Effect of insulin antibodies and their kinetic characteristics on plasma free insulin dynamics in patients with diabetes mellitus

Abstract

To determine the influence of insulin antibodies (and their equilibrium kinetic properties) on the pharmacokinetics of insulin, we examined the relationship between insulin antibody binding and the initial rate of increase, time to peak, and return to baseline of therapeutic doses of insulin injected subcutaneously (0.15 U/kg) and the half-life, distribution space, and metabolic clearance rate of intravenously infused insulin (2 mU/kg/min) in insulin-treated patients with diabetes mellitus. Compared to age-weight-matched nondiabetic subjects, the diabetic subjects had reduced initial rates of increase (0.33 ± 0.2 v 0.44 ± 0.03 μU/mL/min, P < 0.05), delayed time to peak (130 ± 12 v 86 ± 8 min, p < 0.02), and prolonged return to baseline (485 ± 37 v 313 ± 13 min, P < 0.01) of plasma free insulin levels after subcutaneous injection of insulin, and a prolonged half-life (19.8 ± 5.8 v 4.3 ± 0.3 min, P < 0.02), increased distribution space (904 ± 284 v 109 ± 10 mL/kg, P < 0.001), and augmented metabolic clearance rate (28.5 ± 1.8 v 17.3 ± 0.7 mL/kg/min, P < 0.001) after intravenously infused insulin. All of these abnormal parameters were significantly correlated with binding of insulin to insulin antibodies at tracer insulin concentrations (Bo) and with the high affinity of insulin antibody binding sites as determined by Scatchard analysis. However, patients with 125I insulin antibody binding (Bo) less than 10 percent had normal or near normal plasma free insulin pharmacokinetics. We conclude that in patients with insulin antibody binding (Bo) in excess of 10%, insulin antibodies may alter plasma free insulin kinetics so as to make it difficult to achieve near normoglycemia with intensive insulin therapy.