A Long Prelude
A person becomes diabetic when the body starts losing the ability to utilize its fuel. The food taken in is no longer fully transformed, or metabolized, into energy. Instead, nutrients begin passing through the system; hence the origin of “diabetes,” from the Greek word meaning siphon or pipe-like.
A seventeenth-century English surgeon called diabetes “the pissing evile.” The frequent and voluminous urination by severe diabetics (as much as ten to fifteen quarts a day), accompanied by their unquenchable thirst, had caused the disease to be recognized thousands of years before by the Egyptians and Greeks. In the first century A.D., Arataeus described the disease as “a melting down of the flesh and limbs into urine.” When early physicians found that the urine of diabetics was sweet to the taste, they realized it was heavy with sugar. Gradually the Latin word for honey/sweet, “mellitus,” was added to distinguish the disease from diabetes insipidus, a pituitary disorder in which a large volume of sugar-free urine is passed (containing no sugar, the urine is insipid to the taste). Diabetes mellitus was also called the sugar disease or the sugar sickness. That was a fair description, for the most obvious problem in diabetes mellitus is the body’s failure to be able to burn much of the simple glucose made from its food, especially from carbohydrates. Instead of being absorbed into the cells, the glucose remains in the bloodstream. The kidneys normally remove sugar from the body’s waste water, but in a diabetic’s system the sugar overload is too great. Glucose spills into the urine; the quantities of urine greatly increase; and as the body loses liquids a terrible thirst develops as the system craves renewal. Its craving for sugar leads to a terrible hunger, especially for carbohydrates.
Frequent urination (polyuria), constant thirst (polydipsia), and excessive hunger (polyphagia) are the classic symptoms of diabetes. They are often accompanied by fatigue or weakness, and then rapid weight loss as the body begins to fail from lack of nourishment.
Diabetes seems to be brought on by a variety of factors. It is most commonly found in people over forty whose metabolic system has had to work hard during their lives to cope with over-nourishment leading to obesity. That kind of “maturity-onset” (or type 2) diabetes often develops gradually over many years, and the early symptoms are hardly noticeable. In younger people, however, the system’s failure is more commonly sudden and serious. “Juvenile-onset” (type 1) diabetes may in some instances have a viral cause. In both types, however, there is often an hereditary predisposition to diabetes, an inherited genetic or systemic weakness that worsens, either gradually or suddenly, under the influence of other factors.
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.
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.
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
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
As soon as it was realized that the pancreas controls diabetes, attempts began to treat the disease, literally, with pancreas – just as diseases of the thyroid were being treated with thyroid. Minkowski was the first of many researchers to try to restore the pancreatic function to diabetic animals (others experimented on human diabetics) by preparing and administering extracts of pancreas. The extracts could be made in a variety of ways; they could also be administered in a variety of ways, although the most obvious were orally and by injection. The important observation would be of sugar in the urine. If an extract reduced glycosuria it might be potent. It might contain the internal secretion; indeed, it might supply the proof that there actually was an internal secretion, for until its effect could be practically demonstrated, the internal secretion of the pancreas was merely a good-looking hypothesis.
The results of the early experiments with pancreatic extracts were mixed, tending towards the negative. Some extracts had no effect; some had decidedly harmful effects, throwing the animals into shock or worse. Others had temporary sugar-reducing effects that were more than cancelled out by harmful side-effects – so much so that it was impossible to tell whether it was the extract or its toxic effect on the system that was the true cause of the reduction in glycosuria. If an extract caused kidney failure, for example, it might be changing the contents and quantity of the urine without affecting the diabetic condition at all. A few researchers did report encouraging results with extracts, but others who tried to repeat their work got discouraging results. It will never be known precisely how many researchers tried giving pancreatic extracts to diabetic animals and humans. Estimates run to more than four hundred. It was an easy experiment for even a country doctor to try, but if the results were not encouraging many would decide there was no point publishing. As it was, there was no shortage of publication, on every conceivable aspect of the problem of diabetes and the pancreas, it seemed. In 1910 Opie complained that the literature on diabetes was voluminous. A few years earlier Lydia Dewitt estimated that more thought and investigation was going into the islets of Langerhans than any other organ or tissue of the body.11
Despite the discouragement, the search for a workable pancreatic extract continued. Perhaps the problem with extracts was that somehow the pancreas’s external secretion, or the tissues producing it, destroyed the internal secretion in the extirpated organ. Laguesse suggested using extracts made from foetal pancreases, because it seemed that the islet cells develop well before the acinar cells in gestation. If the experiment was tried, it failed. So did a number of other experiments involving fish. In certain species of fish the islet tissue had been found to be anatomically distinct from the acinar tissue, making it possible, it seemed, to get an extract which was more purely an extract of the islets of Langerhans. Between 1902 and 1904 two Scots researchers in Aberdeen, John Rennie and Thomas Fraser, fed an extract of boiled fish islets to four diabetic patients. After inconclusive results, including a toxic reaction when they tried to inject the extract into a fifth patient, they gave up.12
The most persistent and important of the early extractors was Georg Ludwig Zuelzer, a young internist in Berlin who in the early 1900s became interested in the theory that diabetes was actually caused by adrenalin. Experimental evidence that large doses of adrenalin could produce glycosuria convinced Zuelzer that the function of the internal secretion of the pancreas was simply to neutralize adrenalin in the system. He decided to try to prove this by injecting an extract of pancreas into rabbits along with adrenalin. When no glycosuria developed, Zuelzer was encouraged to go on and see if his extract could reduce diabetic symptoms in depancreatized dogs. When it appeared to reduce the sugar excreted in the urine of two diabetic dogs, Zuelzer was encouraged to go further.
