The Discovery of Insulin

by Michael Bliss

  Tasting the urine was doctors’ original test for diabetes. Early in the nineteenth century chemical tests were developed to indicate and measure the presence of sugar in the urine, that is, the condition of glycosuria. A patient showing glycosuria was generally deemed to be diabetic (other disorders that could cause sugar in the urine were far less common than diabetes and were usually ignored), so diabetes was sometimes defined as a condition in which glycosuria exists.

  Perhaps the continual thirst and the constant pissing would develop gradually, as it often did in adults. Perhaps a ten-year-old boy would suddenly want quarts and quarts of milk or water, or be eating to extremes ridiculous even in a ten-year-old. A severe illness might set off the symptoms, which could also include a constant itching in the genital areas, erratic skin sensations, sometimes blurred vision. The symptoms would mount until you visited your doctor. He tested the urine, found sugar, and pronounced you diabetic* By the early twentieth century, urine tests were often being made routinely on hospital patients and as part of life insurance examinations; these disclosed a substantial number of fairly mild diabetics.

  But there was no agreement on the exact definition of diabetes. Diagnostic methods were uncertain and changing. So were statistical methods. This all meant that it was impossible to know how many diabetics there were in any given country in, say, the year 1920. There tended to be more diabetics among peoples who were prosperous and well-nourished rather than among the poor and lean. In the early twentieth century the disease was particularly noticed among wealthy Jewish people, and seems to have been most visible in the richest countries, notably the United States and Germany. As nations became richer and peoples became better nourished, and as vaccines, anti-toxins, and sanitary measures began to reduce the death rate from infectious diseases, the prevalence of diabetes was increasing. By 1920 between 0.5 and 2.0 per cent of the population of industrialized countries had diabetes.

  I

  It was easier to diagnose diabetes than it was to treat the disease. Without treatment the “progress” of diabetes was downwards. The effects of the disease were far more wide-ranging than weight loss and a general weakening of the system. The blood vessels of the eyes and lower extremities of an untreated diabetic are particularly liable to be damaged. Longstanding diabetics often suffered from cataracts, blindness, and severe foot and leg infections which were often accompanied by gangrene. They had lowered resistance to disease of all kinds, and were as likely to be destroyed by tuberculosis or pneumonia as by the deterioration caused by diabetes itself. Boils and carbuncles plagued diabetics, often fatally. Doctors often let gangrene and other operable conditions take their course because few diabetics survived the complications and trauma arising from surgery. All wounds healed badly. Severely diabetic people were often impotent or sterile; those women who could conceive were seldom able to carry the foetus to full term.

  The infections and the other complications were often the cause of death in older diabetics whose condition developed slowly. In the young, and in the severely diabetic older patients, the diabetes itself destroyed the body, often very quickly. The life expectancy of juvenile diabetics was less than a year from diagnosis. The wasting away of the flesh from lack of nourishment could be dreadful in itself: “When he came to the hospital he was emaciated, weak and dejected; his thirst was unquenchable; and his skin dry, hard and harsh to the touch, like rough parchment.”1 But the breakdown was more general, for the body was unable to metabolize its fats and proteins properly either. As it struggled to assimilate fats in place of carbohydrates, the system became clogged with partially burned fatty acids, known as ketone bodies. When the doctors found an abundance of ketones in the urine (ketonuria), they knew the diabetes was entering its final stages. They could smell it, too, for some ketone bodies were also volatile and were breathed out. It was a sickish-sweet smell, like rotten apples, that sometimes pervaded whole rooms or hospital wards.

  The diabetic suffering from acid-intoxication or acidosis (often used synonymously with ketosis) was losing the battle. Food and drink no longer mattered, often could not be taken. A restless drowsiness shaded into semi-consciousness. As the lungs heaved desperately to expel carbonic acid (as carbon dioxide), the dying diabetic took huge gasps of air to try to increase his capacity. “Air-hunger” the doctors called it, and the whole process was sometimes described as “internal suffocation.” The gasping and sighing and sweet smell lingered on as the unconsciousness became a deep diabetic coma. At that point the family could make its arrangements with the undertaker, for within a few hours death would end the suffering.

