of endocrinology.

Frederick Grant Banting

• Born on Nov 14, 1891, in Alliston, ON, Canada, a village 70 km north of Toronto,
• In 1912, he was transferred to the Faculty of Medicine and chose surgery as his specialty.
• His classmate was Norman Bethune, who later served in Mao Zedong’s army and helped to reform medical care in China – Having already enlisted for service in World War 1.
• Banting completed his accelerated medical degree in December, 1916, and reported for duty as medical officer in the Canadian Army Medical Corps. Arriving in England in spring 1917.
• Returned to Canada in early 1919.
• Banting worked at the Toronto Military Orthopaedic Hospital, Toronto.
• Started his own practice but business was slow from the outset, he cared for an average of two patients per month.

Why 1920, October 30 is memorable? EUREKA MOMENTS

• An idea can change life.
• Oct 30, 1920, Banting dropped by the medical school library to review journals in preparation for his lecture on the pancreas.
• He noted an article of interest in his copy of the November issue of Surgery, Gynaecology and Obstetrics. When he saw an article by Moses Barron of the University of Minnesota, Minneapolis and Saint Paul, MN, USA.
• Barron had published four case reports; a stone blocked the pancreatic duct, leading to atrophy of the exocrine pancreas, but preserving the islets of Langerhans.
• The patient did not develop diabetes.
• Banting read it with great interest. After reading this article, Banting seemingly had a so-called eureka moment.
• Banting later wrote “It was one of those nights when I was disturbed and could not sleep. I thought about the lecture and about the article…Finally about two in the morning after the lecture and article had been chasing each other through my mind for some time, the idea occurred to me. I got up and wrote down the idea and spent most of the night thinking about it.”

The original entry of “Oct 30/20”: “Diabetus” by Banting

• Ligate pancreatic duct of dog.
• Keep dogs alive till acini degenerate leaving Islets.
• Try to isolate internal secretion of these to relieve glycosurea.
• The spelling errors are ironic but are characteristic of Banting’s personal writings.

Banting to pitch his idea to Macleod

• Miller and his colleagues at Western University persuaded Banting to pitch his idea to Macleod who worked at the University of Toronto.
• On Nov 8, 1920.2,7–9 Macleod heard the idea. Initially, after hearing Banting’s idea regarding pancreatic duct ligation, Macleod was skeptical.
• 400 previous attempts to treat patients with diabetes by use of pancreatic extracts, proved a futile approach.
• The concept of a pancreatic internal secretion was at least 30 years old.
• In 1890, Josef Freiherr von Mering and Oskar Minkowski (Strasbourg, Germany) reported a dog that survived a total pancreatectomy. Surprisingly, the dog developed polyuria, caused by glycosuria from hyperglycaemia, implicating the pancreas in diabetes.
• Between 1905 and 1920 the accepted wisdom was that impurities were inextricably linked to the pancreas.
• Macleod showed that islets were the source of insulin, although in quantities that were insufficient to be commercially viable.
• Despite reservations, Macleod eventually agreed to allow Banting, a battlefield surgeon with minimal research experience, to enter as a volunteer in his laboratory.
• Banting again met with Macleod on May 17, 1921, to begin the project. They were joined by an undergraduate student assistant, Charles Herbert Best, who either won or lost a coin toss with another student to work with Banting over the summer.
• Macleod also outlined a preparation method for the pancreatic extracts, assisted on the first operation, and oversaw the experiments. A month later, Macleod departed for a vacation in Scotland but kept in touch with the young researchers over the summer.

On Aug 3, 1921 History met a turning point

• It is interesting to know that the Lab condition was pathetic, where Insulin was discovered – Enduring sweltering heat/Poor conditions./Repeated setbacks/An animal mortality rate of 70%.
• Banting and Best began an experiment that eventually showed that their extract, which was administered four times over four days, reduced glucose and improved the status of a dog with diabetes. They called this preparation isletin, which was later renamed insulin.
• Banting wrote to Macleod of their findings on Aug 9, 1921.
• Over this time, Best provided both technical and psychological support for the volatile Banting.
• The results were sufficiently promising.
• Macleod then tried to take the credit, it is a well known fact.
• Macleod recounted that he had gone out of his way to consistently acknowledge Banting. Macleod honoured Banting’s request to invite James Bertram Collip into the project to help purify the crude extract.

Collip not to be forgotten

• On Jan 23, 1922, Collip’s isolate substantially improved the status of Leonard Thompson, a 14-year-old patient with type 1 diabetes.
• Banting and Best’s preparation had caused only sterile abscesses in the same patient.
• The use of insulin in patients was soon published with clinician co-authors.
• The substantial effects of insulin profoundly affected the general public and international diabetologists, such as Elliott Joslin who later wrote-“By Christmas of 1922 I had witnessed so many near resurrections that I realized I was seeing enacted before my very eyes Ezekiel’s vision of the valley of dry bones.”
• The first US patent application for insulin was filed in the names of Collip and Best on June 3, 1922.
• In the autumn of 1922, George Walden, an Eli Lilly scientist, used isoelectric precipitation to drastically increase both the purity and yield of insulin.

The Final Twist

• Furthermore, in November, 1922 Danish Nobel Prize winner August Krogh visited Macleod’s laboratory.
• After meeting the principal investigators personally, Krogh wrote nomination letters to the Nobel Prize committee.
• Krogh received approval from the University of Toronto to produce insulin in Denmark at the Nordisk Insulinlabatorium, which he founded and later became Novo Nordisk.
• The climax event occurred on Oct 25, 1923, when the Karolinska Institute awarded the Nobel Prize in Physiology or Medicine to Banting and Macleod for the discovery of insulin.

Considering all four scientists for Nobel Prize?

• Banting with Best and Macleod with Collip. All four individuals made essential contributions.
• Other diabetes researchers contested the decision to award the prize to the Toronto researchers but were unconvinced.
• History now judges that, if only two of the scientists could be recognised, Krogh’s initial case for Banting and Macleod was appropriate.
• Still, there are disagreements in the scientific world and an argument could be made that all four should have been co-recipients.
• Ultimately, the prize mainly acknowledged the importance of insulin’s discovery.
• Banting is the youngest recipient of the Nobel Prize in Physiology or Medicine.
• Collip grew into a person of great importance in endocrinology, having isolated parathyroid hormone, thyroid stimulating hormone, and follicle stimulating hormone, among other hormones.

CME INDIA Tail Piece

Banting’s original idea was physiologically flawed.

• Unique Fact: There was no need to ligate the pancreatic duct to preserve the β cells or insulin. Although trypsinogen, the precursor of trypsin, is resident in the acinar cells, it does not directly possess digestive capacity until it becomes activated in the intestinal lumen
• Neither Banting nor Macleod realised this fact at first.
• Banting and Best eventually found that whole fresh pancreas, non-duct ligated, could serve as the source of insulin.

Further Reading

Lancet Diabetes Endocrinol 2020. Published Online October 29, 2020 .https://doi.org/10.1016/ S2213-8587(20)30337-5

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