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Islets of Hope information for persons with diabetes |
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Article reprinted with permission, courtesy Wikipedia.com Sources Gerald M Reaven, Ami Laws, Insulin Resistance: The Metabolic Syndrome X, ISBN 0896035883 Jack L Leahy, William T Cefalu, Insulin Therapy, ISBN 0824707117 Sudhesh Kumar, Stephen O'Rahilly, Insulin Resistance: Insulin Action and Its Disturbances in Disease, ISBN 0470850086 Ann Ehrlich, Carol L Schroeder, Medical Terminology for Health Professions, ISBN 0766812979 Draznin, Molecular Biology of Diabetes: Autoimmunity and Genetics; Insulin Synthesis and Secretion, ISBN 0896032868 Links to Diabetes Treatment Information Treatment & Treatment Devices (main) conventional therapy for treatment of disorders associated with diabetes see "disorders" for treatment of diabetes complications see "complications"
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A Brief history of diabetes and treatment through the ages
In 1869 Paul Langerhans, a medical student in Berlin, 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 Polish-German physician Oscar Minkowski in collaboration with Joseph von Mehring removed the pancreas from a healthy dog to demonstrate this assumed role in digestion. Several days after the dog's pancreas was removed, Minkowski's animal keeper noticed a swarm of flies feeding on the dog's urine. On testing the urine they found that there was sugar in the dog's 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 established the link between the Islets of Langerhans and diabetes: Diabetes mellitus.... is caused by destruction of the islets 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 role 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 which 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 traveled 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, and an assistant, medical student Charles Best, and ten dogs, while he left on vacation during the summer of 1921. Their method was 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. Banting and Best were then able to keep a pancreatectomized dog alive all summer. 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 Lilly up on the offer in April. In November Lilly made a major breakthrough, and were able to produce large quantities of very pure insulin. Insulin was offered for sale shortly thereafter. For this landmark discovery, Macleod and Banting were awarded the Nobel Prize in Physiology or Medicine in 1923. Banting, apparently insulted that Best was not mentioned, shared his prize with Best, and MacLeod immediately shared his with Collip. The patent for insulin was sold to the University of Toronto for one dollar. 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. PrinciplesInsulin is absolutely required for all animal (including human) life. The mechanism is almost identical in nematode worms (e.g. C. elegans), fish, and in mammals. In humans, insulin deprivation due to the removal or destruction of the pancreas leads to death in days or at most weeks. Insulin must be administered to patients in whom there is a lack of the hormone for this, or any other, reason. Clinically, this is called diabetes mellitus type 1. The initial source of insulin was from cows, pigs or fish pancreases. Insulin from these sources are effective in humans as they are nearly identical to human insulin (two amino acid difference for bovine insulin, one amino acid difference for porcine). Insulin is a protein which has been very strongly conserved across evolutionary time. Differences in suitability of beef, pork, or fish insulin preparations for particular patients have been primarily the result of preparation purity and of allergic reactions to assorted non-insulin substances remaining in those preparations. Purity has improved more or less steadily since the 1920s, but allergic reactions have continued. Though production of insulin from animal pancreases was widespread for decades, there are very few patients today relying on this form of insulin. Human insulin is now manufactured for widespread clinical use using genetic engineering techniques, which significantly reduces impurity reaction problems. Eli Lilly marketed the first such insulin, Humulin, in 1982. Humulin was the first medication produced using modern genetic engineering techniques, in which actual human DNA is inserted into a host cell (E. coli in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce actual human insulin. Genentech developed the technique Lilly used to produce Humulin. NovoNordisk has also developed a genetically engineered insulin independently. Most insulins used clinically are produced this way, for it avoids the allergic reaction problem. Timeline
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