History of diabetes

Frederick Banting (right) joined by Charles Best in office, 1924

Diabetes is one of the first diseases described^[1] with an Egyptian manuscript from c. 1500 BCE mentioning “too great emptying of the urine.”^[2] The first described cases are believed to be of type 1 diabetes.^[2] Indian physicians around the same time identified the disease and classified it as madhumeha or honey urine noting that the urine would attract ants.^[2] The term "diabetes" or "to pass through" was first used in 250 BCE by the Greek Apollonius of Memphis.^[2] Type 1 and type 2 diabetes were identified as separate conditions for the first time by the Indian physicians Sushruta and Charaka in 400-500 CE with type 1 associated with youth and type 2 with obesity.^[2] The term "mellitus" or "from honey" was added by Thomas Willis in the late 1600s to separate the condition from diabetes insipidus which is also associated with frequent urination.^[2]

Further history

The first complete clinical description of diabetes was given by the Ancient Greek physician Aretaeus of Cappadocia (fl. 1st century CE), who also noted the excessive amount of urine which passed through the kidneys.”^[3]

Diabetes mellitus appears to have been a death sentence in the ancient era. Hippocrates makes no mention of it, which may indicate that he felt the disease was incurable. Aretaeus did attempt to treat it but could not give a good prognosis; he commented that "life (with diabetes) is short, disgusting and painful."^[4] The disease must have been rare during the time of the Roman empire with Galen commenting that he had only see two cases during his career.^[2]

In medieval Persia, Avicenna (980–1037) provided a detailed account on diabetes mellitus in The Canon of Medicine, "describing the abnormal appetite and the collapse of sexual functions," and he documented the sweet taste of diabetic urine. Like Aretaeus before him, Avicenna recognized a primary and secondary diabetes. He also described diabetic gangrene, and treated diabetes using a mixture of lupine, trigonella (fenugreek), and zedoary seed, which produces a considerable reduction in the excretion of sugar, a treatment which is still prescribed in modern times. Avicenna also described diabetes insipidus very precisely for the first time, though it was much later that Thomas Willis differentiated it from diabetes mellitus in a chapter of his book Pharmaceutice rationalis (1674).

The sweet urine symptom of diabetes is evident in the Chinese name for diabetes, táng niǎo bìng (糖尿病), meaning "sugar urine disease". This name has also been borrowed into Korean and Japanese. In 1776 Matthew Dobson confirmed that the sweet taste comes from an excess of a kind of sugar in the urine and blood.^[5]

Although diabetes has been recognized since antiquity, and treatments of various efficacy have been known in various regions since the Middle Ages, and in legend for much longer, pathogenesis of diabetes has only been understood experimentally since about 1900.^[6] An effective treatment was only developed after the Canadians Frederick Banting and Charles Best first used insulin in 1921 and 1922.^[2]

The discovery of a role for the pancreas in diabetes is generally ascribed to Joseph von Mering and Oskar Minkowski, who in 1889 found that dogs whose pancreas was removed developed all the signs and symptoms of diabetes and died shortly afterwards.^[7] In 1910, Sir Edward Albert Sharpey-Schafer suggested that people with diabetes were deficient in a single chemical that was normally produced by the pancreas—he proposed calling this substance'insulin', from the Latin insula, meaning island, in reference to the insulin-producing islets of Langerhans in the pancreas. The endocrine role of the pancreas in metabolism, and indeed the existence of insulin, was further clarified in 1921, when Sir Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski, and went further to demonstrate they could reverse induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs.^[8] The islets of Langerhans was discovered in 1869 by an anatomist named Paul Langerhans. He identified the keys cells in the pancreas which produce the main substance that controls glucose levels in the body.^[9]

Banting, Best, and colleagues (especially the chemist Collip) went on to purify the hormone insulin from bovine pancreases at the University of Toronto. This led to the availability of an effective treatment—insulin injections—and the first patient was treated in 1922. The first successful patient treated was a 14-year-old boy who weighed only 65 pounds. When he was given the extract on January 23, his ketonuria and glycosuria were almost eliminated. His blood sugar levels dropped as low as 77%. Six more patients were treated in February 1922 and quickly experienced an improved standard of life. A pharmaceutical firm named Eli Lilly and Company, with the University of Toronto, began the mass production of insulin by the fall of 1923, 25,000 patients were being treated in Canada and the United States.^[10] For this, Banting and laboratory director John MacLeod received the Nobel Prize in Physiology or Medicine in 1923; both shared their Prize money with others in the team who were not recognized, in particular Best and Collip. Banting and Best made the patent available without charge and did not attempt to control commercial production. Insulin production and therapy rapidly spread around the world, largely as a result of this decision. Banting is honored by World Diabetes Day which is held on his birthday, November 14.

The distinction between what is now known as type 1 diabetes and type 2 diabetes was first clearly made by Sir Harold Percival (Harry) Himsworth, and published in January 1936.^[11]

Other landmark discoveries include:^[6]

• Development of the long acting insulin NPH in the 1940s by Novo-Nordisk^[2]
• Identification of the first of the sulfonylureas in 1942
• Reintroduction of the use of biguanides for Type 2 diabetes in the late 1950s. The initial phenformin was withdrawn worldwide (in the U.S. in 1977) due to its potential for sometimes fatal lactic acidosis and metformin was first marketed in France in 1979, but not until 1994 in the US.
• The determination of the amino acid sequence of insulin (by Sir Frederick Sanger, for which he received a Nobel Prize). Insulin was the first protein that the amino acid structure was determined.^[10]
• The radioimmunoassay for insulin, as discovered by Rosalyn Yalow and Solomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology or Medicine)^[12]
• The three-dimensional structure of insulin (PDB: 2INS​)
• Dr Gerald Reaven's identification of the constellation of symptoms now called metabolic syndrome in 1988
• Demonstration that intensive glycemic control in type 1 diabetes reduces chronic side effects more as glucose levels approach 'normal' in a large longitudinal study,^[13] and also in type 2 diabetics in other large studies
• Identification of the first thiazolidinedione as an effective insulin sensitizer during the 1990s

In 1980, U.S. biotech company Genentech developed biosynthetic human insulin. The insulin was isolated from genetically altered bacteria (the bacteria contain the human gene for synthesizing synthetic human insulin), which produce large quantities of insulin. The purified insulin is distributed to pharmacies for use by diabetes patients. Initially, this development was not regarded by the medical profession as a clinically meaningful development. However, by 1996, the advent of insulin analogues which had vastly improved absorption, distribution, metabolism, and excretion (ADME) characteristics which were clinically meaningful based on this early biotechnology development.

In 2005, a new drug to treat type 2 diabetes, derived from the Gila monster was approved by the Food and Drug Administration.^[14] The venom of the lizard contains exendin 4, which triggers one of the insulin-releasing pathways.^[15]

References

Further reading

• Polonsky, K. S. (2012). "The Past 200 Years in Diabetes". New England Journal of Medicine. 367 (14): 1332–1340. doi:10.1056/NEJMra1110560. PMID 23034021.