DIVISION 1: HISTORY AND EPIDEMIOLOGY: History of DiabetesCHAPTER 1
The history of diabetes has its roots in the Vedic literature of Indian medicine in its mythological epics. The first description has been given in Shiv Puran and Shrimad Bhagwat with a reference to the destruction of “Yagyan” by the followers and disciples of Lord Shiva. Daksha Prajapati (father-in-law of Lord Shiva) organized a “Yagyan” in which he did not invite Lord Shiva. However when his wife “Sati” reached her father's house, she did not find a respectable position in mandap for her husband (Shiva) and she felt humiliated and committed suicide. When the followers of Lord Shiva got the news of death of Sati they reached the “Yagyan” site and destroyed the Yagyan, consumed all the offerings which consisted of “ghee, sugar, barley, high caloric nuts”, etc.1,2
Ever since then the diabetes became a disease of all those people who do not observe ethics, values and consume high caloric fatty diet which is meant for Yagyan and do not observe ritual and virtue of any such Yagyan.
Charak Samhita (2000 BC conceived and re-published 100 AD) (Fig. 1), the first authentic ayurvedic text, describes diabetes as Prameha which is a urinary disorder and present in different 20 forms. Madhumeha is one of the ultimate complications of the all types of Prameha. Some of these Prameha are in the form of passage of formed elements of blood, chyle, bone marrow, semen, pus, and other content which are quite abstract in consistency and do not exist in true clinical form to be separated from each other by the modern physiological and biological description.3
Sushruta (Fig. 2) who practiced surgery in the city of Varanasi during 750–500 BC has also given the description about Prameha, which could be due to vitiation of Kapha with different food items which are consumed with altered lifestyle and can lead to Prameha.
The ayurvedic physicians in India were able to treat and manage diabetes with lifestyle modification, observing strict avoidance of high carbohydrate diet, addition of fiber diet to retard the absorption of sugar from intestine and to reduce obesity. During the period of mediaeval history, Vagbhata and Jeevak in association with many Chinese and Tibetan travelers documented many herbs, leaves and fruits having sour taste and many spices which decreased appetite, reduced polyuria and could take care of “Madhumeha”.
DIABETES MELLITUS AND THE ISLETS OF LANGERHANS
The Egyptians made the first mention of diabetes around 1500 BC. The Greek physician Aretaeus (130–200 CE) noted a disease with symptoms of constant thirst, excessive urination and loss of weight, and named the condition “diabetes”, meaning “flowing through”. The first clear reference to diabetes was made by an Arab physician, Avicenna (980–1037 CE), who accurately described in detail the clinical features and complications of the disease and its progress.4
The term “diabetes” meaning “to pass through” was used first by the Greek physician Apollonius of Memphis around 230 BC (Greek: dia= through, betes= to go) who along with his contemporaries considered diabetes as a renal disease and recommended ineffective treatments through bloodletting and dehydration. The recognition of diabetes in ancient India can be traced to thousands of years, with its earliest description present in the Atharvaveda, a sacred religious text of knowledge dating around 1500-100BC.
Way back in 1552 CE, the primeval evidence of diabetes emerges from Egyptian manuscripts,5 notably the Ebers papyrus excavated from an ancient grave in Thebes, Egypt where Hesy-Ra, an Egyptian physician first documented frequent urination “too great emptying of urine” as a symptom of a mysterious disease that also caused emaciation.
The term “mellitus” meaning “sweet like honey” was added much later in the by the British Surgeon-General John Rollo in 1798, to separate its identity from diabetes insipidus which also presented with frequent urination but urine in insipidus was tasteless and not sweet.
Though there was mention of similar conditions elsewhere such as by the Unani physician Buqrat in 460 BC who wrote about a mysterious condition with signs and symptoms of excessive urine flow and wasting of the body, the first comprehensive clinical description of diabetes dates to 150 AD when the Greek physician Aretaeus of Cappadocia, practising in Rome and Alexandria, described “the melting down of flesh and limbs into urine” noting the excessive passage of urine through the kidneys. He coined the word diabetes (meaning “siphon” in Greek) dramatically stating that “…no essential part of the drink is absorbed by the body while great masses of the flesh are liquefied into urine.” Though he did attempt to treat it, he documented its poor prognosis, describing that “life (with diabetes) is short, disgusting and painful”. Galen (131-201 AD), another roman physician also reported similar observations on diabetes, and felt it was a rare affliction.
