In Vivo Deactivation of Proinsulin Action on Glucose Disposal and Hepatic Glucose Production in Normal Man

We have studied the deactivation of the in vivo actions of insulin and biosynthetic human proinsulin (recombinant DNA) to stimulate the glucose disposal rate (GDR) and to inhibit hepatic glucose output (HGO) in man. Twelve healthy, lean, young subjects were studied using a modification of the euglycemic glucose clamp technique. Subjects received 4-h infusions on separate occasions of insulin (15 mU/m2/min equivalent to 0.54 μg/m2/min) or proinsulin (2.75 μg/m2/min), achieving steady-state serum levels of 32 ± 3 μU/ml (equivalent to 0.23 ± 0.02 pmol/ml) and 3.7 ± 0.2 pmol/ml, respectively. Suppression of HGO was similar (83–84%) with proinsulin and insulin, but stimulation of GDR above basal was greater with insulin (3.41 ± 0.43 versus 1.98 ± 0.28 mg/kg/min, P < 0.001). Following cessation of the hormone infusions, serum proinsulin concentration fell in a biphasic fashion with half-times of 25 and 146 min for the two phases. Serum half-disappearance time for insulin was 5 min. Deactivation of the hormone's effects to stimulate GDR was 50% complete by 35 min after insulin and 71 min after proinsulin. In contrast, 50% of the recovery times for the effect on suppression of HGO were 55 min after insulin and 188 min after proinsulin. Serum glucagon levels did not differ significantly after the insulin and proinsulin infusions. In summary: (1) Deactivation of proinsulin and insulin's effects to suppress HGO proceeds more slowly than deactivation of their effects to stimulate GDR; and (2) There is a markedly prolonged and disproportionately delayed deactivation of proinsulin's effects on suppression of HGO. This later finding may prove of therapeutic value in the treatment of diabetes mellitus.