Proinsulin as a possible therapeutic agent

Gene technology has made significant amounts of biosynthetic human proinsulin (BHP) for biological and clinical studies available. It has been shown both in vitro and in vivo that BHP is about 10% as active as biosynthetic human insulin. More specifically it is 8% as potent regarding its action in stimulating peripheral glucose disposal and 12% as potent in suppressing hepatic glucose output. Its hypoglycemic effect is rather produced by the intact molecule or its intermediates and not by conversion to insulin or C-peptide. BHP appears to exert a more prolonged action when administered subcutaneously compared to NPH insulin. Furthermore because of its weaker effect on peripheral glucose utilization it is expected to create less profound hypoglycemia. Under conditions of equipotency BHP may stimulate triglyceride synthesis in a lower degree and in that way be less lipogenic. On longterm basis BHP proved to have a low immunogenic potential. We investigated the efficacy of BHP in split doses in type II diabetics with relative insulin resistance. Glucose levels at 1600 and 2000 and 0400 hrs as well as integrated glycemia over the 24 h period were lower under BHP. The potency of BHP in this and other studies has been demonstrated after application of greater quantities from it in terms of equimolarity. Nevertheless there are certain features such as the protracted action, the stronger effect on hepatic glucose production and the lower suppression of endogenous insulin secretion which make proinsulin a promising agent in the future management of type II diabetes.