It was in 1425 that diabetes first finds its mention in English language as the middle English word “diabete”. The swiss physician Phillipus Aureolus Paracelsus, often regarded as the ‘ Martin Luther King of Medicine’ in the 16th century identified diabetes as a serious general disorder. It was in 1674 that Professor Thomas Willis from Oxford University described the “wonderfully sweet’ flavour of urine in diabetes mellitus in his treatise Pharmaceutice rationalis. The English physician Matthew Dobson of Liverpool in 1776 measured glucose concentration in urine and showed that it was much increased in patients of diabetes.
It is possible that the sweet taste of the urine in this disease had been noticed by the physician of ancient India, but in modern times this fact was rediscovered by Willis. It may be mentioned that 24 years before Willis observation, there is a reference to the sweet taste of some urine in Moliére's play Le Médecin volant (1650). Reference has been already been made to the differentiation between the urine of diabetes mellitus and that of diabetes insipidus. The proof that the sweet taste of the urine in true diabetes is due to sugar was given in 1776 by Matthew Dobson (1745–1784) of Liverpool, who demonstrated that the residue after evaporation of such urine underwent vinous and acetic fermentation. Dobson made the further important observation that the blood serum in true diabetes also has a sweet taste and he was thus the discoverer of hyperglycemia. That the sugar in diabetic urine is glucose was first shown in 1815 by Michel Eugène Chevreul. Chevreul, one of the great French chemist and a pioneer in the chemistry of the animal fats and vegetable dyes was still as a centenarian carrying out important research; he was also director of the famous Gobelins tapestry works.
Recognition of the association between the pancreas and true diabetes came comparatively late. In 1778, Thomas Cawley, about whom practically nothing was known, reported a case of diabetes in which there were numerous calculi in the pancreas. Richard Bright reported morbid changes in the pancreas in such case in 1831, von Recklinghausen described the presence of calculi in 1864 and Frerichs stated in 1884 that 20% of his cases of diabetes showed gross changes in the pancreas. Meanwhile Claude Bernard had been carrying out his important experiments on glycosuria.
In an inaugural dissertation published at Berlin in 1869, Paul Langerhans (1847–1988) (Fig. 3) first described the islet of tissue scattered through the pancreas which were histologically distinct form and had no direct connection with the glandular tissue proper. The name of Langerhans was attached to these islet by Gustave Édouard Laguesse (1861–1927) of Lille in 1893, and by this name they have since then been known. Meanwhile, the crucial experiment showing that of diabetes is due to a lesion in the pancreas was made by Joseph von Mering (1849–1908) and Oscar Murkowski, then both at Strasbourg. In 1889 they excised the pancreas in animal and thus produced rapidly fatal diabetes. They also showed that the production of this condition was not due to the loss of the flow of pancreatic juice to the bowel. The conclusion was that the pancreas not only secretes the pancreatic juice, but that some part of it was also closely associated with general metabolism. These experiments were confirmed by Laguesse, who in 1893 suggested that the islets of Langerhans produced an internal secretion. In 1900 Eugene Lindsay Opie, then at Johns Hopkins, but later at St. Louis and the Henry Phipps Institute at Philadelphia, showed that in many cases of diabetes the islet have undergone hyaline degeneration. Other pathological changes in the islet have since been recorded, and a clear statement of the relation between lesion in this tissue and glycosuria was made by WG MacCallum in 1909.6
Many attempts were now made to isolate the active principle of the islet, but the difficulties were very great, since the trypsin destroy the internal secretion. It may be said retrospectively that there is no doubt that partial success was achieved in 1908 by Georg Ludwig Zuelzer (1870–1949) of Berlin. Zuelzer succeeded in obtaining a pancreatic extract which was given to eight diabetics with good results. Unfortunately, symptoms later developed which were regarded at the time as toxic, and this important work was abandoned. Eighteen years later, when more was known about the action of the hormone, it was suggested that the supposed “toxic” symptom had really been due to hypoglycemia, resulting from too large or too prolonged doses of a remedy which was successful.