Dying diabetics were hopeless cases, so it must have seemed that nothing could be lost in experimenting on them. On June 21, 1906, Zuelzer injected eight cubic centimetres of his pancreatic extract under the skin of a comatose fifty-year-old diabetic in a private clinic in Berlin. The next day he injected another ten cc. Whatever effect the extract was having on the patient’s glycosuria could not be measured, for the man had lost control of his bladder and was wetting his bed. What was clear was that the patient seemed to be coming back from the edge of the grave. His overall condition improved, his appetite returned, and his severe dizziness disappeared.
But there was no more extract. The patient sank into deep coma on June 30 and died on July 2. What Zuelzer had seen was tremendously encouraging, a diabetic momentarily pulled out of coma. “Whoever has seen how a patient lying in agony soon recovers from certain death and is restored to actual health will never forget it,” he wrote years later just after insulin had been discovered in Toronto. He was almost certainly referring to his first experience with his own pancreatic extract, which he named “acomatol.”13
Zuelzer had immense practical difficulties carrying out his experiments. It was hard to get a supply of pancreases, for example. Workers at local slaughterhouses thought the doctor who wanted them to give him fresh sweetbreads for medical research must be a little crazy. The extract was not at all easy to make, and had a frustrating tendency to lose its potency (Zuelzer tested his batches on rabbits, measuring the potency by the amount of extract needed to neutralize the sugar-creating effects of a unit of adrenalin). But there were those early results, and it was obvious that a workable pancreatic extract would be a wonderful thing. When Zuelzer approached the Schering drug company with his idea they offered him financial support and technical help and applied for patents on his methods. By the summer of 1907 he was ready to try again on humans.
The extract produced the amazing effect of completely suppressing for a few days glycosuria and acidosis in a twenty-seven-year-old man. Other diabetics – a six-year-old, a thirty-five-year-old, and two sixty-five-year-olds – had their symptoms dramatically relieved by acomatol. (Some others, it appears, did not; Zuelzer reported only the most interesting cases.) On the other hand, in every case after the first two there were serious reactions to the injections: vomiting, high fevers, sometimes convulsions. Knowing that his preparation was not yet a practical therapy, Zuelzer was still confident enough to publish his results in 1908. He came to the triumphant conclusion “that it is possible through the injection of a pancreatic extract to eliminate the excretion of sugar, acetone, and acetoacetic acid by a diabetic without making any changes in the patient’s diet.”14
These exciting findings caught the attention of a worker in the clinic directed by Minkowski in Breslau. J. Forschbach obtained samples of Zuelzer’s extract and tested it on three dogs and three humans. His verdict was negative. Yes, Zuelzer’s was the first pancreatic extract to suppress glycosuria in both the short and the long run. But it did so at the cost of severe toxic side-effects, especially fever, so severe that Forschbach stopped his human experiments for fear of doing permanent damage to achieve only temporary relief. “It will be difficult to convince a patient who has been made severely ill by a single injection,” he wrote, “that this result was connected to a significant beneficial effect upon his diabetes.” Forschbach was fairly convinced, especially after some impotent extract caused no ill effects in one case, that the cause of the potency and the cause of the side effects were the same. So there was no future in it. Forschbach’s 1909 paper on his tests of Zuelzer’s extract was decidedly discouraging, and must have been more so because of Forschbach’s association with the great Minkowski himself. The giants in the field had passed judgment.15
At about the same time the Schering company decided that the results did not justify the cost of the work and withdrew their support. Zuelzer’s application for a grant of 500 marks (about $125 at that time) to spend six weeks at a zoological station seeing if he could make an extract from those interesting fish pancreases was rejected by the University of Berlin. Zuelzer was evidently neither wealthy nor well-connected, an outsider in Berlin medical circles now left on his own with his erratic extract. He published nothing more about it.
