The history of diabetes mellitus

1550 BC

In ancient Egypt the typical symptoms of diabetes were documented in the Ebers papyrus, named after its discoverer. This 3500-year-old document contains descriptions of dietary measures to influence the “excess of urine”. Historians still argue whether diabetes mellitus was really the disease referred to.


300 BC

Descriptions in ancient texts from India almost certainly refer to a diabetic disease. It is noteworthy is that the ancient Indian surgeon Susruta already distinguished between two types of this disease: one that appeared in the well-off and well-nourished population and another that appeared predominantly in undernourished people and led rapidly to death. A fattening diet based on rice was recommended as treatment for the latter form.


130 BC

The symptoms of diabetes were described clearly and in detail for the first time by the ancient Greek physician Aretaeus of Cappadocia, particularly with regard to the progression of the disease when it is not treated. Aretaeus suspected that it was caused by an acute disease of the stomach. His proposed therapy was therefore focussed on the purification of the stomach. This was achieved by means of external remedies that were placed on the stomach, as well as by dietary measures such as milk cures, wine, dried fruit and laxatives.

“Diabetes is a puzzling disease, one that does not appear very frequently in people. Flesh and bones melt into urine; moisture and cold are the cause, as with oedema, but the fluid is discharged by the normal path, through the kidneys and the bladder.

The patients never stop producing urine, but rather it continues to flow unceasingly as though from opened pipes.

The emergence and development of the disease are gradual, but when the symptoms are completely present the person finds himself at the end of his days, as emaciation then proceeds rapidly, and after a miserable and painful life a quick death ensues.

The patients have an unquenchable thirst, and drink and urinate a great deal. Meanwhile, the quantity of urine passed exceeds that of the fluid drunk.

Do not try to restrain them from passing water or drinking, because if they stop drinking, even for a short time, the mouth begins to dry out at once, the body withers and it is as though the guts are consumed by fire. They lead a miserable, despairing life and die after only a short time, the thirst tormenting them like a scorching fire. At the beginning of the disease the mouth is dry, the saliva white and foamy as though they were thirsty, but the thirst is not yet fully developed. If the disease continues, a slight but biting heat in the viscera appears. The whole body emaciates, the outflow of urine becomes more abundant, the thirst increasingly fierce.”


600 BC

During this period the ancient Indian physician Charaka described the disease “madhumeha” (honey urine) or “iksumeha” (sugar cane urine) in his work “Charaka Samhita”.

The doctors of this period used ants or insects to aid in diagnosis. Honey-sweet urine attracted ants, confirming the diagnosis.

“You have a patient who passes urine like an elephant in heat and whose urine is called honey or sugar cane urine which tastes sweet and attracts ants and insects.”


16th century

Theophrastus Bombastus of Hohenheim (1493–1541), the Swiss reformer of mediaeval medicine also known as Paracelsus, established new theories about the causes of diabetes.

“Diabetes is a general disease, a corruption of the bodily fluids (blood) which overflow into the kidneys, heating these and causing prolific excretion of urine.”

Paracelsus heated urine from a diabetic person and found white powder. He therefore believed that the composition of the blood of diabetics was altered. He postulated the theory that this salt-like substance “…causes the thirst of the kidneys and promotes the outflow of water”. Although he did not comment on the sweetness of the urine, he treated his patients with starvation diets.


17th century

The English medical scholar Thomas Willis (1621–1675) re-discovered the sweet taste of the urine that had already been described 2000 years previously by Susutra. He stated, “Diabetes is an affection of the blood, the sugar being first in the blood and only then in the urine.” Willis recommended that the urine be identified by tasting to aid in diagnosis. For the first time, Willis noted a correlation between diabetes and socio-economic relations in the different social classes. He described two forms of the disease: a curable one and an incurable one. As treatments he recommended lemon water, rice, mucilaginous plants, and barley mixed with milk.

In 1685 the Swiss doctor Johann Conrad Brunner (1653–1727) investigated the question of whether the pancreas is essential for life or not. He removed the pancreas from dogs and observed what happened. He determined that the animals initially developed a great thirst and passed a great deal of urine, but that the symptoms then regressed. What he expected to see did not occur. The animals did not die and the pancreas was thus declared a non-essential organ. So what actually happened? Only more than 200 years later could it be proved that the tiniest remnants of pancreas are sufficient to provide the body with an adequate supply of insulin. Brunner’s research was incomplete, as he had left remnants of the organ in the animals, allowing him to reach this fatally flawed conclusion.


18th century

In 1776 the English doctor Matthew Dobson (1745–1784) demonstrated that diabetics have too much sugar in the blood as well as in the urine and this is “…similar to the taste of brown sugar. I believe that in diabetes a sugar-like substance is constantly being excreted. This, and this is supported by the sweet taste of the blood serum, is pre-formed in the blood.”