In 1910, Edward Albert Sharpey- Schafer hypothesised that deficiency of a single chemical produced from pancreas lead to development of diabetes, and he called it “insulin”, derived from the Latin word insula meaning island, referring to the islet cells of Langerhans.7
Towards the end of the 19th century, a quantitative blood sugar method was published which used copper reduction and gravimetric measurement. Stanley Benedict devised an improved copper reagent for urine sugar in 1908, and this became, with modifications, the mainstay of urine monitoring of diabetes for over 50 years. Leading specialists in diabetes, notably Elliott Joslin in the USA, advocated a self-management concept relating to diet, exercise and frequent urine testing in an attempt to keep the urine sugar-free. In 1913, Frederick Allen, a leading United States diabetologist, identified a clinical need to develop an accurate method for the quantitation of blood sugar for diagnostic purposes. In the first two decades of the 20th century Bang, Folin, Lewis, Benedict, Shaffer and many others pioneered laboratory methods for quantitative blood sugar. Proteins were removed and the reduction of cupric salts, ferricyanide or picrate used with titrimetric or, more often, colorimetric endpoints. Despite continual improvements in reducing sample volume, improving color stability and precision, manual blood sugar estimations in the laboratory were limited and mainly confined to diagnosis and critical care management, rather than for monitoring purposes. A breakthrough in the treatment and improvement in the lives of diabetics came about in 1921 when Frederick G Banting, his assistant, Charles Best, and JR Macleod succeeded in the identification of insulin, the pancreatic hormone deficient in diabetes, which was confirmed in human studies. Large-scale commercial extraction and purification of animal insulin led the way to the treatment for diabetes and to the development of improved testing systems.8
Frederick Grant Banting (Fig. 4) was born on November 14, 1891, at Alliston, Ontario, Canada. He was the youngest of children of William Thompson Banting and Margaret Grant, educated at the Public and High Schools at Alliston, he later went to the University of Toronto to study divinity, but soon transferred to the study of medicine. In 1916 he took his MB degree and joined the Canadian Army Medical Corps, and served, during the First World War in France. In 1918 he was wounded in the Battle of Cambrai, and in 1919 he was awarded the Military Cross for heroism under fire. When the war ended in 1919, Banting returned to Canada and was for a short time a medical practitioner at London, Ontario. He studied orthopedic medicine during the year 1919–1920, Resident Surgeon at the Hospital for Sick Children, Toronto. From 1920 until 1921 he did part-time teaching in orthopedics at the University of Western Ontario at London, Canada, besides his general practice, and from 1921 until 1922 he was Lecturer in Pharmacology at the University of Toronto. In 1922 he was awarded his MD degree, together with a gold medal. Earlier, however, 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 JJR Macleod, Professor of Physiology at the University of Toronto, and Macleod gave him facilities for experimental work upon it. Dr Charles Best (Fig. 5), then a medical student, was appointed as Banting's assistant, and together, Banting and Best started the work which was to lead to the discovery of insulin.
In 1922 Banting had been appointed senior demon-strator in medicine at the University of Toronto, and in 1923 he was elected to the Banting and Best Chair of Medical Research, which had been endowed by the Legislature of the Province of Ontario. He was also appointed Honorary Consulting Physician to the Toronto General Hospital, the Hospital for Sick Children, and the Toronto Western Hospital. In the Banting and Best Institute, Banting dealt with the problems of silicosis, cancer, the mechanism of drowning and how to counteract it. During the Second World War, he became greatly interested in problems connected with flight.
In addition to his medical degree, Banting also obtained, in 1923, the LLD degree (Queens) and the DSc degree (Toronto). Prior to the award of the Nobel Prize in Physiology or Medicine for 1923, which he shared with Macleod, he received the Reeve Prize of the University of Toronto (1922). In 1923, the Canadian Parliament granted him a Life Annuity of $7,500. In 1928 Banting gave the Cameron Lecture in Edinburgh. He was appointed member of numerous medical academies and societies in his country and abroad, including the British and American Physiological Societies, and the American Pharmacological Society. He was knighted in 1934.9
DISCOVERY OF INSULIN
Before the discovery of insulin, diabetes was a feared disease that most certainly led to death. Doctors knew that sugar worsened the condition of diabetic patients and that the most effective treatment was to put the patients on very strict diets where sugar intake was kept to a minimum. At best, this treatment could buy patients a few extra years, but it never saved them. In some cases, the harsh diets even caused patients to die of starvation. During the 19th century, observations of patients who died of diabetes often showed that the pancreas was damaged. In 1869, a German medical student, Paul Langerhans, found that within the pancreatic tissue that produces digestive juices there were clusters of cells whose function was unknown. Some of these cells were eventually shown to be the insulin-producing beta cells. Later, in honor of the person who discovered them, the cell clusters were named the islets of Langerhans. In 1889 in Germany, Physiologist Oskar Minkowski and Physician Joseph von Mering, showed that if the pancreas was removed from a dog, the animal got diabetes. But if the duct through which the pancreatic juices flow to the intestine was ligated—surgically tied so the juices could not reach the intestine—the dog developed minor digestive problems but no diabetes. So it seemed that the pancreas must have at least two functions: (1) to produce digestive juices, and (2) “to produce a substance that regulates the sugar glucose this hypothetical internal secretion was the key”. If a substance could actually be isolated, the mystery of diabetes would be solved. Progress, however, was slow.10
In October 1920 in Toronto, Canada, Dr Frederick Banting, an unknown surgeon with a bachelor's degree in medicine, had the idea that the pancreatic digestive juices could be harmful to the secretion of the pancreas produced by the islets of Langerhans. He, therefore, wanted to ligate the pancreatic ducts in order to stop the flow of nourishment to the pancreas. This would cause the pancreas to degenerate, making it shrink and lose its ability to secrete the digestive juices. The cells thought to produce an antidiabetic secretion could then be extracted from the pancreas without being harmed.
