20 May, 2010

Insulin - Tissue clumps to Humulin!!

In 1869 Paul Langerhans, a medical student in Berlin, was studying the structure of the pancreas under a microscope when he identified some previously un-noticed tissue clumps(Islets of Langerhans) scattered throughout the bulk of the pancreas.

Edouard Laguesse later suggested that they might produce secretions that play a regulatory role in digestion. Paul Langerhans' son, Archibald, also helped to understand this regulatory role. The term insulin origins from Insel, the German word for islet/island.

In 1889, the Polish-German physician Oscar Minkowski in collaboration with Joseph von Mering removed the pancreas from a healthy dog to test its 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, establishing for the first time a relationship between the pancreas and diabetes.

In 1901, another major step was taken by Eugene Opie, when he clearly established the link - Diabetes mellitus … is caused by destruction of the islets of Langerhans and occurs only when these bodies are in part or wholly destroyed. Before his work, the link between the pancreas and diabetes was clear, but not the specific role of the islets.

In 1906 George Ludwig Zuelzer was partially successful treating dogs with pancreatic extract but was 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 of his work's value; it was shut down.

Israel Kleiner demonstrated similar effects at Rockefeller University in 1919, but his work was interrupted by World War I and he did not return to it.

Nicolae Paulescu, a professor of physiology at the University of Medicine and Pharmacy in Bucharest, was the first one to isolate insulin, which he called at that time pancrein,

In October 1920 Canadian Frederick Banting was reading one of Minkowski's papers and concluded that it is the very digestive secretions that Minkowski had originally studied that were breaking down the islet secretion(s), thereby making it impossible to extract successfully. He decided to Ligate pancreatic ducts of the do, Keep dogs alive till acini degenerate leaving islets and try to isolate internal secretion of these and relieve glycosuria.

Banting's method was to tie 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 an extract from these islets, producing what they called isletin ( now know as insulin), and tested this extract on the dogs. Banting and Best were then able to keep a pancreatectomized dog named Alpha alive for the rest of the summer by injecting her with the crude extract they had prepared. Removal of the pancreas in test animals essentially mimics diabetes, leading to elevated blood glucose levels. Alpha was able to remain alive because the extracts, containing isletin, were able to lower her blood glucose levels.

In December 1921, Macleod invited the biochemist James Collip to help with this task and within a month the team felt ready for a clinical test.

On January 11, 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto General Hospital, was given the first injection of insulin. However, the extract was so impure that Thompson suffered a severe allergic reaction, and further injections were canceled.

Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract, and a second dose was injected on January 23. This was completely successful, not only in having no obvious side-effects but also in completely eliminating the glycosuria sign of diabetes.

In one of medicine's more dramatic moments Banting, Best and Collip went from bed to bed injecting an entire ward with the new purified extract. Before they had reached the last dying child the first few were awakening from their coma to the joyous exclamations of their families.

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 preparation remained impure.

The drug firm Eli Lilly and Company had offered assistance not long after the 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 highly refined, 'pure' insulin. Insulin was offered for sale shortly thereafter.

The amino-acid structure of insulin was characterized in the 1950s and the first synthetic insulin was produced simultaneously in the labs of Panayotis Katsoyannis at the University of Pittsburgh and Helmut Zahn at RWTH Aachen University in the early 1960s.

The first genetically-engineered, synthetic "human" insulin was produced in a laboratory in 1977 by Herbert Boyer using E. coli. Partnering with Genentech founded by Boyer, Eli Lilly went on in 1982 to sell the first commercially available biosynthetic human insulin under the brand name Humulin.

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