24 Sh Hormones: Diverse Structures for Dherse Functions 883 clogs Cana How Is a Hormone Discovered? ‘The Arduous Path to Purified Insulin Millions of people with type I (insulin-dependent) di- betes mellitus inject themselves daily with pure in- sulin to compensate for the lack of production of this critical hormone by their own pancreatic B cells, Insulin injection isnot a cure for diabetes, but it allows peo- ple who otherwise would have died young to lead long, And productive lives, The discovery of insulin, which Degan with an accidental observation, Mustrates the combination of serendipity and careful experimenta- tion that led to the discovery of many of the hormones. 1m 1889, Oskar Minkowski, 2 young assistant at the Medical College of Strasbourg, and Josef von Mering, at the HoppeSeyler Institute in Strasbourg, had a friendly disagreement about whether the pancreas, ‘known to contain lipases, was important in fat diges- tion in dogs. To resolve the issue, they began an ex- periment on fat digestion. They surgically removed the panereas from a dog, but before their experiment got any farther, Minkowski noticed that the dog was now producing far more urine than normal (a common symptom of untreated diabetes), Also, the dogs urine hhad glucose levels far above normal (another symp- tom of diabetes). These findings suggested that lack of some pancreatic product caused diabetes. ‘Minkowsl tried unsuccessfully fo prepare an ex- tract of dog pancreas that would reverse the effect of removing the pancreas—that is, would lower the uri- nary or blood glucose levels. We now know that insulin js a protein, and that the pancreas is very rich in pro- teases (trypsin and chymotrypsin), normally released. directly into the small intestine to aid in digestion. ‘These proteases doubtless degraded the inslin in the pancreatic extracts in Minkovra’s experiments. Despite considerable effort, no significant prog- ress was made in the isolation or characterization of the “antidiabetic factor” until the summer of 1921, GE Frederick , Banting, LR Macteod, ‘when Frederick G. Banting, a young scientist working in the laboratory of J.J. R. MacLeod atthe University fof Toronto, and a student assistant, Charles Best, took ‘up the problem, By that time, several lines of evidence ‘pointed to a group of specialized cells in the pancreas {the islets of Langerhans; see Fig, 23-24) asthe source of the antidiabetic factor, which came to be called in sulin (rom Latin insula, “stand”. ‘Taking precautions to prevent proteolysis, Bant- Ing and Best (later aided by biochemist J. B. Colip) succeeded in December 1921 in preparing a purified panereatic extract that cured the symptoms of ex- perimental diabetes in dogs. On January 25, 1922 Gust fone month later), their insulin preparation was in- jected into Leonard Thompson, @ 14-year-old boy se~ ‘verely il with diabetes mellitus, Within days, the lev- els of ketone bodies and glucose in Thompson's urine Groped dramatically; the extract saved his life In 1928, Banting and MacLeod won the Nobel Prize for their isolation of insulin. Banting immediately an- nounced that he would share his prize with Best; Macleod shared his with Colip. By 1923, pharmaceutical companies were supply- Ing thousands of patients throughout the world with in sulin extracted from poreine panereas. With the devel. opment of genetic engineering techniques in the 1980s (Chapter 9, it became posse to produce unlimited quantities of human insulin by inserting the cloned hu- rman gene for insulin in a microorganism, which was then cultured on an industrial scale. Some patients with Aiabetes are now fitted with implanted insulin pumps ‘which release adjustable amounts of insulin on demane to meet changing needs at meal times and during ex- ercise. There isa reasonable prospect tat, in the fis ture, transplantation of pancreatic tissue will provide diabetic patients witha source of insulin that responds as well as normal panereas, releasing insulin into the bloodstream only when bload glucose rises. Oe cares Bot ——