| • Science | • People | • Locations | • Timeline |
Insulin ( Latin insula, "island", as it is produced in the Islets of Langerhans) is a polypeptide hormone that regulates carbohydrate metabolism. Apart from being the primary effector in carbohydrate homeostasis, it also takes part in the metabolism of fat ( triglycerides) and proteins – it has anabolic properties. It also affects other tissues.
Insulin is used medically in some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on exogenous insulin (injected subcutaneously) for their survival because of an absolute deficiency of the hormone; patients with Type 2 diabetes mellitus have either relatively low insulin production or insulin resistanceIn medicine, insulin resistance denotes a decompensation of glucose homeostasis where the tissues appear to be less responsive to insulin. Introduction In patients who use insulin, "insulin resistance" is production of antibodies against insulin that lead, and occasionally require insulin administration if other medications are inadequate in controlling blood glucose levels.
Insulin has the empirical formula C254 Hhydrogen helium H Li Full table General Name, Symbol, NumberHydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1 (IA), 1 , s Density, Hardness 0. 0899 kg/m3, NA Appearance colorless Atomic properties Atomic weight 1. 00794 amu Atomic radius (ca377 N65 O75 SSulfur (or sulphur see spelling) is the chemical element in the periodic table that has the symbol S and atomic number 16. An abundant tasteless odorless multivalent non-metal, sulfur is best known as yellow crystals and occurs in many sulfide and sulfate6.
In 1869 Paul Langerhans , a medical student in BerlinBerlin [ bɛrˈliːn ] is the national capital of Germany and its largest city, with 3,387,404 inhabitants (as of September 2004); down from 4. 5 million before World War II. Berlin is located on the rivers Spree and Havel in the northea, was studying the structure of the pancreas under a new microscope when he noticed some previously unidentified cells scattered in the exocrine tissue. The function of the "little heaps of cells", later known as the Islets of Langerhans, was unknown, but Edouard Laguesse later argued that they may produce a secretion that plays a regulatory role in digestion.
In 1889, the German physician Oscar Minkowski removed the pancreas from a healthy dog to demonstrate this assumed role in digestion. Several days after the dog's pancreas was removed, Bernardo Houssay, Minkowski's animal keeper, noticed a swarm of flies feeding on the dog's urine. On testing the urine they found that the dog was secreting sugar in its urine, demonstrating for the first time the relationship between the pancreas and diabetes. In 1901 another major step was taken by Eugene Opie , when he clearly identified that Diabetes mellitus.... is caused by destruction of the islands of Langerhans and occurs only when these bodies are in part or wholly destroyed. Before this demonstration the link between the pancreas and diabetes was clear, but not the specific nature of the islets.
Over the next two decades several attempts were made to isolate the secretion of the islets as a potential treatment. In 1906 Georg Ludwig Zuelzer was partially successful treating dogs with pancreatic extract, but unable to continue his work. Between 1911 and 1912 E.L. Scott at the University of Chicago used aqueous pancreatic extracts and noted a slight diminution of glycosuria, but was unable to convince his director and the research was shut down. Israel Kleiner demonstrated similar effects at Rockefeller University in 1919, but his work was interrupted by World War I and he was unable to return to it. Nicolae Paulescu, a professor of physiology at the Romanian School of Medicine published similar work in 1921 that was carried out in France, and it has been argued ever since by Romanians that he is the rightful discoverer.
However the practical extraction of insulin is credited to a team at the University of Toronto. In October 1920 Frederick Banting was reading one of Minkowski's papers and concluded that it was the very digestive secretions that Minkowski had originally studied that were breaking down the secretion, thereby making it impossible to extract successfully. He jotted a note to himself Ligate pancreatic ducts of the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosurea.
He travelled to Toronto to meet with J.J.R. Macleod, who was not entirely impressed with his idea. Nevertheless he supplied Banting with a lab at the University, an assistant, Charles Best, and ten dogs, while he left on vacation during the summer of 1921. Using his idea, Banting and Best were able to keep a pancretized dog alive all summer. Their method worked by tying a ligature (string) around the pancreatic duct, and when examined several weeks later the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated the protein from these islets to produce what they called isletin.
Macleod saw the value of the research on his return from Europe, but demanded a re-run to prove the method actually worked. Several weeks later it was clear the second run was also a success, and he helped publish their results privately in Toronto that November. However they needed six weeks to extract the isletin, dramatically slowing testing. Banting suggested they try to use fetal calf pancreas, which had not yet developed digestive glands, and was relieved to find this method worked well. With the supply problem solved, the next major effort was to purify the protein. In December 1921 Macleod invited the brilliant biochemist, James Collip , to help with this task, and within a month he felt ready to test.
On January 11, 1922, Leonard Thompson, a fourteen year old diabetic was given the first injection of insulin. Unfortunately the extract was so impure that he suffered a severe allergic reaction and further injections were cancelled. Over the next 12 days Collip worked day and night to improve the extract, and a second dose injected on the 23rd. This was completely successful, not only in not having obvious side-effects, but in completely eliminating the symptoms of diabetes. However Banting and Best never worked well with Collip, apparently seeing him as something of an interloper, and Collip left soon after.
Over the spring of 1922 Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the extract remained impure. However they had been approached by Eli Lilly with an offer of help shortly after their first publications in 1921, and they took them up on their offer in April. In November Lily made a major breakthrough, and were able to produce large quantities of very pure insulin. Insulin was offered for sale shortly thereafter.
For this breakthrough discovery, Macleod and Banting were awarded the Nobel Prize in Physiology or Medicine in 1923. Banting, apparently insulted that Best was not mentioned, shared half of his price with Best, and MacLeod immediately shared some of his with Collip.
The exact sequence of amino acids comprising the insulin molecule, the so-called primary structure, was determined by British molecular biologist Frederick Sanger. It was the first protein the structure of which was completely determined. For this he was awarded the Nobel Prize in Chemistry in 1958. In 1967, after decades of work, Dorothy Crowfoot Hodgkin determined the spatial conformation of the molecule, by means of X-ray diffraction studies. She also was awarded a Nobel Prize.