Action profile of biosynthetic human proinsulin trials with the BIOSTATOR in metabolically normal subjects

Studies to examine the pharmacokinetics and pharmacodynamic properties of biosynthetic human proinsulin were conducted with the aid of the "glucose-controlled insulin infusion system BIOSTATOR". Seven metabolically normal healthy volunteers were given subcutaneous injections of 0.1 mg human proinsulin per kg body weight, and the subsequent behaviour of the serum proinsulin concentration was monitored over a period of 21 hours. The drop in the blood-sugar levels was counteracted by corresponding infusions of glucose by the BIOSTATOR via a special clamp technique. The intensity and frequency of the glucose infusions given by the BIOSTATOR equipment enable us to draw conclusions regarding the hypoglycaemic efficacy of human proinsulin. Two to three hours after the subcutaneous injection, the serum proinsulin concentration had reached its plateau-like maximum value. After approximately 5 hours it had dropped to 2/3 of the maximum, and after another 3 to 4 hours it had fallen further to 1/3 of the maximum. It returned virtually to its initial value after a total of 14 to 16 hours. The dextrose infusion rate calculated by the BIOSTATOR reflects these changes in the form of an "action profile". Proinsulin has a mean transit time (MTT) of 322 minutes. This is longer than the MTT of normal insulin (188 minutes) but markedly shorter than that of NPH insulin (625 minutes). If the hypoglycaemic effects of insulin and human proinsulin are compared on the basis of the areas under their respective action profile curves, the hypoglycaemic effect of 1 mg human proinsulin corresponds to 5.2 IU insulin.(ABSTRACT TRUNCATED AT 250 WORDS)