In fact he carried on, a big, shambling doctor hawking his idea and his method from one drug company to another, bribing slaughterhouse workers to give him pancreases. In 1911 the big Hoffman-La Roche chemical firm put him back in business, funding a small lab and some co-workers. The next year Zuelzer took out an American patent on his “Pancreas Preparation Suitable for the Treatment of Diabetes.” The patent was wishful thinking, though, for there were still problems with the extract. When the first big batch was made in the new lab, from 100 kilograms of pancreas, the animals on which it was tested went into severe convulsions. Zuelzer had never seen anything like this before. He decided it was the old story of toxic side-effects, perhaps caused this time by the use of copper containers, and threw out the batch. After more problems with ineffective extracts from horse pancreas, Zuelzer was ready for another round of experiments with what looked like promising material in the summer of 1914. When the war began, the hospital he was working in was turned over to the military. Georg Zuelzer was called to the front.16
The main effect of Zuelzer’s work was probably to set back the search for an effective pancreatic extract. His published findings, plus Forschbach’s report, seem to have convinced researchers of the impossibility of the enterprise: even if you did get an extract with anti-diabetic effects, whatever good effects it might have would be more than cancelled out by its bad effects. Experienced scientists had learned to be cautious, and it became something of a mark of professional prudence to qualify any findings about pancreatic extracts.*
A classic example of this learned cautiousness was the treatment of a student’s work at the University of Chicago in 1911–12. The student, E.L. Scott, who had been deeply affected by the death of a friend from diabetes, took up the search for the internal secretion as the research project for his master’s degree. He reasoned that previous failures had been caused by the external secretion, the powerful proteolytic (protein-destroying) enzymes, destroying the internal secretion. Perhaps the answer lay in getting rid of all traces of these enzymes. One way might be to ligate the ducts of the pancreas; this apparently would cause the tissues producing the external secretions to atrophy; from the remaining tissue an extract could be prepared and then tested. (Lydia Dewitt had already tried this method in 1906, but had tested her extract only on test-tube solutions, not living animals.) Scott abandoned the idea as impractical when, working under primitive conditions in a very hot summer, he found that it was almost impossible to get a pancreas to atrophy after ligation. Instead he turned to alcohol, a fairly common solvent and one that Zuelzer had also used in the preparation of his extract, to do the same job. Using extracts which had gone through various stages of development through mixing the pancreas with alcohol, filtering it, treating the residue, and other chemical procedures, Scott found one formula that gave encouraging results on three of the four diabetic dogs he treated with it. Not only did their sugar excretion diminish, but “if one dared to say it,” Scott wrote, the dogs “seemed even brighter for a time after the injection than before it.”
Like Zuelzer before him and others afterwards who observed the subjective signs of improvement in diabetic animals and patients, Scott was convinced that he had been successful. The first two conclusions of his master’s degree thesis were:
1st. There is an internal secretion from the pancreas controlling the sugar metabolism.
2nd. By proper methods this secretion may be extracted and still retain its activity.
Scott’s thesis adviser, the noted physiologist Anton Carlson, did not share his student’s confidence. Having just read of recent work by Hédon questioning the effectiveness of pancreatic extracts, Carlson worried that Scott had not sufficiently controlled his experiments. He urged that the conclusions be rewritten, probably supplying the new wording himself:
It does not follow that these [good] effects are due to the internal secretion of the pancreas in the extract. The injections are usually followed by a slight temporary rise in the body temperature, and this may be a factor in the lowered sugar output. Physiologists are not agreed as to whether the internal secretion acts by diminishing or retarding the passage of sugar from the tissues into the blood, or by increasing the oxidation of the sugar in the tissues. The pancreas extract may decrease the output of sugar from the tissues by a toxic or depressor action, rather than by a specific regulatory action of the pancreas secretion….The work is being continued in the hope of clearing up these points.17
Despite his conservatism, Carlson urged Scott to continue the research and work out his “salvation or damnation along the pancreas extract line…. There is something ahead in that line – possibly both shoals and open water. Puzzle: find the channel.” Scott tried half-heartedly, attempting to buttress his urinary sugar results with studies of his extract’s effect on the blood sugar of cats. He reported the “very surprising” result that it caused an increase in their blood sugar.18 Having struck a shoal, Scott veered away from pancreatic extracts to study problems relating to blood sugar.
Before giving up the work, Scott chatted about it with some of the other experts in the field. One of these was a professor at Western Reserve University in Cleveland, Ohio, John James Rickard Macleod. Macleod was a Scotsman, trained in Aberdeen, Germany, and London, who had emigrated in 1903 to take his American appointment at the age of twenty-seven. He had been working for several years in the area of carbohydrate metabolism. A competent researcher and a prolific writer and synthesizer of current knowledge in physiology, Macleod was particularly knowledgeable about the literature in his field. The only knowledge we have of his discussion with Scott is that it began with a consideration of how to cure Scott’s child’s diarrhoea. When the talk turned to pancreatic extracts, Macleod may have discouraged the younger man, for about this time he was working on his own main research contribution to the search for the internal secretion of the pancreas. Macleod was able to show that the findings of two leading Britishers, Knowlton and Starling, who thought they had a pancreatic extract which assisted the heart of a diabetic dog to utilize sugar in the blood, were not repeatable.19
Knowlton and Starling’s joined Scott’s and Zuelzer’s in the list of apparently ineffective pancreatic extracts. Two young Americans, John R. Murlin and Benjamin Kramer, continued to fiddle with pancreatic extracts similar to Knowlton and Starling’s, but their work led them off into examinations of the influence of alkaline solutions on metabolism.20
Macleod summarized the state of the search for an internal secretion in his 1913 book, Diabetes: Its Pathological Physiology. After due deliberation he concluded that there was an internal secretion of the pancreas, but suggested several reasons why it might never be captured in a pancreatic extract. The powerful pancreatic juice might destroy it; there might be no reserves of it in the pancreas to be captured by extraction; or it might exist in the pancreas only in latent form and not be activated until secreted into the blood. Macleod’s own interest and his work tended to be on the behaviour of blood sugar rather than pancreatic extracts. He thought the most convincing proof of the existence of an internal secretion came in Hédon’s early work (now questioned by Hédon himself) using grafts of pancreatic remnants to show that a small, isolated portion of the pancreas could stave off diabetes.21
In 1913 Dr. Frederick Allen pronounced what seemed to be the epitaph of a generation’s attempts to treat diabetes with pancreatic extracts: “All authorities are agreed upon the failure of pancreatic opotherapy in diabetes….injections of pancreatic preparations have proved both useless and harmful. The failure began with Minkowski and has continued to the present without an interruption….The negative reports have been numerous and trustworthy.”22
Frederick Madison Allen wrote with particular authority. Born in Iowa in 1876, trained in medicine in California, Allen had come east to do medical research, drifted into a poorly paying fellowship at the Harvard Medical School, and found himself working on problems of sugar consumption. The study turned into three years of intensive research concentrating on diabetes. Most research is reported upon in journal articles. Allen’s was not. His first publication, subsidized by his father, was a remarkable 1913 volume entitled Studies Concerning Glycosuria and Diabetes. “Its spirit is that of an enlarged journal article,” Allen wrote in the introduction, claiming it was a book in which he hoped to give “simplicity and order” to the study of diabetes.23 The reader who waded through the following 1,179 pages – in which Allen set his own research, involving experiments on more than two hundred dogs, the same number of cats, and assorted guinea-pigs, rabbits, and rats, in the context of everyone else’s research (his bibliography contained approximately twelve hundred listings) – knew that the subject was anything but simple and orderly, except possibly in the head of Dr. Allen. Both the research and the book were prodigious achievements in themselves, and even more significant for the revolution in diabetes therapy that flowed from them.
