In the beta-cells of the pancreas, insulin is combined with a little zinc. This leads to the formation of hexamers (groups of 6) of insulin, which results in better water solubility and tighter packaging of the insulin. However, when adding more and more zinc, insulin first crystallizes and then forms insoluble insulin-zinc salts. Upon s.c. injection, these act as a depot from which insulin is slowly released. This mechanism of prolonging insulin action was first used with the animal insulins in 1952. Depending on the quantity of excess zinc, the long-acting 'lente' and the very long-acting 'ultralente' insulins were made. Nowadays, the zinc insulins, which had some disadvantages compared to NPH insulin, are hardly used anymore.
Human lente insulin
Human lente insulin had a peak and duration of action similar to NPH insulin (peak after 4-8 hours, duration of action 14-20 hours). However, when used in insulin mixtures with regular insulin, it was noted that the zinc affected the action of the regular component, so that the first peak in insulin levels was less distinct than in NPH-regular mixtures. Moreover, the variability in absorption was higher than for human NPH insulin. Both factors lessened the popularity of the human lente insulin.
Human ultralente insulin
Human ultralente insulin contains even more zinc than lente insulin, which results in a peak action after 6-8 hours and a duration of action of up to 24 hours. However, even more than lente insulin, ultralente suffered from a high variability in absorption which made its action rather unpredictable; for this reason most people preferred NPH insulin (and later the basal insulin analogues).