On the 30th of July 1921, Frederick Banting and Charles Best injected an extract from a dog's pancreas into another diabetic dog. The blood sugar of the recipient dropped by 40% within one hour. This moment marked the first successful isolation of insulin in history. Before this date, researchers like Nicolae Paulescu had created aqueous extracts that lowered blood sugar in animals but could not be used on humans due to impurities. Paul Langerhans identified the islets of Langerhans in 1869 while studying pancreatic tissue under a microscope. Oskar Minkowski removed a healthy dog's pancreas in 1889 and found sugar in its urine, establishing the link between the organ and diabetes.
In October 1920, Banting reasoned that blocking the pancreatic ducts would cause the digestive glands to atrophy while leaving the islets intact. He jotted a note to himself: "Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets." On the 11th of January 1922, Leonard Thompson, a 14-year-old boy dying at Toronto General Hospital, received the first injection of insulin. The initial extract caused a severe allergic reaction, so further injections were cancelled. Biochemist James Collip worked day and night for 12 days to purify the ox-pancreas extract. A second dose on the 23rd of January eliminated glycosuria without side effects.
The team faced ethical dilemmas regarding patents. John G. FitzGerald stepped in as peacemaker when tensions rose over commercial rights. On the 25th of January 1922, an agreement was signed stating collaborators would not patent with a private firm during an initial working period. The University of Toronto Board of Governors accepted the patent assignment on the 15th of January 1923 for one dollar. Eli Lilly and Company produced large quantities of refined insulin by November 1922 after George B. Walden discovered isoelectric precipitation.
Molecular Structure And Synthesis
Human insulin consists of 51 amino acids linked into two chains called the A-chain and the B-chain. These chains are connected by disulfide bonds between cysteine residues at positions A7-B7 and A20-B19. An additional intrachain bond exists within the A-chain between positions A6 and A11. Frederick Sanger sequenced this structure in 1951, making insulin the first protein fully mapped. Dorothy Hodgkin determined the crystal structure in 1969 using X-ray crystallography.
Insulin is synthesized as preproinsulin, an inactive precursor molecule containing 110 amino acids. This protein enters the rough endoplasmic reticulum where its signal peptide is removed to form proinsulin. Proinsulin folds so that opposite ends fuse together via three disulfide bonds. It then moves through the Golgi apparatus into secretory vesicles. Inside these granules, enzymes cleave off the middle section known as the C-peptide. Carboxypeptidase E removes two pairs of amino acids from the ends to create active insulin.
The molecular mass of human insulin measures 5808 Da with the formula C257H383N65O77S6. Bovine insulin differs from human insulin by only three amino acid residues while porcine insulin differs by just one. In 1974, Hans Weber discovered preproinsulin at UCLA. The first genetically engineered recombinant human insulin was produced in 1978 by Arthur Riggs and Keiichi Itakura using E. coli bacteria. Genentech sold the first commercial biosynthetic version under the brand name Humulin in 1982.