INSULIN for DIABETES

In 1778, Thomas Cawley revealed from an autopsy study of human diabetic patients that diabetes may result from damage to the pancreas(1).

In the 1880s, von Mering was working on fat absorption when Minkowski suggested to him the removal of the pancreas of a dog. Neither thought of diabetes until a dog continuously urinated and they found it contained 10% sugar. An assistant claimed "the relationship between diabetes to the pancreas owes its discovery to the play of chance"(2) - preceded by Cawley, clinically and deliberately, over 100 years earlier. Others followed and tried inducing diabetes experimentally by either tying off or removing part or all of the pancreas of dogs.

Zeulzer, in the early 1900s, injected pancreatic extract into rabbits(3) and into 2 dogs which had been depancreatised - in which the sugar levels fell. In 1907, he injected his extract into human diabetics, who vomited, had high fevers, and convulsions(4).

Meanwhile Hougouneq and Doyon fed dogs with pancreatic extracts - which failed to work(5).

But there were clinical successes. On 12 Jan 1908, Dr Crofton of Wisbech, Cambs, England, gave a pancreatic extract by capsule (which was insoluble in the stomach) to a 13 year old female diabetic human patient. Her weight slowly increased and a year later Crofton reported that "She is excellent health"(6). A problem solved, a clinical success - where animal experimenters had failed. Crofton treated further clinical cases.

MacKenzie Wallis served in India in 1916, 1917, and 1918, and had the opportunity of observing cases of mild diabetes. After working on the problem for 10 years, he wrote "The use of alcohol as an extractive has been proposed for a very long time and tried by various workers for this purpose, without success". So Wallis used chemical methods and hydrochloric acid to prepare an extract, and tested by in vitro methods - not in animals. He wrote "The use of rabbits suggested itself, but was given up for the following reasons. A large number of laboratory rabbits showed variations in normal blood-sugar... Rabbits which had received an injection of any kind a week previously often showed a very low blood-sugar. Rabbits did not serve the purpose and as dogs could not be used the [animal] experimental method of investigation had to be given up. All the extract was prepared in the same way and tested chemically"(7).

Frederick Banting and Charles Best, in Toronto, began experimenting with dogs in 1921, tying off the pancreas to make extracts which they injected into other depancreatised dogs. After six weeks, 14 out of 19 dogs used had died(8). At the end of 1921, James Collip joined the Toronto team. He measured the blood sugar levels in rabbits given pancreatic extracts and noticed blood sugar levels fell(9). Banting and Best went on to use pancreas of cattle to produce extracts which they tested on dogs - amongst which was one named "Majorie"(10).

In January 1922, MacKenzie Wallis`s extract was first given by mouth - which worked. He treated other patients at St Bartholomew`s Hospital, London, including a patient in a diabetic coma, who was given his extract by injection - which worked(11).

On 11 January 1922, Leonard Thompson, a 14 year old boy, was injected with Banting and Best`s dog-tested insulin - it failed(12). Banting wrote: "These results were not as encouraging as Zeulzer`s"(13) and Collip said that their extract was "useless for continued administration to the human subject"(14). On 27 Jan, "Marjorie", the dog which had received more pancreatic extract injections than any other dog, was killed. Autopsy showed a nodule of pancreas was still inside her - she was not totally depancreatised(15).

In March 1922, Collip "lost" his method for producing extracts. In his search for a "new" method, he abandoned alcohol - as used by Zeulzer and himself - as an extractive and turned to acetone. He then tested new extracts on rabbits(15).

On 15 May 1922, Dr Joe Gilchrist was injected with Collip`s new rabbit-tested extract - it worked(15) - but this was not a "benefit" of animal experiments.

NB:

* Banting was preceded by Crofton, who wrote in Lancet "The Toronto workers can-not claim priority of the idea to produce a pancreatic extract containing the internal secretion alone"(16).

* Hedon had found in 1893 that only complete removal of the pancreas made a dog a "model" of diabetes - but Banting and Best`s dog, "Marjorie", had a piece of pancreas left behind - so by vivisector`s rules, she was not "diabetic"(17).

* Dog experiments were never used by Crofton and rejected by MacKenzie Wallis - who both succeded whereas dog-tested extracts used by Banting and Best failed.

* Collip used alcohol for his early extracts (as had Zeulzer - which failed) but Wallis had rejected alcohol and succeeded.

* Collip`s rabbit tests were criticized by Banting, Best and Gilchrist who wrote "There is a great variation in the reaction of normal rabbits to insulin. This variability is very noticeable in [hu]man[s] and dogs. There is only slight co- relation between the relative lowerings of blood sugar in rabbits and in [hu]man[s] with various lots of insulin"(18).

refs

1. Medical History. 1972.

2. Bulletin of Medical History. 1954.

3. Bliss,M. The Discovery of Insulin. Paul Harris Pub. 1983.

4. J of History of Medicine. 1956.

5. Hoskins,RG. Endocrinology. Kegan Paul, Trench, Trubner & Co. 1941

6. Crofton. Lancet. 27 Feb 1909.

7. MacKenzie Wallis. Qtr J Med. 1922.

8. Bliss,M. The Discovery of Insulin. Paul Harris Pub. 1983.

9. J of History of Medicine. 1954.

10. Bliss,M. The Discovery of Insulin. Paul Harris Pub. 1983.

11. MacKenzie Wallis. Lancet. 2 Dec 1922.

12. Bliss,M. The Discovery of Insulin. Paul Harris Pub. 1983.

13. Banting,F. quoted in ibid.

14. Collip,J. quoted in ibid.

15. Bliss,M. The Discovery of Insulin. Paul Harris Pub. 1983.

16. Crofton. Lancet. 2 Dec 1922.

17. Bliss,M. The Discovery of Insulin. Paul Harris Pub. 1983.

18. Banting,F et al. American J of Physiology. 1923.