Most researchers created experimental diabetes in animals by taking out the whole pancreas. Allen’s approach was to remove a large part of the pancreas, about 90 per cent in dogs, but leave the rest. He thus created a state of mild diabetes in animals which was probably much closer to the diabetes most humans experienced than was the severe, quickly fatal diabetes arising from total pancreatectomy. Although he tried some experiments involving pancreatic extracts, Allen’s chief interest was in the effect of diet on the diabetic animals. What kinds of diet would enable an animal with a partial pancreas to keep metabolizing his food without becoming more diabetic? What kinds of diet were harmful to animals with these crippled pancreases, making the diabetes worse?
Allen’s work undercut the view that diabetes was mostly a problem of carbohydrate metabolism. It was not just the carbohydrates, but the proteins and fats as well, that the diabetic’s body was having trouble with, Allen argued. All kinds of food tended to over-burden the system. Diets which involved cutting back sharply on carbohydrates and then increasing the proteins or fats to compensate, achieved nothing – or, worse, caused a higher rate of acidosis and death in coma because of their fat content. The answer was to continue to cut back on carbohydrates, but to cut back on everything else, too, so that the diabetic’s total calorie intake was reduced. If over-nourishment or normal nourishment produced diabetic symptoms, notably glycosuria, then the trick was to find the degree of under-nourishment that would enable a diabetic to live sugar- and symptom-free. Any previous diabetic diets that had actually been effective, Allen claimed -high-fat, oatmeal cure, or whatever – had been characterized by a low total calorie count. There was no way a diabetic could save his carbohydrates and eat his calories too.
An outsider with no advanced degrees, Allen had trouble getting a job until the Rockefeller Institute in New York, impressed by his book, offered him a junior position in 1914. The appointment gave him access to a small ward of diabetic patients, and turned out to be a marvellous opportunity to begin applying his theories to humans.
After four years’ clinical work, Allen and his associates published their results in 1919 in a second massive volume, Total Dietary Regulation in the Treatment of Diabetes, which ran to 646 pages plus charts. Almost half the book consists of exhaustive case records of seventy-six of the one hundred patients Allen had treated.
His methods were tried on all sorts of diabetics, mild and severe, recently diagnosed and terminally comatose, old and young, educated and ignorant, well-to-do and desperately poor. The therapy was almost always the same: When a diabetic was admitted to hospital, he or she was put on a fast (liquids only) until the glycosuria and, in the severe cases, the acidosis disappeared. Then there would be a gradual building up of diet, measuring by carbohydrate tolerance, but with strict weighing of all foods, to see how much the patient could take before becoming glycosurie. When sugar appeared in the urine, the limit had been reached. A fast day would clear the urine again and the diet would be fixed at a total calorie intake just under this tested tolerance.
This quick description of the Allen method might go unremarked by readers unfamiliar with serious diabetes and in an age when most of us have to diet occasionally. At the time he introduced what came to be called the “starvation treatment” of diabetes, Allen was advocating serious dieting in a country where being well-fed was still a sign of good health. More ironically, he was advocating serious dieting to patients two of whose complaints were their terrific hunger and their rapid weight loss. They came to the doctor to be treated for these symptoms and the doctor seemed to be telling them that they had to be hungry more often, that they had to lose even more weight.
The ironies, the Hobson’s choices, the catch-22’s of the treatment were staggering. An adult diabetic, weak, emaciated, wasted to perhaps ninety pounds, would be brought into hospital and ordered to fast. If the patient or the patient’s family complained that he or she was too weak to fast, Dr. Allen replied that fasting would help the patient build up strength. If the patient complained about being hungry, Allen said that the fasting would help ease the hunger. Suppose the method didn’t seem to work and the symptoms seemed to get worse. The answer, Allen insisted, was more rigorous under-nourishment: longer fasting, a maintenance diet even lower in calories. To top it off, Allen and others were also urging diabetics to take as much physical exercise as possible, claiming it would help them burn more food and increase in strength.
Where was the limit to the dieting? Where would you stop? In fact there was no limit. In the most severe cases the choice came to this: death by diabetes or death by what was often called “inanition.”
