Animal research and diabetes: Now the truth must be told – Part 2

In yesterday’s post we described how animal research contributed to the understanding and treatment of diabetes – most importantly with the discovery of insulin. In this post we address some of the common misinformation that activists are circulating on social media about the role of animal experiments in diabetes research.

a)      One of the most valuable advances in understanding diabetes was made by Dr Moses Barron.

Prior to 1920, many researchers had worked on the relationship between the pancreas (or even more specifically, the islets on Langerhans) and diabetes. Banting and Best were by no means the pioneers in this field.  In the literature review of their February 1922 paper (1), they cited the article of Barron for having inspired their work and allowed them to formulate their hypothesis. They also cited precursor work of Mering & Minkowski, and Sscobolew, amongst many others. Banting and Best made use of groundwork already done before them and used this as support to bring their research to higher heights. This is something very usual in biomedical research, groundbreaking discoveries/advances are never achieved in a nutshell – they all rely on previous precursor work.

b)      Barron explained that his discovery ‘could be made in no other way, not even by experimental ligation of the ducts in animals’

In his November 1920 paper (2), Barron was not speaking about his ‘discovery’. In fact the purpose of the paper (page 1) was to present examples of typical changes in the Islets found in cases of true diabetes together with one histopathology case study of pancreatic lithiasis (formation of stones in the pancreas) and to correlate these findings with those recorded in the literature as obtained in experimental ligation of the ducts in animals.

On page 8 of his paper, while he is describing his 4^th case study,  he describes the lesions of pancreatic lithiasis as ‘by their very nature, being of long standing, presents gradually progressive changes in the parenchyma, that could be obtained in no other way, not even by experimental ligation of the ducts in animals”.  This is indeed true as experimental ligation would bring an abrupt obstruction in the pancreatic duct while the formation of stone (lithiasis) would be something gradual and hence bring progressive changes in the functional parts of the pancreas. This has of course been taken completely out of context by activists.

Animal rights activists also conveniently occlude the statement of Barron on the next page of his paper after he finishes describing the case study, that:  “ The study of this case reveals results that are remarkably similar to those found in experimental ligation of the ducts”. Thus the principle impact of Barron’s work was not providing groundbreaking information, the role of the pancreas and the islets of Langerhans in diabetes was already known by the time he published his 1920 paper, but in providing additional evidence that what had been observed in animal studies was also true in humans, and of course in bringing diabetes to the attention of Banting, whose interest in the field was sparked by reading Barron’s paper.

c)       Diabetes was understood and insulin was applied primarily thanks to human clinical study and autopsy.

Prior to 11 January 1922, most of the work done to understand the mechanism of diabetes was on animals (dogs, cats, rabbits). Human clinical studies of pancreatic extracts in the treatment of diabetes were almost inexistent due to problems observed in the preclinical animal studies, and the few clinical studies that had been attempted in the previous decades produced severe adverse effects that prevented the therapy entering clinical use. Toxic reactions due to impurities in the pancreatic extract prevented its application by Banting, Macleod and Best to humans until January 1922, when a sufficiently pure extract was produced to allow human trials.

As for autopsy, it was apparent decades before the paper of Barron from autopsy/surgical findings that the pancreas might play an important role in diabetes, but it was through animal research that the role was confirmed and mechanism through which the pancreas regulated sugar levels was determined. It was only one chance autopsy that indicated to Barron that it was indeed the islets of Langerhans that played an important role in the disease in humans.  The disease that allowed this observation was very rare, in fact, Barron said that this was the first case of pancreatic lithiarsis that he encountered in a series of several thousand autopsies.

The understanding of diabetes and the role of insulin that allowed the development of insulin therapy was obtained from the interplay between crucial discoveries made through both clinical observation and animal research, so assigning primacy to one or the other is nonsensical.

d)      Claude Bernard had by 1895 experimented on dogs and come to the incorrect conclusion that diabetes had nothing to do with the pancreas.

Claude Bernard (who died in 1878 – more than a decade before the discoveries of Von Merin and Minkowski and the discovery of the first hormones) lived in a time where it was generally accepted that diabetes was a disease of the kidney due to the excessive levels of sugar in the urine. In the mid to late 19^th century, various scientists had been exploring other possibilities to the cause of diabetes, including Bernard who believed that the sugar present in diabetic urine was stored in the liver as glycogen.  In a series of animal studies in the late 1840’s and early 1850’s Bernard made crucial discoveries about the role of the liver in storing and producing glucose.  He also found – correctly – that the central nervous system was involved in controlling blood glucose concentration by working with rabbits, though he believed that this was through a direct nerve communication between the CNS and liver, whereas in fact the conversion of glucose to glycogen in the liver was controlled indirectly via the hormone epinephrine – produced by the adrenal gland – and then insulin (and of course insulin also affects other tissues as well as the liver). So the situation is not that Bernard concluded that diabetes had nothing to do with pancreas, it is merely that he did not explore this avenue, principally because he did not think that it was possible to surgically remove the pancreas without killing the animal being studied. Bernard’s animal research did not provide a complete explanation of how glucose levels are regulated, but it was the starting point for the key discoveries made over the next 70 years, as Professor J. Sjöquist of the Nobel Committee for Physiology or Medicine of the Karolinska Institute noted in his presentation speech for the Nobel Prize in Physiology or Medicine on December 10, 1923.

