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Chapter 2 History of diabetes

KEY POINTS

 Diabetes has been known since ancient times.

 A link to the pancreas was established in 1889 culminating in the isolation of insulin in 1921.

 There have been five Nobel Prizes awarded to scientists researching diabetes and carbohydrate metabolism.

 The structure of insulin was finally elucidated in the 1960s.

 Insulin was the first therapy to be manufactured using genetic engineering techniques.

 There are now several biologically engineered designer insulin molecules approved for use in man.

 The range of oral and other therapies for type 2 diabetes has led to the concept of personalised medicine.

Diseases with the clinical features of diabetes have been recognised since antiquity. The Ebers papyrus (Figure 2.1), dating from 1550 BC, describes a polyuric state that resembles diabetes.

The word ‘diabetes’ was first used by Aretaeus of Cappadocia in the second century CE. Aretaeus gave a clinical description of the disease (Box 2.1), noting the increased urine flow, thirst, and weight loss, features that are instantly recognisable today.

The sweet, honey‐like taste of urine in polyuric states, which attracted ants and other insects, was reported by Hindu physicians such as Sushrut (Susruta) during the fifth and sixth centuries CE. These descriptions even mention two forms of diabetes, the more common occurring in older, overweight, and indolent people, and the other in lean people who did not survive for long. This empirical subdivision predicted the modern classification into type 1 and type 2 diabetes.

Diabetes was largely neglected in Europe until a seventeenth‐century English physician, Thomas Willis (1621–75) (Figure 2.2), rediscovered the sweetness of diabetic urine. Willis, who was physician to King Charles II, thought that the disease had been rare in ancient times, but that its frequency was increasing in his age ‘given to good fellowship’. Nearly a century later, the Liverpool physician Matthew Dobson (1735–84) showed that the sweetness of urine and serum was caused by sugar. John Rollo (d. 1809) was the first to apply the adjective ‘mellitus’ to the disease.

Figure 2.1 The Ebers papyrus. The Wellcome Institute Library, London, UK.

Box 2.1 Description of diabetes by Aretaeus.

Diabetes is a dreadful affliction, not very frequent among men, being a melting down of the flesh and limbs into urine. The patients never stop making water and the flow is incessant, like the opening of aqueducts. Life is short, unpleasant and painful, thirst unquenchable, drinking excessive, and disproportionate to the large quantity of urine, for yet more urine is passed. One cannot stop them either from drinking or making water. If for a while they abstain from drinking, their mouths become parched and their bodies dry; the viscera seem scorched up, the patients are affected by nausea, restlessness and a burning thirst, and within a short time, they expire.

Adapted from Papaspyros S. The History of Diabetes Mellitus, 2nd edn. Stuttgart: Thieme, 1964.

Figure 2.2 Thomas Willis. The Wellcome Institute Library, London, UK.

In the 19th century, the French physiologist Claude Bernard (1813–78) (Figure 2.3) made many discoveries relating to diabetes. Among these was the finding that the sugar that appears in the urine was stored in the liver as glycogen. Bernard also demonstrated links between the central nervous system and diabetes when he observed temporary hyperglycaemia (piqûre diabetes) when the medulla of conscious rabbits was transfixed with a needle.

In 1889, Oskar Minkowski (1858–1931) and Joseph von Mering (1849–1908) from Strasbourg removed the pancreas from a dog to see if the organ was essential for life. The animal displayed typical signs of diabetes, with thirst, polyuria, and wasting, which were associated with glycosuria and hyperglycaemia. This experiment showed that a pancreatic disorder causes diabetes, but they did not follow up on their observation.

Figure 2.3 Claude Bernard. The Wellcome Institute Library, London, UK.

Paul Langerhans (1847–88) (Figure 2.4) from Berlin, in his doctoral thesis of 1869, was the first to describe small clusters of cells in teased preparations of the pancreas. He did not speculate on the function of the cells, and it was Edouard Laguesse in France who later (1893) named the cells ‘islets of Langerhans’ and suggested that they were endocrine tissue of the pancreas that produced a glucose‐lowering hormone.

In the early twentieth century, several workers isolated impure hypoglycaemic extracts from the pancreas, including the Berlin physician Georg Zuelzer (1840–1949), the Romanian Nicolas Paulesco (1869–1931), and the Americans Ernest Scott (1877–1966) and Israel Kleiner (1885–1966).