  II

  Turn-of-the-century doctors tried to neutralize the fatty acids by giving comatose diabetics alkali solutions, most commonly sodium bicarbonate. The procedure was seldom effective in the early stages of diabetic coma, never effective in deep coma. If diabetes was to be treated at all, it had to be in the early stages. Perhaps something could be done about the sugar problem.

  Like almost all other patients, diabetics before the mid-1800s were done more harm than good by doctors’ bleeding and blistering and doping. The last vestige of these futile practices was the use of opium to treat diabetes; it was still being mentioned by William Osier in 1915, and in 1919 the leading American diabetologist, Frederick Allen, complained that the opium habit in diabetic treatment “is very difficult to break even at the present time.”2 Opium dulled the despair.

  Another treatment lasting into the twentieth century was based on the notion that a diabetic needed extra nourishment to compensate for the nutritive material flowing out in his urine. Therefore the patient should eat as much as possible. A French doctor in the late 1850s, Piorry, refined the idea and advised diabetics to eat extra large quantities of sugar. A physiologist who became an advocate of his views had the misfortune to become diabetic himself, practised what he preached, and died very quickly. In the early 1900s there were still ignorant diabetics and ignorant doctors for whom diabetes therapy involved increasing the sugar consumption. Even sophisticated doctors were constantly tempted to try to help diabetics gain weight. Allen believed it was still vital to combat “the modern fallacy of replacing through the diet the calories lost in the urine.”3

  The first important advance came when doctors gradually came to espouse the reverse of the extra-feeding idea. If the system could not handle all its food, perhaps it should not be given so much food to try to handle. Perhaps the extra food diabetics took in because of the body’s lust for nourishment actually increased the strain on the system, making things worse. Carbohydrates seemed particularly villainous. If the diabetic’s body could not metabolize them, perhaps he should be given a diet low in carbohydrates.

  Another French doctor, Bouchardat, more than made up for Piorry’s disaster by beginning to work out individual diets for his diabetic patients. Already experimenting with the use of periodic fast days, on which no food would be taken, Bouchardat observed the actual disappearance of glycosuria in some of his patients during the rationing while Paris was besieged by the Germans in 1870. He also noticed that exercise seemed to increase a diabetic’s tolerance for carbohydrates. “You shall earn your bread by the sweat of your brow,” Bouchardat remarked to a patient pleading for more of what was then everyone’s staple.4

  The unwillingness of diabetics to follow diets was and still is the single most difficult problem physicians had to face as they tried to treat the disease. The important late nineteenth century Italian specialist, Cantoni, isolated his patients under lock and key. A disciple of his system, the German physician Bernard Naunyn, would lock patients in their rooms for up to five months when necessary to obtain “sugar-freedom.”5 Because diabetes was then thought to involve only a failure of carbohydrate metabolism, the diets contained a minimum of carbohydrates and a very high proportion of fat, sometimes extremely high if a doctor believed he should replace lost calories and build up a diabetic’s weight and strength.

  Any low carbohydrate diet, even if
fats more than compensated for the calories lost, was unappetizing over a long period of time. So it seemed a great breakthrough in 1902 when the German, von Noorden, announced his “oat-cure” for diabetes. Suddenly a diabetic could increase his carbohydrate rations so long as they were in the form of foods made from oatmeal. An enormous research effort was begun by nutritionists to find out what it was that made oatmeal more assimilable than other carbohydrates (bananas, the von Noordenites found, seemed to be the next best). Actually, the oat-cure was only the most popular of a long line of carbohydrate “cures” offered from time to time – the milk diet, the rice cure, potato therapy, and others.6 There may be a direct link between these early fads in diet therapy for diabetes and popular fad diets of the late twentieth century.