It is true that the observation by Tidemann and Gmelin in 1827, that starchy foods are under normal conditions transformed into sugar in the intestinal canal and that this is absorbed by the blood, marks an important advance; but really epoch-making was the discovery of the great French physiologist Claude Bernard in 1857 that the liver is an organ that contains a starch-like substance, glycogen, from which sugar is constantly being formed during life; in the words of Claude Bernard, the liver secretes sugar into the blood.

In connection with his investigations into the circumstances that affect the formation of sugar, Claude Bernard observed that in certain lesions of the nervous system the sugar content of the blood was increased and that the sugar passed into the urine of the animals in the experiments. For the first time, therefore, an appearance of sugar in the urine – a glycosuria, though of a transitory nature – was experimentally produced; and consequently this discovery by Claude Bernard may be characterized as the starting-point of a series of experimental researches into the causes and nature of diabetes.”

e)      Macleod and Banting did not discover insulin as it had been identified and named before their experiments.

It was strongly hypothesized that the pancreas and more specifically the islets of Langerhans were producing a substance responsible for controlling blood sugar levels well before 1920 on the basis of animal research and clinical observations. Various names were proposed for this substance, insulin being one of them as this particular name had its Latin root derived from ‘islets’ (Latin: insula,island), but there is a big difference between inventing a name for a hypothetical substance and actually proving it exists and purifying it.

The quest for insulin was the ‘holy grail’ amongst scientists working in this field. Macleod, Banting and their fellow co workers had devised a series of experiments whereby they proved the hypothesis that insulin indeed came from the islets of Langerhans, they managed to produce an extract containing insulin and purify it to a degree that it retained its potency and efficiency in animal testing. They then further purified it to allow clinical testing, with the same positive results. They even refined their techniques to eventually reduce and replace animals that had to be used in the research and managed to produce the insulin in a stable, pure form in commercial quantities – making it available to the general public for diabetes treatment.

Irrespective of the controversy regarding who identified/named insulin, two things must be considered:

i)                    Almost all the scientists working in this field had been using animals as research models.

ii)                   The work of Macleod, Banting and their team was done over a short time (2 years) at the end of which, this resulted in clinical treatment of diabetes .Their Nobel Prize in Medicine/Physiology was amply deserved as they had according to the will of Alfred Nobel, made a discovery during the preceding year, “that conferred the greatest benefit on mankind”.

f)       Use of dogs was not necessary as human tissue was available

The study of diabetes required whole organisms – not just tissue/organ samples. The complex interactions behind production of insulin and its action in the metabolism of carbohydrates as well as the fact that diabetes affects several organ systems in the body made it crucial that whole organisms were studied. In addition insulin could not be obtained from any source other than as an extract from the pancreas, and human pancreases were not available for this purpose.

Dogs were the preferred animal model in the initial studies on diabetes because of their availability, the fact that their anatomy was well understood, hence making surgical techniques more efficient and most importantly, because at the time they began their experiments a large volume of blood needed to be sampled, thus the research animal could not be any smaller.

While in the course of their work, with newer methods being developed to test blood sugar levels in smaller volumes of blood, the team switched to smaller animals (rabbits). In fact, they acknowledge that the development of such techniques allowed their work to be done more precisely and more quickly.

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g)      Synthetic insulin was developed in 1936

Synthetic insulin could not be made until a full understanding of its molecular structure was achieved. Sequencing of insulin was achieved in 1958 ; Chemical synthesis was first achieved in the lab in 1974 and it was only in the 1980s that synthetic insulin made by recombinant DNA technology was made available to the public. Until recombinant insulin became available almost all insulin was obtained from cattle, horses, pigs or fish.

h)      Diabetics owe nothing to animal experimenters.

Diabetics owe everything to animal researchers. The basic understanding of the anatomy and physiological functions of the pancreas was made possible thanks to work on animals. Duct ligations and depancreatisation experiments which gave insights into the functioning of the islets of Langerhans and allowed the isolation of pancreatic extracts containing insulin were made on animals. Although later this stage was deemed unnecessary due to the development of alcohol extraction methods, it provided the key stepping stones to the team to better understand the mechanism and properties of insulin, allowing them to move on to better techniques of obtaining insulin from whole pancreas. The testing of the pancreatic extract containing insulin of various degrees of purity had to be tested first on animals before being considered safe enough for humans. Even today, new insulin analogues need to be tested first on animals for efficacy and toxicity before moving on to human trials.

Research in the field of diabetes is still ongoing nowadays. Scientists are working to find alternative routes of insulin administration either by the oral route or by inhaling. Hopefully, in the near future, insulin injections will be something of the past. Work is being undertaken in the field of pancreatic or islet cell transplantation to cure Type I diabetes, including innovative stem cell based therapies that are being developed through animal research. Newer classes of therapy, including insulin pumps and insulin sensitizers that allow more precise control over blood sugar levels are being developed. All this progress relies on the continuing use of animals in the research.

So tomorrow on World Diabetes Day remember the many millions of lives around the world that have  been saved through animal research conducted by scientists over many decades, and also the thousands of scientists around the world who continue to strive to develop even better therapies – and even cures – for diabetes.

Nada and Paul

1)      Banting F.G. and Best C.H. “The internal secretion of the pancreas.” The journal of Laboratory and Clinical medicine, 1922;Vol VII No 5: 251-266

2)      Barron M. “The relation of the islets of Langerhans to diabetes with special reference to cases of pancreatic lithiasis.” Surg Gynec Obstet 1920;31:437-448.

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