Early definitions of a unit of insulin were based on a rabbit’s physiological response.

The definition of one unit of insulin evolved.  The initial definition was highly dependent on the rabbit.  Larger rabbits needed more insulin compared to a smaller rabbit.  The rabbit’s diet also affected the definition of a unit.  Later definitions were “one unit of insulin is one-third amount necessary to cause convulsions by hypoglycemia in a rabbit weighing 2 kg,” and “one unit is the amount of insulin which on subcutaneous injection lowers a rabbit’s blood sugar by 50% in one to three hours.”

Major decisions on the manufacture and distribution of insulin were made by a committee in Toronto.  The committee first met in August 1922 and became known as the Insulin Committee.  It initially consisted of Banting, Best, Dr. Robert Defries (the founder and director of Connaught Laboratories), TA Russell (a wealthy businessman and benefactor of the University of Toronto) and its chair, Colonel Albert Gooderham, who was another wealthy benefactor of the University.

Once clinical use began, the Insulin Committee decided to change the definition of a unit. To avoid the use of fractional units with patients, the old unit of insulin was recalibrated. Initially, the Insulin Committee demanded that insulin for clinical use be labelled with units that were one fifth the rabbit units, but then changed to one third.

Clowes complicated this redefinition by altering Eli Lilly’s definition in a slightly different way.  Perhaps for marketing reasons, he wanted Eli Lilly’s insulin to be known as potent.  Instead of dividing by five, he divided by four and added a factor (25%) to make up for deterioration. [Sinding, p. 244]

These differences in definition were a source of contention, but there were other inconsistencies also.  For instance, Eli Lilly was performing their tests on 1 kg rabbits that had been starved for 24 hours, while Connaught was using 2 kg rabbits that were normally fed.

The modern definition of a unit of insulin, called the international unit (IU), is based upon the mass of insulin.  However, at the time, no one knew the chemical structure of insulin nor the mass of the molecule. Thus, the only way to characterize the amount of insulin in a sample was to test it in a physiological system (rabbits).