In 1780 the English doctor Francis Home (1719–1813) discovered a method for the detection of sugar. By adding yeast, the sugar in the urine of diabetics was brought to fermentation. Home discovered that, at the end of the fermentation, the sweet taste of the urine had disappeared.

The English military doctor John Rollo (1749–1809) was able to demonstrate the presence of sugar in the blood indirectly. He established that blood samples from healthy people showed traces of decomposition after four days, but not those of diabetics. If the blood samples from healthy people were mixed with cane sugar, the decomposition was also stopped. Rollo devised a low carbohydrate diet, which he tested successfully on the overweight Captain Meredith. The diet consisted of milk and limewater for breakfast and supper, plain blood pudding for lunch and well-seasoned, preferably even rancid, meats for dinner. He observed that the sugar content in the urine increased when his patient ate an apple cake or drank beer. The conclusion that he drew from the experiment was that this is a disease of the digestive tract.


19th century

In 1835 the Italian Felice Ambrosiani (1790–1843) successfully isolated sugar crystals from the blood and urine of diabetics.

In 1838 two Frenchmen, Peligot and Bouchardat, provided proof (independently of each other) that this sugar is in fact glucose.

In France Apollinaire Bouchardat (1809–1886) made the discovery that during the siege of Paris (1870–1871) many diabetics excreted no sugar in their urine as a result of malnutrition. He therefore made the recommendation, “Eat as little as possible”.

The breakthrough in diabetes research began in 1869 when the German pathologist and biologist Paul Langerhans (1847–1888) discovered island-shaped cell structures in the pancreas. However, their function remained unknown to him.

In 1889 the Strasbourg pharmacologist and internist Joseph Freiherr von Mering (1849–1908) and the internist Oskar Minkowski (1858–1931) removed the pancreas from dogs. Unlike Brunner 200 years previously, however, they removed the organ completely. The animals then displayed the typical symptoms of diabetes, such as excessive thirst, large volumes of urine that contained sugar, and emaciation, despite being provided with sufficient food, and died very quickly. The pancreas was once again considered to be an essential organ and the disease was named pancreatic diabetes. In further work, they discovered the occurrence of acetone in the urine, or acetonuria. Minkowski was also able to show that diabetic symptoms do not materialise when parts of the previously removed pancreas are transplanted back beneath the skin. In the period following these experiments, the race began to identify the pancreatic extract that is necessary for life.

At the beginning of the 19th century a diagnosis of diabetes was a death sentence. Children in particular were afflicted by this disease.


20th century

In 1908 Georg Ludwig Zuelzer (1870–1949) developed a pancreatic extract from calves. Although the preparation (which he called “acomatol”) appeared to work, its use was soon discontinued due to its serious side effects. Zuelzer improved the purification of his preparation and continued to use it in animal experiments. The consequences were tremors, sweating and accelerated heart rate. It is still uncertain whether hypoglycaemia was observed in these cases.

The breakthrough finally came in 1921. The Canadian surgeon Frederick Banting (1891–1941) suspected that the digestive juices present in the pancreatic extract also destroyed the glucose-reducing substance. He therefore did not try to cut up the pancreas, unlike Minkowski, since the digestive juices would destroy everything. Together with Charles Best (1899–1978), he ligated the pancreatic ducts so that the pancreas atrophied, with the exception of the apparently well-protected islet cells. A dog was then successfully treated with the “isletin” extract that was produced in this manner. Together with the biochemist James Bertrand Collip (1892–1965), they subsequently extracted and refined large quantities of the highest possible purity from the pancreatic tissues of calves from the Toronto slaughterhouse.

In 1922 a human being, 13-year-old Leonhard Thomas, who had had diabetes for one and a half years and had already fallen into a coma, was treated for the first time. Immediately after the treatment, his blood sugar levels dropped rapidly – the child’s life had been saved. In the same year, an agreement between the University of Toronto and Eli Lilly & Co. for the large-scale production of insulin came into effect.

Frederick Banting and John McLeod, the director of the institute, received the Nobel Prize for Medicine in 1923 for their work on the discovery of insulin. The physiology student Charles Herbert Best, who played a substantial part in the isolation of insulin, was not acknowledged in the honour. Banting and McLeod, however, voluntarily shared their prize with Best and Collip. In the same year industrial production of insulin began under the control of the Insulin Committee, headed by Professor Minkowski.