“The plain meaning of this term,” Allen wrote, “is that the diabetes was so severe that death resulted… from starvation due to inability to acquire tolerance for any living diet.” “The best safeguard against inanition,” he added, “consists in sufficiently thorough undernutrition at the outset.” In those situations where the awful choice between death from diabetes and death from starvation could not be avoided, “comparative observations of patients dying under extreme inanition and those dying with active diabetic symptoms produced by lax diets or by violations of diet have convinced us that suffering is distinctly less under the former program.”24
To illustrate, consider Rockefeller case 60, a forty-three-year-old housewife who came into the hospital on New Year’s Day, 1916, having lost 60 pounds in the few months since the onset of her diabetes. She weighed 36 kilograms or 79 pounds on admission, and was so weak that even Allen hesitated to go ahead with severe fasting:
The experiment was tried of feeding more liberally for a short time in the attempt to restore some strength, so as to get a fresh start for further fasting….the attempt caused only harm instead of benefit, as always in genuinely severe cases. The question thereafter was whether the glycosuria could be controlled without starving the patient to death….Though the food was thus pushed to the utmost limit of tolerance, it was not possible to prevent gradual loss of weight.
She was utterly faithful in following her diet, which during hospital stays averaged 750 calories a day and about 1,000 calories when she was at home. When Allen last saw her, in April 1917, her weight was down to 60 pounds and falling. “Perhaps better results might have been obtained by cutting down the weight to perhaps 30 K (66 pounds) at the outset,” he mused in the conclusion to the discussion of her case. “The question remains whether the pancreatic function is absolutely too low to sustain life, or whether by sufficiently rigid measures downward progress can be halted even at this time.” The answer was given in a footnote added in the final revision of the manuscript: “Largely on account of her residence in a city too far away to permit personal supervision and encouragement, this patient finally broke diet, and after a rapid course of glycosuria and acidosis, died in Feb. 1918.”25
Many of Allen’s patients broke diet out of hospital, some sooner than others. Case 1 embraced Christian Science four months after her release, began eating everything at will, and died in a few more months. Case 51, a seven-year-old Polish-American schoolboy, was able to sneak food at home unknown to his parents, and died from it; “the essential cause of trouble lay in the home conditions of an uneducated Polish laboring family.” Case 18 was a sixteen-year-old errand boy who adhered to his diet fairly well until summertime when he had a feast of cherries. After that he became uncontrollable and went downhill.26
Even inside the hospital the staff had to be constantly on the alert to stop the pilfering of “forbidden food.” The most extreme example was case 4, a twelve-year-old boy whose diabetes had already caused blindness when he was admitted. No matter how carefully he was treated, his urine tests on some days would show sugar. It could not be accounted for from his diet. The staff could not understand what was happening:
It had seemed that a blind boy isolated in a hospital room and so weak that he could scarcely leave his bed would not be able to obtain food surreptitiously when only trustworthy persons were admitted. It turned out that his supposed helplessness was the very thing that gave him opportunities which other persons lacked…. Among unusual things eaten were tooth-paste and bird-seed, the latter being obtained from the cage of a canary which he had asked for….These facts were obtained by confession after long and plausible denials. The experience illustrates what great care is necessary if records of diabetic patients are to be vouched for as correct.
The gods had their revenge. Thinking the glycosuria was caused by too high a normal diet, the staff cut the boy’s normal food supply further and further. It was too late when they realized their mistake. He weighed less than 40 pounds when he died from starvation.27
Allen was a stern, cold, tireless scientist, utterly convinced of the validity of his approach. His therapy for diabetes seemed immensely hard-hearted in the extreme cases, and met much resistance from diabetics, their families, other physicians, and other workers at the Rockefeller Institute. Allen defended himself with iron logic. Yes, the method was severe; yes, many patients could not or would not follow it faithfully; yes, in the worst cases it led to death from starvation; yes, all it could do was prolong the lives of diabetics, in some cases for a few years, in severe cases perhaps only a few months. But what was the alternative? All of Allen’s experimental and clinical evidence showed that total dietary regulation was the only way of prolonging the lives of diabetics. Nobody had a better way. Besides, he claimed, his diet was not impossible to follow: because they were better balanced Allen’s diets were often more tolerable than the destructive high-fat alternatives. Most of his disobedient patients had actually been on the more liberal of the series of diets, “and were the sort of persons who would not abide by any restrictions no matter how slight.” Some of his most undernourished patients had borne their diet in the most faithful way.28
Generally, diabetics on the diet did feel better than those who broke it, the “simple hunger” from careful fasting or dieting being less tormenting than the sick hunger, or polyphagia, of diabetes. Allen’s “faithful” patients, even those under an obvious sentence of death, regained a degree of strength and comfort and the ability to enjoy life. “Though always hungry, excessively emaciated, and lacking strength for any real exertion,” he wrote of case 60, “some of the noteworthy features are her constant cheerfulness, freedom from infection, and comfort in all other respects. She is able to be up and about, carries on light household duties, and – the point of most importance to her – attends to the bringing up of her child.” By her faith and determination, case 60 had won for herself about two extra years of life.29
In the final analysis, the only argument against the thorough treatment was the cruelty of prolonging a patient’s suffering. “Euthenasia is no more justified in diabetes than in numerous other diseases,” Allen argued. “Diabetics who overeat for the deliberate purpose of killing themselves are uncommon.”30 Allen was proud that he was not only keeping diabetics alive longer, but was pioneering in methods of keeping starving people alive; some of his patients were living in stages of inanition not thought possible.
