A short history of insulin
The history of insulin starts in 1889. At a congres in Heidelberg, the then 31-year old Oskar Minkowski reported on the results of experiments he and von Mering performed with dogs. They did pancreatectomies in dogs in order to study their digestion. However, one of their lab-assistants noted an unexpected side-effect: the dogs started to suffer from polyuria. Well-aware that this was a symptom of diabetes in humans, Minkowski tested their urine for glucose and demonstrated that the dogs had indeed become diabetic. In subsequent experiments he ligated the ductus pancreaticus, performed subtotal pancreatectomies, and performed pancreas transplants, all of which led to the conclusion that the pancreas had to produce a hormone that was released in the blood and that influenced glucose levels.
In the years after Minkowski's initial report, researchers across the world tried to isolate this elusive pancreatic hormone. However, suppletion of patients with all kinds of pancreatic extracts failed to produce the wanted results.
Banting and Best
It was only in 1921 that Frederick Banting and Charles Best, who worked under Collip and John Macleod in Toronto, succeeded in extracting the pancreatic hormone.
Charles Best (left) and Frederick BantingThe hormone was given the name insulin (at the suggestion of Sir Edward Sharpey-Schafer) to mark the fact that it was produced in the pancreatic islets. The first patient treated was a 14-year old boy named Leonard Thompson who was in diabetic coma and made a remarkable recovery. In 1923 Banting and MacLeod received the Nobel Prize for their discovery[a], and Banting was named Time's 'Man of the year'.
The discovery of insulin revolutionized both the treatment of, and research into, diabetes. Initially, pancreatic extracts from slaughtered animals were the main source of insulin. These extracts were fairly crude and impure, and subcutaneous injection frequently led to local tissue inflammation. Gradually, more pure forms of insulin became available. The duration of action of these early animal insulins was about 6 hours, so frequent injections were necessary. In order to alleviate the pain and difficulty associated with these injections, a search was started for insulin preparations that had a longer duration of action. The main breakthrough came from Denmark, where Hans Christian Hagedorn discovered that combining insulin with protamin resulted in a stable insulin preparation with a prolonged duration of action. This became known as NPH insulin, from Neutral Protamine Hagedorn. Another route to get a prolonged duration of action proved to be the addition of Zinc to the insulin. Various other insulin preparations, such as histone and globin insulin were experimentally used but did not make it in clinical practice.
Biosynthesis of insulin
In the second half of the 20th century the realisation started to grow that aiming for near-normal glucose levels might reduce the risk of complications of diabetes. In attempts to mimick physiological insulin secretion, more intensive insulin therapy with multiple injections was advocated. However, the insulin absortion of the animal zinc-insulins proved to be erratic, and the animal insulins were associated with considerable immunogenicity. Also, the availability of cadaveric animal insulin was expected to fall short of global insulin needs. Thus, when biosynthesis was developed, human insulin was the first protein to be produced with this method on a grand scale.
Human insulin was available in a few basic variants: regular short-acting, NPH insulin, Zinc-insulin and mixtures of short-acting and NPH insulin. However, in their pursuit of physiological insulin substitution doctors were dissatisfied with the characteristics of these insulins. They felt that the short-acting insulin should have a quicker and shorter action, to mimick the rapid insulin secretion around a meal. At the same time, they felt that the duration of action of NPH insulin should be longer, with less of a peak in action, to more closely mimick the physiological low basal insulin secretion between meals and overnight. Building on the work of Jens Brange and his team, modifications in the insulin molecule were bio-engineered to attain these two goals. While the change in structure sometimes also altered the biological effects (with harmful side-effects as a result), various useful insulin analogues were developed and are being used today.
^ Brange J et al. Nature 1988;679-682.
^ See the website of the Nobel prize for his full acceptance speech, which gives remarkable details about the discovery and the extraction process. //nobelprize.org/nobel_prizes/medicine/laureates/1923/banting-lecture.html