Kinetics of biosynthetic human proinsulin in patients with terminal renal insufficiency

Eight volunteers with terminal renal insufficiency having consented to the investigation, were given an i.v. bolus administration of 40 pmol biosynthetic human proinsulin on their dialysis-free day. Intravenous blood for the determination of blood glucose proinsulin, insulin and C-peptide was collected in short intervals for 6 hours and thereafter in longer intervals for 24 hours. Proinsulin was determined by immunoradiometric assay with monoclonal antibodies. The proinsulin kinetics were compared with the kinetics of normal volunteers. The behaviour of proinsulin concentration-time is best described with a 3-compartment model. The dominant biological half-life in terminal renal insufficiency was 6.8 hours which signifies a 4.4-fold increase of the normal half-life. The distribution volumes (V1) in the central compartment do not differ in the two groups, whereas the distribution volume after complete distribution (Vss) is significantly increased in renal insufficiency. The total metabolic clearance in renal insufficiency namely 0.63 ml/kg/min is 2.6 times lower compared to normal subjects with 1.67 ml/kg/min. The extra-renal clearance is 39% of the total metabolic clearance rate, whereas the renal clearance comprises 61%. Peripheral conversion from proinsulin to insulin and C-peptide does not occur in terminal renal insufficiency. The basal endogenous proinsulin secretion rate in renal insufficiency does not differ from that of normal volunteers. The following conclusions can be drawn: 1) Hyperinsulinism observed in renal insufficiency can be explained by circulating proinsulin. 2) In the potential therapeutic use of biosynthetic human proinsulin in diabetics with renal insufficiency dosis adjustment according to the remaining renal function would probably be required.