Frederick Allen’s determination to apply his methods ruthlessly (to prove his theories absolutely he wanted to be able to control his patients as thoroughly as laboratory animals were controlled) were probably responsible for a decision at the Rockefeller Institute to take away his control of the diabetes clinic. Instead of being the triumph of medical research it appears, the 1919 volume, Total Dietary Regulation in the Treatment of Diabetes, actually veils a bitter controversy about the treatment of those hundred cases. The book was later denounced by Allen as an inconclusive, failed study. The diabetologist did not believe there were many shades of grey in medical research, or in life generally. He left the Rockefeller Institute intensely frustrated, served in the army diabetes service during the war, and in 1919 launched a daring bid for personal and professional independence by purchasing the Morristown, New Jersey, mansion formerly owned by Otto Kahn. There he founded the Physiatric Institute, intended to be a prestigious centre for treatment of Americans suffering from diabetes, high blood pressure, and Bright’s disease. The fees paid by rich patients for the luxurious facilities in one department of the Institute supported more plebeian facilities in other departments as well as the ongoing research work. One of Allen’s rules was that all in-coming patients had to promise their sincere co-operation in the prescribed treatment. As the Institute flourished in 1919–20, Allen worked frantically to pay off his debts and build the resources to support the grand research plan he felt had been frustrated at the Rockefeller.31
The total dietary approach to diabetes was the best therapy available at that time. How widely it was actually used is difficult to estimate. In medical schools and among up-to-date practitioners Allen’s methods seem to have been universally adopted. But Allen and the other diabetologists often wrote scornfully of the ignorance with which doctors treated diabetes – at worst with opium and over-feeding, at best by handing out printed, out-of-date diets. And even they were better than the patent medicine men who offered nostrums such as Bauer’s Antidiabeticum, and the religious people who offered prayer, faith, and Christian Science. At his own professional level, as well, Allen was under attack from several researchers, especially Woodyatt in Chicago, who worked out elaborate theoretical critiques of “starvation” and new justifications for high-fat and fairly high calorie diets.32 In these clinics, too, the thorough treatment of diabetes was expensive and complicated, involving prolonged hospital stay, careful preparation and weighing of individually tailored diets, elaborate daily tests, and special nursing for children. In prosperous North America diabetes was becoming something of a specialist’s disease, with special diabetic wards being set up at hospitals and physicians building whole practices on nothing but the treatment of diabetes.
Other than Allen, the most prominent American specialist in diabetes was Dr. Elliott P. Joslin. A New Englander, a graduate of Yale and Harvard, and student of Naunyn at Strasbourg, Joslin gradually narrowed his medical practice in Boston to diabetes. He was a prolific writer, particularly at the semi-popular level aimed at physicians and the diabetics themselves, and a warm enthusiast. In his writing Joslin tried to put the best face on the diabetic’s situation, stressing that it was “the best of the chronic diseases,” clean and seldom unsightly, not contagious, often painless, and usually susceptible to treatment.33
A friend of Allen and a strong supporter of under-nutrition, Joslin tended to be optimistic about the therapy. He was almost certainly over-optimistic, possibly deliberately so to bolster his patients’ morale and his own.34 It was hard to keep up your spirits to face each day of urging sick people to keep starving. A nurse at the Physiatric Institute remembered how horrifying it was to watch the starving children lying in their beds. “It would have been unendurable,” she wrote, “if only there had not been so many others.”35
Because he tempered his own rock-hard puritanism with warmth and charm and a sense of hope, Joslin may have had more success with his patients than the forbidding Dr. Allen. He was particularly popular with children, some of whom were brought to him because no one else would treat them. When von Noorden came to Boston, Joslin remembered, he shuddered and turned away when shown one of Joslin’s skeleton-like diabetic girls. A quarter of a century after the discovery of insulin the doctors were reminded of these pre-insulin diabetics when they saw the pictures of the survivors of Belsen and Buchenwald.36
Despite the record of failure, and despite the pessimism of men like Allen, Carlson, and Macleod, attempts to find an effective pancreatic extract continued, “because of the strong theoretical inducements,” Allen noted.37 The most interesting and important of these new attempts involved experiments measuring the effect of pancreatic extracts on blood sugar. High blood sugar, or hyperglycemia, had been recognized for many years as a sine qua non of the diabetic condition. Measurements of blood sugar had not usually been involved in diabetes therapy or research, however, because they were very difficult. The chemical tests required to estimate the amount of sugar in the blood called for a lot of blood, usually twenty cc. or more. It was difficult and possibly dangerous to take many of such large blood samples from either humans or animals. As well, methods for testing the sample were time-consuming and so crude that the margins of error in estimating the percentage of blood sugar were very high. It was much more practical, safer, and perhaps more accurate to test the diabetic condition through urine samples alone.