Insulin was discovered in 1921 at the University of Toronto, Canada, through a collaboration between the surgeon Frederick G Banting (1891–1941), his student assistant Charles H Best (1899–1978), the biochemist James B Collip (1892–1965) and the physiologist JJR Macleod (1876–1935). Banting and Best made chilled extracts of dog pancreas, injected them into pancreatectomised diabetic dogs, and showed a fall in blood glucose concentrations (Figure 2.5).

Figure 2.4 Paul Langerhans. The Wellcome Institute Library, London, UK.

Figure 2.5 Charles Best and Frederick Banting in Toronto in 1922 (the dog is thought to have been called Marjorie). The Wellcome Institute Library, London, UK.

Banting and Best’s notes of the dog experiments refer to the administration of ‘isletin’, later called insulin at the suggestion of Macleod. They were unaware that the Belgian Jean de Meyer had already coined the term ‘insuline’ in 1909. (All these names ultimately derive from the Latin for ‘island’.)

Collip improved the methods for the extraction and purification of insulin from the pancreas, and the first person with diabetes, a 14‐year‐old boy called Leonard Thompson, was treated on 11 January 1922. A commercially viable extraction procedure was then developed in collaboration with chemists from Eli Lilly and Co. in the USA, and insulin became widely available in North America and Europe from 1923. The 1923 Nobel Prize for Physiology or Medicine was awarded to Banting and Macleod, who decided to share their prizes with Best and Collip.

The American physician Elliot P Joslin (1869–1962) was one of the first doctors to gain experience with insulin. Working in Boston, he treated 293 patients in the first year after August 1922. Joslin also introduced systematic education for his diabetic patients.

In the UK, the discovery of insulin saved the life of the London physician Robin D Lawrence (1892–1968), who had recently developed type 1 diabetes. He subsequently played a leading part in the founding of the British Diabetic Association now Diabetes UK.

Among the many major advances since the introduction of insulin into clinical practice was the elucidation in 1955 of its primary structure (amino acid sequence) (Figure 2.6) by the Cambridge UK scientist Frederick Sanger (b. 1918), who received the Nobel Prize for this work in 1958.

Oxford‐based Dorothy Hodgkin (1910–1994), another Nobel Prize winner, and her colleagues described the three‐dimensional structure of insulin using X‐ray crystallography (1969). In total, there have been five Nobel Prizes awarded for scientific discoveries related to diabetes and carbohydrate metabolism.

By the 1950s, it was accepted that tissue complications, such as those that occur in the eye and kidney, continued to develop in long‐standing diabetes, in spite of insulin treatment. The definitive proof that normalisation of glycaemia could prevent or delay the development of diabetic complications had to wait until 1993 for type 1 diabetes (the Diabetes Control and Complications Trial in North America) and 1998 for type 2 diabetes (the UK Prospective Diabetes Study – UKPDS).

Until the 1980s, insulin was derived only from animal pancreata, in increasingly more refined preparations. Using additives such as protamine or zinc, the subcutaneous absorption could be delayed, thus providing 24‐hour availability using 2–4 injections a day of different preparations.

With the development of genetic engineering, it became possible to produce human insulin and subsequent further manipulations of the molecule have led to a wide range of preparations (Figure 2.6) with different absorption profiles (Chapter 10). There has been extensive research into an orally effective form of insulin but a continuing dependence upon subcutaneous injection as the main route of administration is likely for the foreseeable future.

Figure 2.6 Schematic amino acid sequence of human insulin; porcine and bovine insulin; the short‐acting insulin analogues aspart, lispro, and glulisine; and the long‐acting analogues glargine, detemir, and degludec.

In the 1980s, capillary blood glucose testing was a major breakthrough for patients allowing them to precisely assess their blood glucose levels and check for hypoglycaemia. Modern meters allow downloading of results enabling better informed modification of insulin regimens.

The rapid evolution of insulin delivery devices and continuous subcutaneous glucose sensing over the last decade has led to the production of closed loop systems which are effectively acting as an artificial pancreas. These systems are revolutionising the management of type 1 diabetes, although their cost poses significant challenges for health care funders and has inevitably limited their use.

In type 2 diabetes oral agents have been available since the 1950s, bur the last few decades have seen the production of many different classes of compound that affect insulin secretion, its efficacy and sensitivity, as well as whole body glucose dispersal and excretion. This has led to the development of personalised diabetes therapy based upon the likely defect in the individual patient. This concept of personalised medicine forms the basis of recent guidelines for type 2 diabetes (Chapter 11).

FURTHER READING

1 Bliss, M. The Discovery of Insulin. Toronto: McLelland and Stewart, 1982.