In the following decades insulin was extracted from the pancreas of cattle and pigs on an industrial scale. Cow and pig insulin differs only marginally from human insulin: in pigs only a single amino acid is replaced by another amino acid, whereas in cows this involves three acids. Although animal insulin was effective in humans, continued attempts were made to produce human insulin, since treatment with unmodified animal insulin often led to serious immunological side effects (see the 1980s). The increasing global demand for insulin could not have been met in the long term by depending solely on animal sources. 50 pigs had to be slaughtered to provide a year’s supply for one diabetic.

In 1926 the blood sugar-lowering effect of biguanide was discovered.

In 1936 Hans Christian Hagedorn (1888–1971) developed a process by which the many daily injections of insulin could be reduced to two. Insulin was attached to the protein protamine (derived from the sperm of certain fish species), by means of which a delayed effect with an insulin depot could be achieved. This mechanism is still used today (NPH, or neutral protamine Hagedorn, insulin). Other processes were developed in which insulin is bound to zinc ions, a method that is also used by the healthy pancreas to store insulin.

In 1940 Hoechst developed a new storage insulin, surfen insulin. Problems arose with NPH insulin and zinc-bound insulin due to inaccurate dosages resulting from insufficient mixing, but this was avoided with surfen insulin because it was available in a clear solution.

In 1941 Bayer introduced Clinitest^® onto the market. A small amount of urine is placed on a reagent tablet so that the amount of sugar in the blood can be estimated.

In 1942 Lobatire discovered the blood sugar-lowering effect of sulfonylureas.

In 1955, after 10 years of research, Frederick Sanger analysed the chemical structure of cow insulin. This work provided the foundation for the production of synthetic insulin. In 1958 Sanger received the Nobel Prize in Chemistry for his work.

In 1955 sulfonylurea was introduced for the treatment of diabetes.

In 1960 Nicol and Smith analysed the structure of human insulin.

In 1965 an article about dextrostix, the first test strip for the measurement of blood sugar levels, appeared in an American journal. A heated discussion about the dangers of self-testing by people with diabetes ensued. The recommendation of well-known American diabetologists was an absolute “no” to self-testing.

In 1967 the previous mixtures of pig and cow insulin were changed to isolated pure pig or cow insulin. Since pig insulin only differs from human insulin by a single amino acid, it is much better tolerated. Thanks to an additional improvement in the purification of insulin, the number of cases of resistance and allergies was greatly reduced.

In 1969 the first portable blood sugar measuring device was introduced by Bayer.

In 1977 the HbA1c test was introduced.

In 1980 the first accurate insulin pumps were introduced in Germany. The Promedeus from Siemens was calibrated with insulin and delivered a constant background rate. At the end of the 1970s, pumps such as the Mill Hill infuser or the Auto Syringe 6c were in use, both of which had long been used in the management of chronic pain. These pumps were not calibrated for insulin. Adjustments to the background rate were made by changing the mixing ratio of insulin and saline and peak insulin was delivered by turning a screw.

Since the 1980s, so-called human insulin has been available. Up until this time treatment was based exclusively on animal insulin. Human insulin was produced using two processes:

1. Biotechnological semi-synthetic production from pig insulin. Human and pig insulin differ by a single amino acid. By exchanging these amino acids using biotechnology, human insulin could be produced from pig insulin.

2. Using genetic engineering to produce recombinant insulin. Genetic production is not based on animal source material, which substantially reduces the costs. Instead, synthetically produced DNA is used. Biosynthesis is carried out with the help of bacteria (Escherichia coli) or yeast (Saccharomyces cerevisiae).

In 1982 genetically engineered human insulin was introduced by Eli Lilly and Co. Biosynthetic production is carried out with the help of bacteria.

In 1984 the Hoechst MRS1 insulin pump was launched on the market. Unlike the earlier rather “experimental” insulin pump therapy, the possibility now existed of a “providential” insulin pump therapy. The MRS1 permitted an hourly background rate to be programmed for the first time. Moreover, numerous alarm systems provided the necessary security. With the development of H-Tronin 100 two years later, insulin became available specifically for pumps. Due to its greater stability, this insulin had improved flow properties and was thus less prone to damage.

In 1985 the first insulin pen, the NovoPen 1, was introduced in Germany. The pen had no dose preselection, however, and was only suitable for 1.5 mL ampoules, but it was very successfully marketed on the basis of its small size and its appearance.

In 1996 the first genetically engineered insulin types (insulin analogues) became available. The first insulin was called insulin lispro. By changing a single amino acid, a more rapid onset and a shorter duration of action was achieved compared to human insulin.

In 2000 the first long-acting insulin analogue, glargin, became available.

In 2006 the first inhalable insulin from Pfizer was approved in the USA and Europe. According to the manufacturer, the substance is particularly suitable for Type 2 diabetics, who require insulin at meals in addition to blood sugar-lowering medication. The rapidly-acting insulin powder is breathed in with the aid of an inhaler.