But accurate blood sugar readings would obviously be a useful research tool, supplying a far more reliable guide to diabetes than urine tests. All of the problems and complications and alternative interpretations of glycosuria created by the possibility of kidney disorder could be avoided. If good testing procedures (the lack of which was probably central in E.L. Scott’s failure) could be developed, it would be much easier to check short-term fluctuations of blood sugar than to measure, say, the hourly inflow of sugar into the urine. The single most important development in diabetes research, next to Allen’s diets, was the rapid improvement between about 1910 and 1920 in techniques for measuring blood sugar. In 1910 a blood sugar test still required 20 cc. or more of blood; by 1920 it could be done with as little as 0.2 cc.38 The use of blood sugar estimations was soon reflected in the research.
A young American, Israel Kleiner, became interested in pancreatic extracts and blood sugar while working with S.J. Meltzer at the Rockefeller Institute during the time of Allen’s researches. Pioneering studies were being done there on the speed with which injections of sugar normally disappeared from circulation (that is, were assimilated by the system). By contrast, in diabetic animals much of the sugar continued to circulate. But when an emulsion of pancreas was mixed and injected along with the sugar solution, the diabetic animal handled it almost normally. Observing this, Kleiner and Meltzer began experiments to see how pancreatic extracts would affect the ability of depancreatized dogs to deal with their system’s own excess sugar.
They reported very promising preliminary findings in 1915, but their work was interrupted by the war. In 1919 Kleiner returned to it, running many more experiments. Late in 1919 he published his findings in the Journal of Biological Chemistry. Of all publications before the work at Toronto, it was the most convincing.
Kleiner had made solutions of ground fresh pancreas in slightly salted distilled water. These were slowly injected intravenously into depancreatized dogs, with blood sugar readings taken before and after infusion and at later intervals. The 1919 experiments were much easier to do because the new blood testing method (Myers and Bailey’s modification of Lewis and Benedict’s) required much smaller samples. In both the 1915 and 1919 series of experiments the results were the same and were important: without exception in sixteen experiments the pancreatic extract caused a decline in the blood sugar of diabetic dogs. It was often a very sharp decline, sometimes more than 50 per cent.
Kleiner had not used any chemicals in the preparation of his extract because some of Murlin’s recent work suggested that the chemicals themselves, especially alkalis, could artificially reduce blood sugar. He ran checks on the hemoglobin content of his dogs’ blood to make sure that the effect he was getting was not just a result of the injected liquid diluting the blood, and checks on the urinary sugar to make sure some strange “washing out” effect was not taking place. Emulsions made from other tissues were injected to see if the effect might be something any ground-up tissue could produce. They caused no significant change in the blood sugar (that they did sometimes cause a reduction in glycosuria indicated the weakness of older methods: “the mere reduction of glycosuria is no proof of a beneficial effect of any agent,” Kleiner noted with emphasis).
Kleiner began the “Discussion” section of his paper triumphantly:
Many investigators have recognized that the best evidence for the internal secretion theory of the origin of diabetes would be an antidiabetic effect of a pancreatic preparation, administered parenterally. The experiments just described show that such a result has been obtained….
His controls had been impressive, his follow-up discussion was a beautiful piece of scientific writing. There was one problem, he reported: the slight toxic symptoms, usually a mild fever, associated with the extract. These symptoms were not particularly marked, and the overall result of the work “indicates a possible therapeutic application to human beings.” Before this happened, Kleiner suggested, further knowledge should be obtained. Many other tests could be run. “Finally, the search for the effective agent or agents, their purification, concentration, and identification are suggested as promising fields for further work.”
Kleiner did not do any of that further work. In 1919 he left the Rockefeller Institute, and did not return to the problem. The only published comment Kleiner ever made on why he did not continue “and attempt to isolate the antidiabetic factor” was that it was “a long story.” As far as can be determined, the university he went to in 1919 did not have the resources to support major animal research.39
Another scientist whose work on pancreatic extracts had been interrupted by the war was Nicolas Paulesco, professor of physiology in the Romanian School of Medicine in Bucharest. Paulesco was already a physiologist of substantial achievement and distinction when he returned to an interest in the internal secretion of the pancreas first developed during his student years in Paris in the 1890s. In 1916 he began experimenting with extracts. The Austrian occupation of Bucharest and then the postwar turmoil in Romania delayed his research for four years. Paulesco resumed his experiments in 1919 and published his first results in 1920 and 1921.
Like Kleiner, Paulesco concentrated on measuring the impact of his extract on blood sugar. He, too, reported spectacular decreases in blood sugar after intravenous injections of a solution of pancreas and slightly salted distilled water. He also reported a decrease in urinary sugar and in the presence of ketones in blood and urine. He checked for dilution, controlled with non-pancreatic extracts, and induced fever in his dogs to show that fever itself (which his extract often caused) would not cause a reduction in the sugar content of the blood or urine. He also tried his extract on a normal dog and found that here, too, it caused a reduction in blood sugar.
Paulesco published his earliest findings in his 1920 treatise on physiology, written in French. These and further experiments were described in four short papers published in Comptes rendus des séances de la Société de biologie between April and June 1921. A summarizing paper was received by Archives internationales de physiologie on June 22 and published on August 31. Paulesco had done fewer experiments than Kleiner, not least because he must have been hampered by the very primitive techniques he was using for measuring blood sugars. These techniques also produced some remarkably low figures, almost certainly based on error. Unlike Kleiner, Paulesco did not set his work and its implications in the context of past and current knowledge. On the other hand his results looked very good, his experiments were more varied than anyone else’s had been, and he clearly intended to persist. In his August 1921 paper he mentioned that it would be followed up by “une méthode de traitement du diabète, de l’obésité et de l’acidose, méthode qui est issue de ces reserches expérimentales.”40
In Germany at the same time, Georg Zuelzer was still trying to find a drug company to take up production of his extract, acomatol. No one in that devastated country was very interested.
