From muck to molecule: insulin discovery over 50 years

A pancreatic extract which was successful in lowering glucose in diabetes was developed and commercialized with leader-ship from the University of Toronto in 1921-1922. The active principle remained unknown, though it was assumed to be the ‘insulin’ (or ‘isletin’ or ‘insuline’) identiﬁed microscopically in the islets of Langerhans from work in the previous 50 years. Within four years the active principle was crystallized by Abel and co-workers, and convincing proof given that it was a peptide. Determining the amino acid sequence of this relatively small protein proved a 30-year task for science, due to the confounding effects of two short chains united by di-sulphide bridges. Even then it was a mystery how the sequence related to insulin activity. That remained the case when the early X-ray diffraction work in the 1930s by Crowfoot (Hodgkin) matured in 1969 with the determination of the 3-dimensional structure of the insulin hexamer. Meanwhile 25 years of work, much in industry, invented useful extended-acting insulin preparations and, over an even longer time course, insulin preparations of high enough purity to be non-immunogenic in clinical practice. In the 1960s and 1970s work on radioimmunoassay and on glucose clamps provided tools that would prove critical to the further development of insulin as a medication over its second 50 years.