  Low-carbohydrate diets did often reduce or eliminate glycosuria (leading almost as often to the conclusion that the diabetes was cured, followed by a resumption of normal diet, followed by more glycosuria). Milder diabetics, usually older ones, who kept to a diet reasonably well were sometimes able to live with their disease for years without too much discomfort. Severe diabetics, especially children, seemed seldom helped by high-calorie, low-carbohydrate diets. They deteriorated almost as quickly as before, and in fact it was later argued that the high fat content of the diets speeded the development of acidosis leading to coma. Like cancer, diabetes was not a satisfying disease to treat. (It could be financially rewarding to treat, of course, particularly if a doctor specialized in mild cases and thereby claimed a high success rate as measured by the long lives of his patients; it also helped if all patient deaths from infections, tuberculosis, or other complications were not counted as deaths from diabetes.) A British doctor made a famous flippant remark about a French diabetologist: “What sin has Pavy committed, or his fathers before him, that he should be condemned to spend his life seeking for the cure of an incurable disease?”7

  III

  The quip was actually a tribute to the dedication of medical scientists. Their basic strategy in the search for a cure for diabetes involved first finding the cause of the disease. The common-sense assumption that the problem was in the stomach gradually faded as physiologists came to understand the role of other organs in metabolism. Claude Bernard, for example, showed that it is the liver, transforming material assimilated in digestion, that dumps sugar into the bloodstream. So perhaps diabetes was a liver disease. Except that from the middle of the nineteenth century there was a gradually accumulating body of evidence from autopsies on diabetics that the disease was sometimes accompanied by damage to a patient’s pancreas – and, more important, that patients with extensively damaged pancreases almost always had diabetes.8

  The pancreas is a jelly-like gland, attached to the back of the abdomen behind and below the stomach. It is long and narrow and thin, irregular in size, but in humans usually measuring about 20 x 6 x 1 centimetres and weighing about 95 grams. To the layman the pancreas appears to be a not very interesting cluster of blobs of fleshy material. Animal pancreases, along with thymus glands and sometimes testes, have long been considered delicacies; their gourmet name, sweetbreads, appears to have nothing directly to do with sugar or diabetes.

  The main function of the pancreas appeared to be to produce digestive enzymes. These are secreted through the pancreatic ducts into the duodenum (or small intestine), where they become the important constituents of the juices working to break down foodstuffs passing down the alimentary canal. Surely a straightforward enough job for an organ.

  Close studies of the pancreas under the microscope revealed a situation not quite so straightforward. In 1869 a German medical student, Paul Langerhans, announced in his dissertation that the pancreas contains not one, but two systems of cells. There are the acini, or clusters of cells, which secrete the normal pancreatic juice. But scattered through the organ and penetrating the acini in such a way that they often seem to be floating in a sea of acinar cells, Langerhans found other cells, apparently unconnected to the acini. He declared himself completely ignorant of their function. Several years later the French expert, Laguesse, named these mysterious cells the islands or islets of Langerhans (îles de Langerhans). He suggested that if the pancreas has some other function in the system besides secreting digestive juice, the islet cells are probably involved.

  Evidence connecting the pancreas and diabetes was still tenuous in 1889 when an astonishing discovery was made in the medical clinic of the University of Strasbourg. Oskar Minkowski and Joseph von Mering had disagreed on whether or not the pancreatic enzymes were vital to the digestion of fat in the gut. To settle the issue they decided to try the very difficult experiment of removing the pancreas from a dog, and then observing the result. What would happen to digestion without pancreatic juice?