In the conclusion to his 1919 study, even while underlining the limits of his diet treatment, Frederick Allen had tried to be optimistic. “The knowledge of diabetes is advancing rapidly enough that even the patient whose outlook seems darkest should take courage to remain alive in the hope of treatment that can be called curative.” He must have been discouraged in the next year or two as the most faithful of the cases reported in his Rockefeller study died one after another, with no cure in sight. The idea of advancing beyond diet, perhaps with a pancreatic extract, had been in the back of his mind for some time. In 1921 he began installing facilities for animal experimentation at the Physiatric Institute. He planned to try a new approach to the extract problem when they were ready.41
One of Allen’s most faithful patients was a young girl named Elizabeth Evans Hughes. She was also his most prominent patient, for her father, Charles Evans Hughes, was one of the most visible men in the public life of the United States. Elizabeth had been born in the New York state governor’s mansion in 1907. Her father was later appointed to the Supreme Court, resigned from it to run as the Republican candidate for the presidency against Woodrow Wilson in 1916, and in 1920 became Secretary of State in the administration of Warren Harding. Later he would be reappointed to the Supreme Court and become one of its most distinguished Chief Justices.
One of four children of Charles and Antoinette Hughes, Elizabeth grew up as a lively, intelligent little girl, never very big or strong, but otherwise normal. She had an interesting and exciting girlhood, a beneficiary of all the opportunities open to a family of American aristocrats. It was in 1918, when Elizabeth was eleven or twelve, that something started to go wrong. She would come home from birthday parties, where there had been lots of ice cream and cake, with a ravenous thirst, and would drink glass after glass of water, sometimes two quarts. She was often weak and tired in the winter of 1918–19, and showed increasing tendencies to polydipsia and polyuria. That spring she was taken to Dr. Allen. He diagnosed diabetes and prescribed an immediate fast. Whatever the fasting would do, the diagnosis was like knowing a sentence of death had been passed.
At the onset of her diabetes Elizabeth Hughes was 4’ 11½” tall and weighed 75 pounds. After the first week’s fasting Allen put her on a very low diet, 400 to 600 calories a day for several weeks (with one day’s fasting every week), then raised it to 834 calories. He brought her weight down to 55 pounds, then allowed her to rise into the low 60’s on a diet going as high as 1,250 calories (350 on fast days). The Hughes family hired a special Joslin-trained nurse to prepare Elizabeth’s meals and help her with her tests. Every gram of food she consumed had been weighed beforehand. Sweets and bread disappeared from her diet. She lived on lean meat, eggs, lettuce, milk, a few fruits, tasteless bran rusks, and tasteless vegetables (boiled three times to make them almost totally carbohydrate-free). A birthday cake became a hat box covered in pink and white paper with candles on it. On picnics in the summertime she had her own little frying pan to cook her omelet in while the others had chops, fresh fish, corn on the cob, and watermelon.
Elizabeth disliked Dr. Allen, a square-faced, jowly man who never seemed to smile, never seemed anything but strict. Charles Evans Hughes was one of the sponsors of the Physiatric Institute and had helped Allen with the legal work involved in setting it up; but Elizabeth, who spent several weeks there, found it a horrible place. She disliked her diet, and found the fast days a special nightmare – she tried to plan every minute of these days in advance so she would be distracted from the hunger. She was a vivacious, articulate adolescent, eager for all the experiences life had to offer, and apparently unaware of what was in store for her. Her nurses never told her how serious her problem was. They never told her why friends she had made at Morristown stopped writing or never appeared there again.
She was an obedient little spartan, though, and kept her diet perfectly. She hardly ever showed sugar. Just once, at Thanksgiving, she sneaked into the kitchen and snitched a piece of turkey skin. Her nurse caught her and gave her a severe bawling out. She must never take extra food.
Had she been untreated, Elizabeth Hughes would probably have died in the summer of 1919. With stern Dr. Allen’s stern diet, her own discipline, and her sheer strength of character, she carried on very well through the winter of 1919–20. She had a difficult time in the spring of 1920, when colds and tonsillitis threw her out of balance, and was often cut back to a diet of less than 500 calories. But she recovered that summer and fall, and at Christmas 1920 weighed in at 62¼ pounds. The winter and spring were bad again, though; by the end of March she was down to 52 pounds. Her diet in April averaged 405 calories. The doctor got her back up to 700 to 900 calories, but her weight was now at a new low plateau, between 52 and 54 pounds. At the age of thirteen, Elizabeth was a semi-invalid. There was great sorrow in the family when one of her older sisters died in 1920 of tuberculosis. While the Hughes family sweltered in Washington in the summer of 1921, Elizabeth enjoyed the fresh air and cool breezes of the Adirondacks. Her condition stayed about the same. In cheerful letters she chatted on about when she would get married and what she would do on her twenty-first birthday. Reading them must have been heart-breaking for Antoinette Hughes. The best medical talent in the world was the Hughes family’s to command. But the “curative treatment” for diabetes that Dr. Allen had written about was nowhere in sight.42