History to 1900

Recognisable features of the diabetes syndrome can be identified in some of the ancient Hindu, Graeco-Roman and mediaeval Arab literature, but it was frequently confused with other causes of excessive urination. Greater understanding came with the rediscovery of the sweet taste of the urine in the seventeenth century. Chemical tests for glycosuria were introduced in the nineteenth century, although measurement of blood glucose remained difficult. This led to the slow realization that diabetes was not a kidney disease, as previously believed, but was caused by excessive glucose levels in the blood, associated with overproduction by the liver. A meat (low carbohydrate) diet was introduced at the start of the nineteenth century, and was followed by many other special diets. Restricted calorie intake may have been the common factor in determining success, but patients tended to rebel against the more demanding regimens. Diabetes was linked to the pancreas in 1889, and several lines of evidence suggested that the pancreas released a circulating product that influenced glucose production by the liver. Decades were to pass before this could be confirmed.

Classifying the history of diabetes

The history of diabetes is sometimes divided into the ancient, mediaeval and modern periods, but more usefully (and as proposed by Frederick Allen) into the periods of (1) clinical description, (2) diagnosis, (3) empirical treatment and (4) experiment[1]. This scheme will be followed here.

Textbook accounts of the history of diabetes typically consist of a few hasty inaccuracies, often copied from one edition to another. Furthermore, medical history is often presented as brilliant discoveries by great men. This frequently gives a totally false impression as to how progress has been made. The reality often is that progress is made in slow and wandering steps by a lot of people whose contribution is now forgotten. Aretaeus, for example, is often (and rightly) celebrated for his clinical descriptions, but he was never cited by contemporaries, and had little recognition until his works were printed in 1552. Paul Langerhans apologised that his thesis describing what became the islets of Langerhans "contained nothing new".

A more interesting history of diabetes could be written about what doctors and scientists believed, and why: the mistakes of clever people are often just as informative as their insights. The centre of gravity of medical belief moves more slowly than the pace of scientific discovery, and medical history should perhaps focus more upon this phenomenon than upon seeking to assign retrospective credit.

The Period of Clinical Description

The first recognisable description comes from the ancient Sanscrit teachings, passed on by word of mouth for many centuries before first being written down. Modern historians frequently use one single overworked quotation to summarize this wisdom, and other vedic sources are less illuminating. The ancient Hindus undoubtedly recognised some key features of the condition, including the association with wealth, the sweetness of the urine, the association with boils on the skin, and the observation that ants were attracted to to the urine of those affected.

The Ebers papyrus from Egypt, circa 1500 BC, mentions excessive urination without further details.

The word "diabetes" is first known to have been used by Demetrius of Apamea (1st-2nd century BC) to describe the excessive passage of urine[2]. Graeco-Roman physicians inspected the urine but did not taste it, and therefore could not distinguish what we now call diabetes mellitus from other causes of polyuria. Diabetes was also known as "diarrhoea of the kidneys". Since the kidney was thought to be in intimate connection with the stomach, some (including Aretaeus of Cappadocia) thought the problem might originate in a leaky stomach rather than leaky kidneys.

Hippocrates and his school make no mention of diabetes, and Galen states that he had encountered only two cases. He described the role of the kidneys in the production of urine, and considered diabetes to be a kidney complaint. This dogma persisted largely unchallenged until the nineteenth century[3].

Aretaeus of Cappadocia provided easily the best clinical description of diabetes before modern times, reporting a slow chronic prodrome and acute final phase, together with the three cardinal features of thirst, polyuria and wasting.

Byzantine and Arab physicians often referred to diabetes but added little to the clinical description of the condition.

The Diagnostic Period

Mediaeval and early modern physicians routinely inspected the urine (the technique was known as uroscopy) but few went so far as to taste it. The Arab physician Ibn Sina, otherwise known as Avicenna (980-1037) was among these, but the credit for rediscovering the sweet taste of the urine has gone to Thomas Willis , who mentions the honey taste in one of his late writings; the term "diabetes mellitus" meaning "honeyed urine" was not used until the following century.

Some time before this, Paracelsus noted a residue from the evaporation of urine but did not taste it; he thought that diabetic urine contained some form of salt. Matthew Dobson (1745-1784) tasted the brown residue, and guessed it was sugar because it fermented when yeast was added. The distinction between honey urine and tasteless (insipid) urine was made by William Cullen (1709-1790), who introduced the terms diabetes mellitus and diabetes insipidus; Johann Peter Frank (1745-1821) made the same distinction.

The urine of diabetic patients was shown to contain grape sugar (glucose) rather than cane sugar (glucose complexed with fructose) by workers including Eugene Chevreul (1786-1889) in the early nineteenth century, and chemical tests replaced fermentation. Fehling developed a test based on the conversion of copper sulphate to cuprous oxide when heated with glucose in alkaline solution; this (with many variants) remained the basis of diabetes diagnosis for more than a century.