Early in 1921, Banting took his idea to Professor John Macleod at the University of Toronto, who was a leading figure in the study of diabetes in Canada. Macleod did not think much of Banting's theories. Despite this, Banting managed to convince him that his idea was worth trying. Macleod gave Banting a laboratory with a minimum of equipment and ten dogs. Banting also got an assistant, a medical student by the name of Charles Best. The experiment was set to start in the summer of 1921 (Fig. 5).
Banting and Best began their experiments by removing the pancreas from a dog. This resulted in the following: its blood sugar rose. It became thirsty, drank lots of water, and urinated more often. It became weaker and weaker. The dog had developed diabetes. Experimenting on another dog, Banting and Best surgically ligated the pancreas, stopping the flow of nourishment, so that the pancreas degenerated. After a while, they removed the pancreas, sliced it up, and froze the pieces in a mixture of water and salts.
When the pieces were half frozen, they were ground up and filtered. The isolated substance was named “islet in”. The extract was injected into the diabetic dog. Its blood glucose level dropped, and it seemed healthier and stronger. By giving the diabetic dog a few injections a day, Banting and Best could keep it healthy and free of symptoms. Banting and Best showed their result to Macleod, who was impressed, but he wanted more tests to prove that their pancreatic extract really worked.
For the increased testing, Banting and Best realized that they required a larger supply of organs than their dogs could provide, and they started using pancreases from cattle. With this new source, they managed to produce enough extract to keep several diabetic dogs alive. The new results convinced Macleod that they were onto something big. He gave them more funds and moved them to a better laboratory with proper working conditions. He also suggested they should call their extract “insulin”. Now, the work proceeded rapidly. In late 1921, a third person, biochemist Bertram Collip, joined the team. Collip was given the task of trying to purify the insulin so that it would be clean enough for testing on humans. During the intensified testing, the team also realized that the process of shrinking the pancreases had been unnecessary. Using whole fresh pancreases from adult animals worked just as well.
Testing on Humans
The team was eager to start testing on humans. But on whom should they test? Banting and Best began by injecting themselves with the extract. They felt weak and dizzy, but they were not harmed. Collip continued his work to purify the insulin. He also experimented with trying to find the correct dosage. He learned how to diminish the effect of an insulin overdose with glucose in different forms. He discovered that the glucose should be as pure as possible. Orange juice and honey are good examples of foods rich in glucose. In January 1922 in Toronto, Canada, a 14-year-old boy, Leonard Thompson, was chosen as the first person with diabetes to receive insulin. The test was a success. Leonard, who before the insulin shots was near death, rapidly regained his strength and appetite. The team now expanded their testing to other volunteer diabetics, who reacted just as positively as Leonard to the insulin extract.
The Nobel Prize
The news of the successful treatment of diabetes with insulin rapidly spread outside of Toronto, and in 1923 the Nobel Committee decided to award Banting and Macleod the Nobel Prize in Physiology or Medicine. The decision of the Nobel Committee made Banting furious. He felt that the prize should have been shared between him and Best, and not between him and Macleod. To give credit to Best, Banting decided to share his cash award with him. Macleod, in turn, shared his cash award with Collip. The Nobel Prize in Physiology or Medicine for insulin has been much debated. It has been questioned why Macleod received the prize instead of Best and Collip. However, Macleod played a central role in the discovery of insulin. It was he who supported the project from the beginning. He supervised the work, and it is also most likely that Macleod's contacts in the scientific world helped the team in getting a speedy recognition of their discovery. Frederick G Banting and John Macleod were awarded the Nobel Prize in Physiology or Medicine in 1923 “for the discovery of insulin”.10
The legacy of insulin; Banting, Macleod, and the rest of the team patented their insulin extract but gave away all their rights to the University of Toronto, which would later use the income from insulin to fund new research. Very soon after the discovery of insulin, the medical firm Eli Lilly started large-scale production of the extract. As early as 1923, the firm was producing enough insulin to supply the entire North American continent. Although insulin does not cure diabetes, it is one of the biggest discoveries in medicine. When it came, it was like a miracle. People with severe diabetes and only days left to live were saved. And as long as they kept getting their insulin, they could live an almost normal life.
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- Nobel Lectures, Physiology or Medicine 1922–1941. Amsterdam: Elsevier Publishing Company; 1965.
- Charles H Best. The Biography.com website. Retrieved. 2015;11:26.