  In an account written many years later,9 Minkowski described how he had kept the depancreatized dog tied up in his lab while waiting for von Mering to return from a trip. Even though the animal was housebroken and regularly taken out, it kept urinating on the laboratory floor. Minkowski had been taught by his supervisor, Naunyn, to test for the presence of sugar in urine whenever he noticed polyuria. His tests revealed 12 per cent sugar in the dog’s urine, the realization that it was suffering from something indistinguishable from diabetes mellitus, and the hypothesis, subsequently demonstrated in case after case, that without its pancreas a dog becomes severely diabetic. Somehow the absence of the pancreas caused diabetes. This was a great experimental breakthrough, due not just to good luck and close observation, but also to the skill of researchers who apparently were performing some of the first successful total pancreatectomies. (Much of the fair amount of skepticism with which their finding was greeted related to doubts that they had actually excised the whole pancreas, for parts of it could be easily missed.)*

  The next problem was to discover how the pancreas regulated sugar metabolism. Was it the absence of pancreatic juice, for example, that brought on the diabetes in a depancreatized dog? Apparently not, for Minkowski confirmed the observations of other experimenters who had ligated and/or cut the ducts leading from the pancreas to the duodenum. Stopping the flow of pancreatic juice in this way caused minor digestive problems, but it did not cause diabetes. Only total pancreatectomy did. When critics pointed out that duct ligation often failed to work, for tied ducts were by-passed and new ducts often formed to replace cut ones, the French researcher, Hédon, in 1893 devised a compelling proof. In the first stage of his operation he would take out almost all of the pancreas, completely and irrevocably cutting off the supply of pancreatic juice. He would leave only a small remnant of pancreas, still nourished by its blood supply, which he pulled out through the wound and grafted under the dog’s skin. Although the dog had lost most of its pancreas, and was getting no pancreatic juice at all, it did not become diabetic. But when Hédon completed the pancreatectomy by cutting off the remnant of the graft (without having to open the abdomen again), diabetes immediately developed. Minkowski and von Mering did similar experiments.

  It was hard to dispute the conclusion that the pancreas must have two functions. The digestive juices, poured into another organ, were the pancreas’s external secretion. Its other function must be to produce some other substance, an internal secretion, which fed directly into the bloodstream and regulated carbohydrate metabolism. In 1901 an American at Johns Hopkins University in Baltimore, Eugene Opie, supplied a missing link in the argument by showing a pathological connection between diabetes and damage to the mysterious cells Langerhans had discovered. From then on it was widely believed that the islets of Langerhans produced an internal secretion of the pancreas. That hypothetical internal secretion was the key. If it could ever be discovered, actually isolated, it would unlock the mystery of diabetes.

  The new ideas about the pancreas fitted with exciting new concepts and empirical findings about organs and their secretions. There were several ductless glands – such as the suprarenals, thymus, thyroid, ovaries, and pituitary – whose chief function appeared to be to
produce powerful internal or endocrine secretions. In the 1890s a great deal of excitement was generated by the discovery that several diseases – endemic goitre, cretinism, and myxoedema – could be succesfully treated by feeding patients extracts of thyroid. Evidently the gland produced a secretion whose deficiency could be supplied artificially. The discovery of a secretion from the suprarenal, or adrenal medulla, named adrenalin, was another exciting milestone at the turn of the century. Adrenalin was a bit of a disappointment in that it could not keep animals who had lost their suprarenals alive, but it was obviously a powerful secretion of the greatest physiological importance. There were more to come: after Bayliss and Starling discovered secretin (a secretion from the duodenal epithelium that triggers the flow of pancreatic juice) in 1902, Starling coined the term “hormone” to describe these chemical messengers. The body’s endocrine system seemed to be as important as or more important than the nervous system in regulating its vital functions.

  How many more hormones were there? How did they work? Within a few years thousands of articles were being published on research in this new field of endocrinology. It was a young field in terms of solid achievements, and a highly speculative one (leading to wild quackery) when people thought about the ultimate discoveries that might be made regarding the secretions of the sex organs. Back in the 1880s one of the eccentric pioneers of endocrinology, Brown-Séquard, had received much attention with his announcement that extracts of tissue of the testicle were the secret of his own rejuvenation. If nothing else this somewhat premature revelation helped spread the idea that these hormones, the “vital juices” of popular lore, could be very potent. In the less exotic field of diabetes research, it certainly seemed that both theory and experimental observation pointed towards a potent hormone being produced in the pancreas to regulate metabolism.10