Matthew Dobson tasted the serum of his patient Peter Dickonson and considered it to taste sweet, but it took a long time before chemical tests were developed that were sufficiently sensitive to detect glucose in the blood. Early tests relied on fermentation (carbon dioxide is produced when yeast is added to serum), and Claude Bernard used this method to identify glucose even in the circulation of starved animals, and showed that it derived from glycogen (literally the "glucose maker") in the liver. Blood tests for glucose required up to 300 ml of blood and were tedious to perform; tests that could measure glucose in small quantities of blood were not available until the period around World War 1.

The period of empirical treatment

Physicians of all historical periods have set out to align their treatment to the presumed cause of diabetes. Aretaeus thought the stomach was leaky, and prescribed what he thought would help. The realization that glucose was lost in the urine led to attempts to restrict the intake of starchy (vegetable) foods. John Rollo (died 1809) reported two patients treated with an animal diet, which can now be estimated to have contained about 600 calories of carbohydrate and 1200 of fat - not unlike the Atkins diet of more recent notoriety!

One patient, a corpulent gentleman called Captain Meredith, lost 23 kg on the diet, his urine fell in volume from 12 to 2 litres daily, and no longer tasted of sugar. This may be the first documented reversal of diabetes. His second patient, a retired general, soon tired of the regimen and died 3 months after resuming a free diet.

Many other diets were tried during the nineteenth century. Most began with a period of fasting, followed by (for example) the skim milk diet of Donkin, the potato diet of Mosse, or the oatmeal diet of von Noorden. Many such diets may have worked by making those subjected to them disinclined to eat at all, and physicians throughout the ages have bemoaned the fact that so many of their patients have opted for a short life with a full belly rather than a long life with an empty one.

Needless to say, there were countless quack remedies for diabetes, and no effective ones. Forty-two such medicines were available in the USA in 1894, and the proliferation of such useless treatments caused the medical profession to campaign in favour of the useless medications prescribed by its own practitioners, of which opium was considered the most uniformly efficacious.

The period of experimentation

The foundations of modern experimental medicine were laid in the nineteenth century. These included the development of clinical-pathological correlations, linking the clinical features of an illness to its post-mortem and histological appearances, and to the more functional aspects of disease as these related to normal physiology. The chemical (later biochemical) laboratory appeared at the shoulder of the clinician, and Claude Bernard and others introduced the concept of the constancy of the internal environment together with the beginnings of metabolic medicine. The concept of ductless glands (glands which secreted into the blood stream rather than to a body surface) took hold and endocrinological treatment became a reality when thyroid extract was used to treat myxoedematous patients.

The developments of most relevance to diabetes were that glucose is present in the blood stream even when fasting, and that this glucose is secreted into the circulation by the liver. Not surprisingly, some investigators concluded that the liver was the organ responsible for diabetes. Although physicians still tended to equate diabetes with glycosuria, the concept of diabetes as hyperglycaemia gradually took hold.

Attempts to locate diabetes within the body by post-mortem examination were generally unsuccessful. Some patients had pancreatic damage (atrophy or calculous disease), and this was linked to diabetes by several investigators, including Apollinaire Bouchardat but in many cases the pancreas appeared healthy. Furthermore, it was noted that some patients with pancreatic atrophy (due for example to impaction of a gall stone in the pancreatic duct) did not develop diabetes.

Experimentalists attempted to take out the pancreas, but this was technically demanding - complete removal was difficult without damaging the duodenum, and Claude Bernard thought that it could not be done. Oskar Minkowski finally achieved it in 1889, although the possibility that diabetes might result does not seem to have crossed his mind.

This observation represented a paradigm shift in the understanding of diabetes. H├ędon demonstrated that transplantation of the pancreas under the skin prevented the onset of diabetes following pancreatectomy, with the clear implication that a blood-borne factor was responsible. Laguesse speculated that this factor derived from the pancreatic islets, which he named in honour of Paul Langerhans. Minkowski and others tried oral administration of pancreas to people without success, and the first attempts were made to administer it by injection. The hunt for insulin was on.

References

  1. ^ Schadewaldt H. The history of diabetes mellitus. Chapter in: Diabetes: its medical and cultural history, edited by von Engelhardt D, Springer-Verlag 1989

  2. ^ Orth H. Synonyms for diabetes in antiquity and their etymology. Chapter in Diabetes: its medical and cultural history, von Engelhardt D (Editor), pages 112-9

  3. ^ Eknoyal G, Nagy J. A history of diabetes mellitus, or how a disease of the kidneys evolved into a kidney disease. Advances in Chronic Kidney Disease 2005;12:223-9

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