1. The metabolism of unlabelled monocomponent human insulin and porcine proinsulin was studied in ten normal subjects (five males and five females) by using a priming dose-constant-infusion technique. In each subject, the metabolic clearance rate (MCR) was measured at four separate steady-state hormone concentrations averaging 16–216 μunits/ml (insulin) and 4·2–42·8 ng/ml (proinsulin).
2. For insulin the MCR fell progressively from 34 ml kg−1 min−1 at a mean fasting insulin concentration of 3·8 μunits/ml to 11·4 ml kg−1 min−1 at the highest concentration achieved (280 μunits/ml); for proinsulin MCR averaged 3·7 ml kg−1 min−1 at a mean plasma concentration of 4·2 ng/ml and fell to 2·71 ml kg−1 min−1 at 10·7 ng/ml, remaining constant thereafter at concentrations up to 71 ng/ml.
3. The half-disappearance time (T½) from the plasma, after the end of the infusion, averaged 4·3 min for insulin and 25·6 min for proinsulin.
4. The apparent distribution space (DS) was similar for both hormones (83 ml/kg of insulin and 98·9 ml/kg of proinsulin).
5. There was a direct correlation between T½ and DS for both hormones.
6. Although the higher MCR of insulin was reflected in its shorter T½ there was, for each hormone, no relationship between MCR and T½.
7. The biological potency of porcine proinsulin, as judged by its effect on plasma glucose, was approximately 5% of that of insulin.
8. The responses of serum growth hormone and Cortisol were shown to be directly related to the degree of hypoglycaemia induced.