Diabetes and the pharmaceutical industry

A short history of insulin

Although diabetes has been recognised since antiquity, the first standardised pharmaceutical treatment for the disease became available only in 1922, with the start of the manufacture of insulin.

The first type of insulin to be introduced was relatively short-acting and needed to be injected into muscle two to four times a day. Extracted from beef or pig pancreas, it was recognised by the body as foreign and often provoked an immunological response, or even allergic shock. Over time, significant levels of antibodies could build up and reduce the effectiveness of the injected insulin. Because of its relatively crude preparation methods, it was contaminated with various other proteins which could also provoke an immune response.

Much effort was expended to improve the purity of the insulin preparations and increase their potency. However, they were still relatively short-acting (with a peak action of 2-4 hours) and there was a clear need for a longer-acting form.

Such a form was eventually introduced in 1936 as protamine zinc insulin, in which mixing the insulin with the protein protamine (isolated from salmon or trout) and zinc slowed down the release of the injected insulin into the blood stream.

A further development in this direction was introduced by Nordisk Insulin in 1946 (Isophane or NPH insulin) and is still used today. Unlike the earlier protamine zinc insulin, it could be mixed with regular insulin without affecting the action profile of either component. Various pre-mixed forms containing regular and NPH insulin were subsequently made available.

In 1953 Novo introduced an additional series of three types of insulin (Ultralente, Lente and Semilente) which gave doctors an extensive array of purified animal insulins with differing characteristics that could be used to tailor treatment for individual patients.

In 1955, Frederick Sanger of the University of Cambridge determined the chemical structure of insulin and in 1969 its three-dimensional crystal structure was described by the X-ray crystallographer Dorothy Hodgkin of the University of Oxford. These advances, together with the development of biotechnological production methods and genetic engineering, paved the way for the next major step in insulin therapy - the introduction of human insulin.

The first human insulin was introduced by Novo in 1982. It was made from pig insulin that was modified to make it chemically identical with human insulin. In the same year, Eli Lilly introduced a human insulin made using recombinant DNA technology to insert the insulin genes into E.coli bacteria. Novo Nordisk later also introduced a recombinant human insulin, but chose to insert the genes into yeast cells instead of E.coli.

From the 1990s onwards, recombinant methods have been used to prepare other modified human insulins with specific properties. Three of these (Insulin Lispro, Insulin Aspart and Insulin Glulisine) have a shorter activity curve than regular insulin, while two others (Insulin Glargine and Insulin Detemir) have a longer action, with a flat release curve.